About this Author
Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe
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Category Archives
June 9, 2009
Posted by Derek
Here's a fascinating (and alarming) look at the clinical data from the recent trial of Avastin (bevacizumab) in adjuvant colorectal cancer (that is, post-surgical therapy). This was an issue in the recent Roche/Genentech takeover, since it could significantly enlarge the market for the drug. According to the In Vivo Blog, the one-year interim look at the data (adding Avastin to the standard chemotherapy regimen) was nearly good enough to stop the trial early. There were 2,710 patients enrolled, and an additional six events would have pushed things over the top, statistically.
The trial went on, though, with two more years of standard therapy as follow-up. But by the (pre-set) three-year endpoint it turned out that there was no eventual real benefit to adding Avastin back in that first year. So what's the story? Is it that you need to keep giving the combination regime? Would those-one year results have held up? Or is this just a case of real long-term survival numbers wiping out what seems to be a promising short-term result?
It looks like Genentech may be gearing up to put that first theory to a test, and I wish them luck. Long-term tolerability will be an issue, and long-term cost will be a big one, too. They're going to have to show some pretty impressive numbers to overcome those two concerns. . .as impressive as, well, as those first-year interim ones they had. Will that effect dissipate or not?
Time and money will answer that little question. But for now, consider what would have happened if a few more patients had shown disease-free survival in time for that interim analysis. The trial would have been stopped early, all kinds of people would have gone on Avastin for their first year of adjuvant therapy. . .and this year we would have seen that it was apparently doing no good at all, at least in the take-it-for-a-year-and-stop mode. Clinical trial design: a real high-wire act.
Comments (8)
+ TrackBacks (0) | Category: Cancer | Clinical Trials
June 1, 2009
Posted by Derek
Well, the ASCO meeting has been roaring along, with dozens of press releases coming out. (Go to Google News and type that acronym in if you want to get the full experience). They range from the pretty-interesting to the despair-inducing, but one bit of news struck me as particularly worth noting. That's the early-stage deal between Merck and AstraZeneca to combine two of their development candidates in a Phase I trial.
That's Merck's AKT inhibitor MK-2206 and AZ's Mek inhibitor AZD6244, and there's room to think that combining those two mechanisms could be beneficial. But as that In Vivo Blog link details, this deal wasn't initiated through any official contact between the two companies. Rather, someone from Merck and someone from AZ got to talking while they were going through airport security in Dublin, and recognized each other's names. A mere year and a half later, the deal was born.
There's a lot to learn from that story. For one, big drug companies are not, for the most part, looking to do early-stage deals with other big drug companies. Perhaps we'll see more of these in the future, but in general, it's about the least likely form of partnership. Another thing to note is how long it took for this idea to bear fruit. Eighteen months is about right for companies of this size to make up their minds about something like this - and you can decide that (since the oncology field is so complicated) that this is a reasonable period of evaluation, or you can decide, equally objectively, that delays of that magnitude remind you of a sauropod turning around in puzzlement three hours after something bit its tail.
I'm impressed that the deal was made at all. The usual path for new ideas of this sort is to the graveyard, especially in very large organizations, so I have to assume that some people within each company must have really pushed things along to make it happen. It's part of the general bias toward inaction: it's harder to get beaten up for decisions that you didn't make, compared to decisions that you did. Missed opportunities are often invisible.
So, no matter how long it took, or even whether it works out, I still have to congratulate the people involved on getting this agreement to happen. It's worthwhile, I think, just because it's the sort of thing that doesn't happen very often. And I have the feeling that (in the coming years) we're going to have to explore a lot of things in this industry that haven't happened very often. We'll need the practice!
Comments (4)
+ TrackBacks (0) | Category: Business and Markets | Cancer | Clinical Trials | Drug Development | Drug Industry History
May 20, 2009
Posted by Derek
Well, we can all study biochemical mechanisms in tumor cells every day of the week. And we can crank out tens of thousands of potential clinical candidates to hit them, run the assays, and then turn around and do it again. We can send things through all sorts of tox testing, take them to the clinic, try them against all sorts of terrible cancers, and amass enough data to make it through the FDA. Then we can let the oncologists continue to try variations, combinations, and regimens in the continuing search for something that works.
And every so often, we actually succeed. Childhood Hodgkin's lymphoma has one of the highest cure rates of all cancers. We can actually do something about that one (as opposed to, say, pancreatic cancer, which we can't do much about at all). Children who would otherwise die - and die slowly - now get a chance to live, to grow up.
But we can't, apparently, convince everyone of this. Many readers will have heard over the last few days of the case of Daniel Hauser of Minnesota, a 13-year-old diagnosed with Hodgkin's a few months ago. Instead of going in for rounds of chemotherapy, the boy (who has said that he doesn't believe that he's sick) and his family have opted for "Native American alternative therapy", and have fled from a court order. The boy's mother, who apparently does believe that he's sick, has said that she's treating him with "herbal supplements, vitamins, and ionized water".
These will, almost certainly, allow the lymphoma to kill him. Chemotherapy and radiation, on the other hand, will very likely allow him to live. If someone is bleeding to death from an arterial wound, anyone trying to heal them by invoking spiritual powers or alternative therapies would (and should) be shoved aside by any onlooker with a tourniquet. Daniel Hauser is bleeding to death as well: just more slowly, and in front of many more onlookers.
Comments (31)
+ TrackBacks (0) | Category: Cancer | Current Events | Snake Oil
May 7, 2009
Posted by Derek
Now, here’s something to think about: can angiogenesis inhibitors, the famous class of tumor-starving cancer drugs, actually make some kinds of cancer worse?
This unnerving thought comes courtesy of two recent studies on VEGF pathway inhibitors which present what calls "intriguing, almost perplexing evidence" of just that. One team studied the effects of an anti-VEGF-receptor antibody or the VEGF kinase inhibitor Sutent (sunitinib) in mouse models of pancreatic cancer or glioblastoma multiformis. These are two very nasty tumors, and they’re just the sort of thing that people would like to be able to treat when a new drug comes along. But treatment with either the antibody or the small molecule significantly increased the number of metastatic cancers in the animal models, and I mean significantly: like 6% highly invasive tumors in the controls versus over 50% in the treated group. Admittedly, those numbers were in immune-compromised animals, but in mice with normal immune function, the numbers of metastatic tumors still rose by two- to four-fold.
The other study looked at injections of either metastatic breast cancer cell lines or melanoma lines in mouse models. The authors reproduced the effects of Sutent on the former – it inhibits growth of locally placed tumors, as it should (on past evidence). But if you inject cells into the bloodstream, the story is different. Pre- or post-injection treatment of the mice with Sutent led to an increase in metastatic tumors and a decrease in survival relative to untreated mice. Similar results were obtained with Nexavar (sorafenib), which also hits the VEGF kinase, among others.
That “among others” might be significant. The antibody study does make you think that this is a VEGF-driven effect, but it’s important to remember that both Sutent and Nexavar hit a famously wide variety of kinases. And as a Nature item on these results points out:
It is important to emphasize that both studies clearly recapitulate the clinical data that anti-angiogenic therapies can have significant, albeit transitory, effects on localized tumour growth. However, they raise interesting questions about the timing of anti-angiogenic therapy and whether combining these agents with chemotherapy or other targeted agents can counteract the observed unfavourable effects.
Oh, yes. Among these questions are whether the other VEGF-targeting drugs (like Genentech's Avastin) have this effect. You'd have to presume that they would. And what about other therapies directed at other anti-angiogenic targets?. They might, if the effect is brought on simply by low oxygen levels in tumor cells, or it might be something specific to VEGF. We also don't know, in general, which sorts of tumors respond in this way and which don't. But these findings should have effects on clinical practice, and soon. They didn't quite come out of the blue - it's been known since the anti-angiogenic drugs were developed that they didn't actually seem to cure cancers so much as knock them down for varying lengths of time. And in many cases, patients only survive a few months longer after treatment.
Every time I write something like that, though, I'm tempted to quote Peter Altenberg and say "What's so only"? But there still seems to be so much more potential in the idea - the same potential that led to a lot of hype and craziness a few years ago - and perhaps we're beginning to see where things went wrong. Can they be put right, or not?
And you know, perhaps it's for the best that Judah Folkman himself isn't still around to see these latest results. I don't think he would have despaired, but it wouldn't have been easy news for him to hear. . .
Comments (21)
+ TrackBacks (0) | Category: Cancer
May 6, 2009
Posted by Derek
Here's a good example of why all of us in the industry tiptoe into Phase I trials, the first-in-man studies. A company called SGX, recently acquired by Eli Lilly, has been developing a kinase inhibitor (SGX523) targeting the enzyme cMET. That's a well-known anticancer drug target, with a lot of activity going on in the space.
SGX's specialty is fragment-based design, and they've spoken several times at meetings about the SGX523 story. The starting point for the drug seems to have come out of X-ray crystallographic screening (the company has significant amounts of X-ray synchrotron beamline time, which you're going to need if you choose this approach). They refined the lead, in what (if you believe their presentations) was a pretty short amount of time, to the clinical candidate. It seems to have had reasonable potency and pharmacokinetics, very good oral bioavailability, no obvious liabilities with metabolizing enzymes or the dreaded hERG channel. And it was active in the animal models, however much you can trust that in oncology.
So off to the clinic they went. Phase I trials started enrolling patients in January of last year - but by March, the company had to announce that all dosing had been halted. That was fast, but there was a mighty good reason. The higher doses were associated with acute renal failure, something that most certainly hadn't been noticed in the mouse models, or the rats, or the dogs. It turns out that the compound (or possibly a metabolite, it's not clear to me) was crystallizing out in the kidneys. Good-looking crystals, too, I have to say. I can't usually grow anything like that in the lab; maybe I should try crystallizing things out from urine.
Needless to say, obstructive nephropathy is not what you look for in a clinical candidate. There's no market for instant kidney stones, especially when they appear all over the place at the same time. The patients in the Phase I trial did recover; kidney function was restored after dosing was stopped and the compound had a chance to wash out. But SGX523, which was (other than its unlovely structure) a perfectly reasonable-looking drug candidate, is dead. It didn't take long.
Comments (38)
+ TrackBacks (0) | Category: Cancer | Clinical Trials | Toxicology
April 30, 2009
Posted by Derek
We now have more data on Dendreon’s results for their prostate cancer therapy Provenge, and the numbers do, in fact, look good. This isn't a cure for refractory prostate cancer, but there seems to be a real statistical improvement in survival, with side effects no worse than the placebo group, and that should be enough for the FDA. In oncology you have to take what you can get.
What’s bizarre is the trading that went on in the company’s stock just before they started presenting on Tuesday. For reasons that are still unclear, a horrendous wave of selling hit within the space of a few minutes, and the stock went down as if hit with a club. Having risen to nearly $25 by about 1 PM, trading was halted in the stock at 1:27, with it now going for $11.81. As the company’s shareholders raved and cursed in utter consternation, the company was detailing exactly the results they’d been hoping to hear.
Wednesday, the stock shot straight back up to its former levels, but that doesn’t help the many people who (prudently, they thought) had put stop-loss orders in and had thus already been sold out. This Bloomberg story has a fellow who was cashed out at $9.31, which must make him wonder (1) just what the hell was going on, anyway, and (2) just what it means to halt trading in a stock, if you’re going to find yourself traded out of it at an even lower price.
I can’t help out with question (1) – I have to say, I’d like to know the answer to that one myself. But as for (2), that’s the problem with stop-loss orders, particularly in a stock that doesn’t have much of a float. Movements, especially downward ones, come suddenly and discontinuously, and the stock doesn't hit all the grace notes on the way down (as Fred Schwed
used to say).
So good luck to Dendreon, and to the patients who will use Provenge. Dendreon's investors, on the other hand, have probably been through the power-wash and spin cycle so many times that they hardly know what's hit them.
Comments (6)
+ TrackBacks (0) | Category: Business and Markets | Cancer
April 14, 2009
Posted by Derek
Post updated below - DBL Dendreon is a company that's really been through it, as have their investors. Many will remember the upheaval back in 2007, when the company showed what they felt were impressive results for their autologous prostate cancer immunotherapy Provenge, got a favorable reception from the FDA's advisory panel, but were then hit with an "approvable" letter asking for more data. (Here are three posts on that: before, during, and after).
Well, the company is back with more data, in 512 patients. And initial reports are that the numbers look good. They're doing a conference call as I write, so we'll know more shortly, and I'll update this post as things become more clear.
Update: Hmmm. On the conference call, the company has declined to present any numbers, saying that it's bound by a blackout requirement for its presentation at the American Urological Association on April 28th. Their main statement seems to have been that the drug met its primary endpoint, reducing the risk of death compared to a placebo. There are a lot of other questions about Provenge - whether it slows the progression of prostate cancer or not, for example - but survival is presumably the bottom line. That was the main focus of the whole trial (as opposed to the cancer-progression endpoint of their smaller, earlier one).
So we'll see at the end of the month how impressive the statistics look. The market's reacting well to the news, although you could argue that the stock has pulled back a bit. It closed yesterday at 7 and change, traded over 21 during the morning, and is around 17 now. (Of course, some of that pullback could be from people giddily selling their shares on the news, just as some of the spike could well have been some people rather less giddily covering their short positions).
Comments (16)
+ TrackBacks (0) | Category: Business and Markets | Cancer | Regulatory Affairs
March 26, 2009
Posted by Derek
So, people like me spend their time trying to make small molecules that will bind to some target protein. So what happens, anyway, when a small molecule binds to a target protein? Right, right, it interacts with some site on the thing, hydrogen bonds, hydrophobic interactions, all that – but what really happens?
That’s surprisingly hard to work out. The tools we have to look at such things are powerful, but they have limitations. X-ray crystal structures are great, but can lead you astray if you’re not careful. The biggest problem with them, though (in my opinion) is that you see this beautiful frozen picture of your drug candidate in the protein, and you start to think of the binding as. . .well, as this beautiful frozen picture. Which is the last thing it really is.
Proteins are dynamic, to a degree that many medicinal chemists have trouble keeping in mind. Looking at binding events in solution is more realistic than looking at them in the crystal, but it’s harder to do. There are various NMR methods (here's a recent review), some of which require specially labeled protein to work well, but they have to be interpreted in the context of NMR’s time scale limitations. “Normal” NMR experiments give you time-averaged spectra – if you want to see things happening quickly, or if you want to catch snapshots of the intermediate states along the way, you have a lot more work to do.
Here’s a recent paper that’s done some of that work. They’re looking at a well-known enzyme, dihydrofolate reductase (DHFR). It’s the target of methotrexate, a classic chemotherapy drug, and of the antibiotic trimethoprim. (As a side note, that points out the connections that sometimes exist between oncology and anti-infectives. DHFR produces tetrahydrofolate, which is necessary for a host of key biosynthetic pathways. Inhibiting it is espccially hard on cells that are spending a lot of their metabolic energy on dividing – such as tumor cells and invasive bacteria).
What they found was that both inhibitors do something similar, and it affects the whole conformational ensemble of the protein:
". . .residues lining the drugs retain their μs-ms switching, whereas distal loops stop switching altogether. Thus, as a whole, the inhibited protein is dynamically dysfunctional. Drug-bound DHFR appears to be on the brink of a global transition, but its restricted loops prevent the transition from occurring, leaving a “half-switching” enzyme. Changes in pico- to nanosecond (ps-ns) backbone amide and side-chain methyl dynamics indicate drug binding is “felt” throughout the protein.
There are implications, though, for apparently similar compounds having rather different effects out in the other loops:
. . .motion across a wide range of timescales can be regulated by the specific nature of ligands bound. Occupation of the active site by small ligands of different shapes and physical characteristics places differential stresses on the enzyme, resulting in differential thermal fluctuations that propagate through the structure. In this view, enzymes, through evolution, develop sensitivities to ligand properties from which mechanisms for organizing and building such fluctuations into useful work can arise. . .Because the affected loop structures are primarily not in contact with drug, it is reasonable to envision inhibitory small-molecule drugs that act by allosterically modulating dynamic motions."
There are plenty of references in the paper to other investigations of this kind, so if this is your sort of thing, you'll find plenty of material there. One thing to take home, though, is to remember that not only are proteins mobile beasts (with and without ligand bound to them), but that this mobility is quite different in each state. And keep in mind that the ligand-bound state can be quite odd compared to anything else the protein experiences otherwise. . .
Comments (3)
+ TrackBacks (0) | Category: Biological News | Cancer | Chemical News | In Silico
February 11, 2009
Posted by Derek
For the last ten or fifteen years, untold amounts of time and money have been spent developing drugs to inhibit kinase enzymes. Just go take a look at KinasePro’s archives; that’ll give you the idea. Huge programs have been run at all the major drug companies, and any number of smaller ones have been founded just on the strength of one kinase inhibitor or another.
The enthusiasm isn’t hard to understand. For those of you outside the med-chem / biochem worlds, kinase enzymes are there to stick phosphate groups into other molecules, which is a very widely used signaling pathway. A phosphate completely changes the character of the part of a molecule where it’s attached, changing what other partners it will recognize and bind to. This takes place generally on to some sort of free OH group. That doesn’t narrow things down much, though, since there a lot of incredibly important small molecules with OH groups that get phosphorylated. Adding to the fun, several amino acids (serine, threonine, and tyrosine) have OH groups on them, and the means that nearly every decent-sized protein has plenty. The patterns of their phosphate groups turn their activities on and off, determine where they go and what they’ll recognize. It’s a major, major switching mechanism for protein activity – you can’t overstate its importance. Here's the classic family tree of the protein kinases, just to give you the idea. (And in case you’re wondering, there is indeed a whole different class of enzymes, the phosphatases, that take the things back off again - whole different bag of snakes, those guys).
There are hundreds and hundreds of kinase enzymes, and I think it’s safe to say that they’re involved in just about every important biochemical process you can think of. The downside of working on them is that, well, they’re involved in just about every important biochemical process you can think of. (Try this on for size, or this, to get the idea). How do you get them to do what you want?
Well, we’re still not sure about that. I go back far enough to remember when kinases were considered nearly impossible to work with as drug targets, because no one could figure out how you’d get selectivity. But once we figured out how to make molecules that recognized the “hinge” region common to most of these enzymes, the game was on. You can make blunderbuss molecules that inhibit dozens of enzymes at the same time, or (in some cases) you can narrow down on a mere handful, or on just one.
But how far do you want to go? That’s where we’re “over-asked”, as the German expression translates. The downstream effects of many of these enzymes are absolutely bewildering in normal cells, and the differences in disease states are even more of a tangle. It’s no surprise at all that most kinase inhibitors have shown up first in oncology, because that’s where you can get away with the most severe side effects. There are plenty of tempting opportunities in inflammation, diabetes, cardiovascular disease, and other areas, but those have been slower to come along.
The experience with the cancer-targeting drugs has been mixed. You have your Gleevec (imatinib) – pretty selective, works pretty well on a very limited group of patients. And you have your hand grenades, like Sutent (sunitinib) or Nexavar (sorafenib), which hit a lot of kinases and work (to some degree) on a lot of different things. But none of them are magic bullets, for sure. So do you want selectivity or not? The only answer we can offer is (still) “that depends”.
These days, there’s a distinct “kinase hangover” in the industry. It’s not as hot a field as it was. “Not again” is the usual feeling on seeing yet another patent or publication on yet another structure that inhibits XYZ kinase. It’s not as hot an area as it was a few years ago – the belief is that many of the best targets have either wiped out in the clinic, are being tried there now, or haven’t yielded reasonable chemical matter to even get there.
My guess is that we’re waiting, whether we know it or not, for our understanding of the biology to catch up. We have all these compounds, with all these different fingerprints, and we’ve generated this huge pile of mixed data that we can’t quite make sense of. That adds to the frustrated “been there” feeling. The cure for it is to have a better idea of what we’re doing and why, but that’s coming on much more slowly. And because that’s slow, the kinase field may never regain its hot status. But who knows, it may make it all the way to useful and valuable, bypassing “hot” completely.
Comments (19)
+ TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History
December 4, 2008
Posted by Derek
There are some groups of compounds that seem to have a curse on them. They show up in drug screening, they have activity that’s often too good to ignore, but hardly anyone can manage to turn one of them into a drug.
Trifluoromethyl ketones are one example of this. They’re classic inhibitors of proteases, especially serine proteases, and of other enzymes that depend on a serine in their active site. That’s because that ketone really isn’t much of a ketone – the fluorines make the carbon rather unhappy when it’s in that state, electron-poor and ready to pick up a nucleophile and go tetrahedral again. Trifluoromethyl ketones are generally seen in their hydrated state, unless you take care to dry them out, and they’ll work an active-site serine OH into their scheme as well. So you end up with a covalent inhibitor, but a reversible one – the activity comes on slowly, and the compound comes off slowly, too. That trick can work with cysteine nucleophiles, and the hydrate form is also known to coordinate with active-site zinc atoms – so it’s no surprise that the enzyme inhibition literature on these things is mighty extensive: proteases, lipases, esterases, deacetylases, the list goes on for a while.
But although several of these have gone into the clinic over the years, I can’t think of one that’s make it all the way to the market (I’d be glad to hear of any that I’ve overlooked). The best guess is that this isn’t the fault of the functional group, but of the targets it’s been applied to. Some of these enzymes just haven’t panned out, so perhaps the trifluoromethyl ketone awaits its day in the sun.
Another group of this sort is the hydroxamic acid. Its strength is its coordination to zinc atoms, so you see it all over the place in the metallaloprotease literature, and in other zinc-y fields like histone deacetylases. And in vitro, it hardly has a peer. I’ve seen list after list in the literature comparing various zinc-binding head groups, and likely as not, the hydroxamic acid sets the standard every time.
But the reason you see those lists is that people are trying to find something that’ll work other than a hydroxamic acid. There are numerous complaints, ranging from “hydroxylamine is explosive on large scale, you know” and “they’re a pain to make reproducibly” through “they have ugly PK in the animal models” all the way up to “they’re toxic” and “how many of them have ever made it through the clinic?”. How much merit each of these have can be debated, but all together they make an unpleasant picture.
In this case, though, I do know of one that’s made it - SAHA (Zolinza, vorinostat). That one came out of a long-term academic project involving Paul Marks at Sloan-Kettering and Ron Breslow's lab at Columbia, and is one of the not-so-numerous examples of drugs that have made it from the university to the marketplace. Merck signed up to do the clinical and regulatory lifting on this one, and it's now marketed for cutaneous T-cell lymphoma.
So it is possible to get a hydroxamic acid through. "Well, yeah," say the voices, "for cancer, sure. Home of the world's only boronic acid-containing drug. Home, if you really want to get down to it, of nitrogen mustards and God knows what else. Cancer." And it's true that the standards are a bit more relaxed there. I wouldn't necessarily want to give someone a hydoxamic acid every day for the rest of their life, true - the things coordinate iron, for one thing, which isn't always good. But there are other fields where short-term therapy makes sense, and we probably haven't seen the last of this functional group, either.
Comments (10)
+ TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History
September 19, 2008
Posted by Derek
A colleague mentioned to me the other day that Sunesis Pharmaceuticals had let many of its remaining research staff go back during the summer – they’re battening down to try to get their main clinical candidate through for leukemia and ovarian cancer. That’s a common phase of life for a small company trying to go it alone. Clinical trials are expensive, and so are scientists, and sometimes a company finds that it can’t afford both at the same time. Amylin, to pick one example, went through so many cycles of that (starting in the mid-1990s) that I completely lost count.
The Sunesis news struck me, though, because if you go back a few years in the literature, they’re all over the place. The company was aggressively investigating (and promoting) a technique called “tethering” as a platform for drug discovery. Back around 2003, they were all over the journals with it.
Tethering was one of those neat ideas which seems to have been a lot of work to reduce to practice. It’s a variation, in its way, of another one of those techniques called Dynamic Combinatorial Chemistry. In DCC, you take a good-sized collection of compounds which can form reversible bonds with each other. Thiols (R-SH) have been used a lot, since they can form disulfides (R-SS-R), which can easily come apart and re-form with other thiols. In the presence of some target or template, such as the binding site of a protein, the idea is that any disulfide combination that manages to bind well will get enhanced in the final mixture, since it spends more time out of the swim of potential reactants. Comparing the product distribution with and without the target protein can point you to a potential lead structure to optimize. (You can also turn it around and make synthetic receptors (PDF) for molecules that you're interested in).
The idea behind tethering was, at least in one of its main variations, to introduce an extra thiol group into a target protein somewhere close to its active site. Then this mutant protein would be screening against a library of small molecules with thiol groups of their own, with the idea that if there was a binding site near that thiol that it would be found by preferential disulfide formation between it and some member of the screening library. Then came the second step. Normal, unmutated protein would be exposed to a mix of that preferred thiol and a library of other potential thiol coupling partners, in an attempt to find another preferred extension into the binding cavity. So this was basically a way to do DCC, but giving it a leg up by trying to make sure that there was a good amount of at least one thing that could bind to some relevant part of the target.
That tells you that standard from-the-ground-up DCC must have some difficulties, since if it worked as well as its concept you wouldn’t need to put your thumb on the scales like that. But I was never sure how well tethering worked, either. The company published numerous examples of it, but I don’t know if any of these compounds ever got anywhere (and indeed, I’m not at all sure that their current clinical candidate was discovered by this technique).
There are several places where things could break down. Making a mutant protein introduces some uncertainty, for starters. That SH group might not change things, or it might change them just enough so that the binding site you find doesn’t quite exist when you switch to the wild type. And any binding site you find in the first round isn’t necessarily a productive one – the original protein SH group was targeted to try to dangle out over the right part of the protein, but there are no guarantees about that. Past that, even if you get through the second round and find some new disulfide hits (no sure thing), they are, well. . .they’re disulfides. And those are poor bets for drugs.
That’s where the real weak point of DCC is in general, to my mind. Using reversible reactions gives you compounds with too much potential to fall apart, so the first thing you have to do is replace those bonds with something sturdier – and that’s not always easy, or even possible. There are very, very few clean substitutions available in the chemical world. Nothing’s quite like a nitrile except a nitrile, and there’s only one thing shaped exactly like a t-butyl group: another t-butyl. Likewise, the only thing that’s guaranteed to look and act like a disulfide is a disulfide. A two or three carbon chain replacement is the logical place to start, but that might be synthetically tricky, or (even more often) might turn out to be a completely different sort of compound once you’ve made it.
In the end, I think tethering turned out to be an excellent means to get some very interesting papers published in some good journals. (The publications have continued to this day). But beyond that, I’m not so sure. I’d be glad to hear from any ex-Sunesis people with other views. . .
Comments (23)
+ TrackBacks (0) | Category: Cancer | Drug Industry History
September 12, 2008
Posted by Derek
I haven’t mentioned the attempt by Bristol-Meyers Squibb to buy out Imclone until now, but there’s a nice . The reasons for the move are unsurprising – BMS would like all the revenue from Erbitux, instead of just a share of it, and sees some value coming up in Imclone’s pipeline (such as their development drug candidate IMC-11F8, vide infra). They’ve waiting quite a while, and apparently feel that the time is right – the only question is how much money such a move will cost them.
And that’s the question, all right, since Carl Icahn started talking this week about a mysterious preliminary offer from some unnamed other company for significantly more money ($70/share) than BMS is putting up. A lot of investors seem to have expected a sigh, a roll of the eyes, and a reach back into the pocket for more money - IMCL has been trading above the original $60/share offer. But that’s not what they’re getting, at least so far.
In a letter, Bristol-Meyers Squibb’s CEO is now reminding Icahn of a few things that you’d think would be obvious. One of them is that their offer is well-supported and requires no due diligence, as opposed to nebulous preliminary figures from companies that no one will name. The next paragraph is even more to the point:
As you know, Bristol-Myers holds the exclusive, long-term marketing rights in the United States to ERBITUX® and related compounds, including IMC-11F8. Bristol-Myers has no intention of agreeing to any modifications to these rights. ImClone also should understand that our offer is for the entire company, and any potential restructuring of the company could severely jeopardize ImClone’s value and deprive ImClone’s stockholders of the benefits of our offer.
That’s about the size of it, and I think that this message is being delivered in the way that Icahn understands best – right across the top of the head, with some good wrist action. There’s no reason for BMS to give up on their rights to Imclone’s products, except on terms that would make other potential buyers lose interest. Why would they? There is, I should add, quite a dispute between the two companies about who has the rights to that development antibody, IMC-11F8. Imclone has recently been acting as if BMS has no rights to it at all, but as that WSJ link makes clear, two years ago they clearly stated to Merck KGaA that the antibody falls within the scope of the BMS agreement. It's hard for me to see how they'll get out of that, and even if they do, it'll take a lot of expensive wrangling.
So, if there really is a company willing to go to $70 a share for Imclone, with revenue still flowing to BMS and plenty of legal uncertainty on top of that, well, this is the time for them to speak up. I’m not sure that there is one, despite what Icahn says, but perhaps he’s hoping for one to materialize. He’s always reckoned Imclone to be worth vast amounts more than people who know anything about oncology think it is, so maybe he sees no problem with those figures. Anyone else live in the same world?
Update: Icahn has already replied, in a fashion that makes this affair look to go on a while. He says that he "doesn't understand the point" of the BMS letter, and goes on to say:
. . .With respect to a potential restructuring of ImClone, rest assured that we will act in what we consider the best interests of all our shareholders and not just Bristol.
Obviously, should you wish to make another offer which you believe we would not find inadequate, you are free to do so. Upon receipt of that offer, we will respond appropriately.
Well! My guess is at this point that BMS will sit tight and wait to see if anyone really wants to get in on all this action - betting, reasonably I think, that no one will. I would enjoy it if they raised their bid to, say, $60.25, just to steam up Icahn's windows, but I assume that they're above that. As time goes on, with no competing bids in sight, I would think that Icahn and his board-of-buddies would have to submit the BMS bid to the shareholders - wouldn't they?
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+ TrackBacks (0) | Category: Business and Markets | Cancer
September 8, 2008
Posted by Derek
Since I was just banging on the table (or the lab bench) the other day about how many diseases aren’t single-factor, and about how many diseases (like cancer) aren’t even single diseases, I thought this would be a good time to haul out some evidence for that. The data are here thanks to some recent papers by groups who are sequencing various tumor lines, looking for common mutations as new drug targets. (The Cancer Genome Atlas, an NIH project, is behind a lot of work in this area).
But what’s become clear, if it wasn’t already, is that various cancer lines have a startlingly wide array of mutations. Recent work from Bert Vogelstein’s group at Johns Hopkins (with a host of collaborators) and from the CGA itself now show that there are an average of 63 mutations in pancreatic cancer cells, and 47 in glioblastomas, two of the nastiest tumors around. The first impulse might be to think “Great! Plenty of drug targets to go around!”
But hold on. For one thing, even though these mutations are surely not all equal, the fact that there are so many makes you wonder about whether attacking any one of them alone can make much of a difference. And different patients can have varying suites of those mutations, so it’s difficult to imagine that going after just one or two of those targets will be enough to treat a majority of cases. This work follows up on earlier studies in other tumor lines, all of which seem to point in the same direction: patients who are currently classed as having the same type of cancer really don’t.
This won’t come as a surprise to most oncologists, who have seen for themselves the widely varying responses to current therapies. The challenge is to figure out what these various changes mean, and how to classify patients to give them the best therapy. It’s not going to be easy. Just doing the math on the possible interactions of several dozen mutations with a list of possible treatment regimes is enough to make you pause. The hope is that most patients will fall into broad categories, which will line up, more or less, with broad categories of treatment. But it’s not going to be a good fit, most likely, and even getting those approximations to work is taking a lot of time and effort. (Just think back about how long you’ve been hearing about the wonderful new age of personalized medicine. . .)
We're not going to be able to do this, either, without a second (and much harder) stage of research: figuring out why these various mutations are important. Some of them seem to make reasonable sense, but it's not at all clear what a lot of them are doing, especially in concert with each other. There's an awful lot of ditch-digging work out there waiting to be done. For now, the quotes from Vogelstein in a Nature News summary can’t be improved on, though. This is the current state of the art, and it’s up to us to improve on it:
"It is apparent from studies like ours that it is going to be even more difficult than expected to derive real cures. . . It is extremely unlikely that drugs that target a single gene, such as Gleevec, will be active against a major fraction of solid tumours”
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August 1, 2008
Posted by Derek
The ax is falling again at GlaxoSmithKline. This time it’s the oncology group.
Last month the cardiovascular people got this same treatment, you’ll recall, and there was some disagreement about how many jobs were being affected. But it looks like the company is moving one by one through its Centers of Excellence in Drug Discovery (CEDDs) and running a most excellent scythe through them. By the time they’re through, the total number of layoffs looks like it will be substantial indeed.
That’s because inside each area so far the cutbacks are pretty sweeping. Total oncology head count is apparently being reduced by about 40%. Discovery chemistry seems, unfortunately, to be getting it a bit worse, since some of the sub-areas aren't losing head count at all. The estimates I have are that of the c. 120 chemists in the area, about 60 are losing their jobs. That includes the entire oncology med-chem group at the Research Triangle Park location, and from what I'm told, none of them are being relocated to the Philadelphia-area sites. So much for discovering Tykerb, et al.
Are all of the CEDDs going to get this same treatment, or to the same degree? GSK isn’t saying, but I’d certainly bet on this sort of thing happening again as the year goes on. What the company’s research arm will look like when it’s all over is anybody’s guess, too, but there’s one thing for sure: it’ll be a heck of a lot smaller.
And whether this new trimmed-down inlicensed/outsourced GSK will be any more productive is anybody’s guess either. But we won’t know that for a long time. It’ll take quite a while just for all of these changes to stop reverberating through the company, for one thing, and then it’ll be several years after that before it’ll be possible to look at the pipeline and have a majority of it be a product of the new organization. As I’ve said before, this is one the biggest challenges in trying to engineer a large-scale change in a drug discovery shop – the lag time before you see the effects.
I’m already seeing resumes, but I’d like to invite any readers who know of openings for experienced drug discovery positions to either mention them in the comments or email me about them for a future post. (I did a lot of that during my own experience with a site closure, but of course, this time I don’t know most of the people involved personally). At the rate things are going, I’m going to have to start running classified ads down the right side of the page.
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July 22, 2008
Posted by Derek
Merck took the unusual step of delaying its earnings release yesterday until after the close of the market. A report on another clinical study of Vytorin (ezetimibe), their drug with Schering-Plough, was coming out, so they put the numbers on hold until after the press release yesterday afternoon. Naturally, this led to a lot of speculation about what was going on. A conspiracy-minded website vastly unfriendly to Schering-Plough suspected some sort of elaborate ruse to drum up publicity.
But that sort of thinking doesn't take you very far, unless you count the distance you rack up going around in circles. As it turned out, the SEAS trial (Simvastatin and Ezetimibe in Aortic Stenosis) was, in fact, very bad publicity indeed for the drug and for both companies. In fact, a real conspiracy would have made sure that these numbers never saw the light of day, or were at least released at 6 PM on a Friday. But no, the spotlight was on them good and proper.
This trial studied patients with chronic aortic stenosis, which is a different condition than classic atherosclerosis. The two have enough similarities, though, that there has been much interest in whether statin treatment could be effective. The primary endpoint, a composite of aortic valve and general cardiovascular events, was missed. Vytorin was no better than placebo. It reached significance against one secondary endpoint, reducing the risk of various ischemic events, but not in any dramatic fashion.
That's not necessarily a surprise, since there's not a well-established therapy for aortic stenosis (thus the trial design versus placebo). As several commenters to the conference call after the press conference pointed out, this shouldn't change clinical practice much at all. But it's not what Merck and Schering-Plough needed to hear, that's for sure, because the sound bite will be "Vytorin Fails Again".
Actually, the sound bite will be even worse than that. There are a lot of headlines this morning about another observation from the SEAS trial: that significantly more patients in the treatment arm of the study were diagnosed with cancer. That's a red warning light, for sure, but in this case we have at least some data to decide how much of one.
For one thing, as far as I know there have been no reports of increased cancer among the patients taking Vytorin out in the marketplace - of course, one could argue that this might have been missed, but if the effect were as large as seen in the SEAS study, I don't think it would have been. Analyses of the earlier Vytorin trials and the ongoing IMPROVE-IT trial versus Zocor have also shown no cancer risk, and the latter trial is continuing. So for now, it would appear that either this was a nasty result by chance, or (a longer shot) that there's something different about the aortic stenosis patients that leads to major trouble with Vytorin.
None of these scientific and statistical arguments, and I mean none of them, will avail Schering-Plough and Merck. Among people who've heard of Vytorin at all, the first thing that will come to mind is "doesn't work", and after today's headlines, the second thing that will come to mind is "cancer". Just what you want, to put out press releases that your compound, even though it failed to work again, isn't actually a cancer risk. You really couldn't do worse; a gang of saboteurs couldn't have done worse. Of course, there's no such gang: the companies themselves authorized these trials, thinking that there were home runs to be hit. But all these sidelines - familial hypercholesteremia, aortic stenosis - have only sown fear, confusion, and doubt. The only thing that I can see rescuing Vytorin as a useful drug is for the IMPROVE-IT results to show really robust efficacy in its real-world patients. And I wonder if even that could be enough.
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+ TrackBacks (0) | Category: Business and Markets | Cancer | Cardiovascular Disease | Clinical Trials | Toxicology
June 23, 2008
Posted by Derek
If you go to the med-chem or pharmacology literature databases and type "Aurora kinase", you'd better stand back. A geyser of publications will come spraying out, most of them having to do with Aurora A and/or Aurora B as possible targets for cancer therapy. These enzymes are involved in different phases of cell division, among other things, and a lot of evidence points to them as key players in several cancer lines. There are a number of inhibitors compounds known for them as well, in various stages of development, some of which are selective and some of which hit both to different degrees. Attempts to unravel all the functions of the kinases through these compounds, and through various loss/gain of function mutations in cells, have been. . .well, "complex" is a judicious term to use. The functions of the two enzymes may well be tied to each other, so getting a clear look has been hard.
There's a new paper that illustrates just why it hasn't been easy. This one looks at an AstraZeneca compound, ZM447439, which inhibits both Aurora A and Aurora B in enzyme assays, but in cells seems to be the closest match to a clear knockout of B. The authors started with a well-known cancer cell line (HCT-116), and picked out mutants that had acquired resistance to the drug. They turned out, indeed, to have mutated forms of Aurora B in them, and when they introduced those mutant forms into other cells, they also became able to grow in the presence of ZM447439. That's about as good a test of mechanism as you're going to get in the oncology field, and as the commentary on the paper says, "Even had the authors stopped at this point, it would have been an important contribution."
But they kept on digging, and good for them - perhaps they were (rightly) suspicious that everything was working out a bit too neatly. They then chose two other Aurora inhibitors, VX-680 (which hits both forms) and MLN8054, which is known to be selective for Aurora A. When the cells with mutant forms of Aurora B were exposed to the VX compound, they grew anyway - which makes sense from the Aurora B side of things, since they could well have mutated the efficacy away from this compound, in the same way they got away from the AstraZeneca one. But VX-680 definitely seems to hit Aurora A, too - so is that pathway not doing anything at all for efficacy?
Well, when they treated the Aurora B mutant lines with the Aurora-A-selective MLNM compound, they died off, implying that Aurora A inhibition can do the job all by itself, so there's a pretty blatant contradiction here. The authors advance the two hypotheses that have to be looked at: either Aurora A is a good target and the VX compound isn't doing as much against it as everyone thought, or Aurora A inhibition is largely useless (at least in HCT-116 cells!), and the MLNM compound has another target that no one's realized yet. (It's important to realize that this situation could vary from tumor to tumor - here's a suggestion that Aurora A might be the way to go for pancreatic cancer, for example).
And there's another, rather troubling take-home lesson, having to do with the alacrity with which these cells mutated away from sensitivity to the Aurora inhibitors. As the authors put it:
"The rather surprising picture emerging from our studies and from previous studies on Abl and other tyrosine kinases is that the kinase scaffold is very tolerant of mutations in the hinge loop that lines the ATP-binding site. A discouraging consequence of this fact is that these mutations are likely to affect a wide range of ATP-competitive inhibitors—even ones from distinct chemical classes—as most ATP competitors are sensitive to the active site's architecture, to which the mutated residues contribute considerably."
Put simply, the kinases we're targeting have more room to maneuver than we do as medicinal chemists. They can mutate quite a bit and still function, shedding the key binding motifs that our drugs are targeting along the way. We're going to have to work a lot harder to come up with effective combinations.
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April 9, 2008
Posted by Derek
I don't usually do more than one post a day, but this really caught my eye. In an ongoing review of Pfizer's (now discontinued) inhaled insulin (Exubera), an increased chance of lung cancer has turned up among participants in the clinical trials. Six of the over four thousand patients in the trials on Exubera have since developed the disease, versus one of the similarly-sized control group. Six isn't many, but with that large a sample size, it's something that statistically can't be ignored, either.
The concerns would have to be, naturally, that this number could increase, since damage to lung tissue might take a while to show up. This, needless to say, completely ends Nektar's attempts to find another partner for Exubera. Their stock is getting severely treated today (down 25% as I write), but things are even worse for another small company, Mannkind, that's been working on their own inhaled insulin for years now (down 58% at the moment).
There's no guarantee that another inhaled form would cause the same problems, but there's certainly no guarantee that it wouldn't, either. Whether this is an Exubera-specific problem, an insulin-specific one, or something that all attempts at inhaled proteins will have to look out for is just unknown. And unknown, in this case, is bad. It's going to be hard to make the case to find out, if this is the sort of potential problem waiting for your new product. Inhaled therapeutics of all sorts have taken a huge setback today.
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+ TrackBacks (0) | Category: Cancer | Clinical Trials | Diabetes and Obesity | Toxicology
April 3, 2008
Posted by Derek
I was having a discussion the other day about which therapeutic areas have the best predictive assays. That is, what diseases can you be reasonably sure of treating before your drug candidate gets into (costly) human trials? As we went on, things settled out roughly like this:
Cardiovascular (circulatory): not so bad. We’ve got a reasonably good handle on the mechanisms of high blood pressure, and the assays for it are pretty predictive, compared to a lot of other fields. (Of course, that’s also now one of the most well-served therapeutic areas in all of medicine). There are some harder problems, like primary pulmonary hypertension, but you could still go into humans with a bit more confidence than usual if you had something that looked good in animals.
Cardiovascular (lipids): deceptive. There aren’t any animals that handle lipids quite the way that humans do, but we’ve learned a lot about how to interpolate animal results. That plus the various transgenic models gives you a reasonable read. The problem is, we don’t really understand human lipidology and its relation to disease as well as we should (or as well as a lot of people think we do), so there are larger long-term problems hanging over everything. But yeah, you can get a new drug with a new mechanism to market. Like Vytorin.
CNS: appalling. That goes for the whole lot – anxiety, depression, Alzheimer’s, schizophrenia, you name it. The animal models are largely voodoo, and the mechanisms for the underlying diseases are usually opaque. The peripheral nervous system isn’t much better, as anyone who’s worked in pain medication will tell you ruefully. And all this is particularly disturbing, because the clinical trials here are so awful that you’d really appreciate some good preclinical pharmacology: patient variability is extreme, the placebo effect can eat you alive, and both the diseases and their treatments tend to progress very, very slowly. Oh, it’s just a nonstop festival of fun over in this slot. Correspondingly, the opportunities are huge.
Anti-infectives: good, by comparison. It’s not like you can’t have clinical failures in this area, but for the most part, if you can stop viruses or kill bugs in a dish, you can do it in an animal, or in a person. The questions are always whether you can do it to the right extent, and just how long it’ll be before you start seeing resistance. With antibacterials that can be, say, "before the end of your clinical trials". There aren’t as many targets here as everyone would like, and none of them is going to be a gigantic blockbuster, but if you find one you can attack it with more confidence than usual.
Diabetes: pretty good, up to a point. There are a number of well-studied animal models here, and if your drug’s mechanism fits their quirks and limitations, then you should be in fairly good shape. Not by coincidence, this is also a pretty well-served area, by current standards. If you’re trying something off the beaten path, though, a route that STZ or db/db rats won’t pick up well, then things get harder. Look out, though, because this disease area starts to intersect with lipids, which (it bears saying again) We Don't Understand Too Well.
Obesity: deceptive in the extreme. There are an endless number of ways to get rats to lose weight. Hardly any of them, though, turn out to be relevant to humans or relevant to something humans would consider paying for. (Relentless vertigo would work to throw the animals off their feed, for example, but would probably be a loser in the marketplace. Although come to think of it, there is Alli, so you never know). And the problem here is always that there are so many overlapping backup redundant pathways for feeding behavior, so the chances for any one compound doing something dramatic are, well, slim. The expectations that a lot of people have for a weight-loss therapy are so high (thanks partly to years of heavily advertised herbal scams and bizarre devices), but the reality is so constrained.
Oncology: horrible, just horrible. No one trusts the main animal models in this area (rat xenografts of tumor lines) as anything more than rough, crude filters on the way to clinical trials. And no one should. Always remember: Iressa, the erstwhile AstraZeneca wonder drug from a few years back, continues to kick over all kinds of xenograft models. It looks great! It doesn’t work in humans! And it's not alone, either. So people take all kinds of stuff into the clinic against cancer, because what else can you do? That leads to a terrifying overall failure rate, and has also led to, if you can believe it, a real shortage of cancer patients for trials in many indications.
OK, those are some that I know about from personal experience. I’d be glad to hear from folks in other areas, like allergy/inflammation, about how their stuff rates. And there are a lot of smaller indications I haven’t mentioned, many of them under the broad heading of immunology (lupus, MS, etc.) whose disease models range from “difficult to run and/or interpret” on the high side all the way down to “furry little random number generators”.
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+ TrackBacks (0) | Category: Animal Testing | Cancer | Cardiovascular Disease | Diabetes and Obesity | Drug Assays | Drug Development | Infectious Diseases | The Central Nervous System
January 16, 2008
Posted by Derek
So Judah Folkman is no longer with us. He's considered to be the father of the idea that many tumors help to make their own blood supply, through angiogenesis, and that this could be a way to impede their growth. Since his first papers on the topic were published back in 1971, I think he does indeed get the credit. And he should not only get the credit for having the idea, but for publishing it and sticking with it. (Here's an interview with Folkman where he talks about this and much more).
Interestingly, it had been noted as long ago as 1941 that transplanted tumors in animals managed to link in to the existing blood supply through the formation of new vessels, but no one knew what to do with this result. (Here's a history of the field from a few years ago). It's not surprising that it took so long for the idea to catch on, though. It was by no means clear back in 1971, much less 1941, how blood vessels could be raised up by signaling from their target tissue. It wasn't until much later that the signaling pathways for blood vessel growth were discovered. Vascular endothelial growth factor, for example, was only found in 1983, and its functions didn't become clear until 1989 (timeline).
Folkman's death (which took place in the Denver airport, of all places) has brought back memories of the (in)famous Gina Kolata article on Folkman's work in the New York Times from 1998, a front-pager which featured James Watson's notorious quote about how Folkman was going to cure cancer in two years. I wrote about that one in the early days of my blog, and again here when Entremed finally gave up on the compounds that Kolata and the Times had hyped to the skies. The year 2000 came and went without a cancer cure, and many more years are going to go by as well. That's because, as I and many others never tire of pointing out, cancer isn't a single disease, and will never have a single cure. It's like looking for a cure for bad writing - it comes in so many different varieties, for so many different reasons, and therefore needs many different fixes.
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+ TrackBacks (0) | Category: Cancer | Current Events | Drug Industry History
January 4, 2008
Posted by Derek
A reader sends along this article from the New York Times about Chris Kilham, an ethnobiotanist from U. Mass - Amherst looking for medicinally active plants in Peru. The article has lots of local Peruvian color, but it doesn’t neglect the money involved:
” Products that once seemed exotic, like ginseng, ginkgo biloba or aloe vera, now roll off the tongues of Westerners. All told, natural plant substances generate more than $75 billion in sales each year for the pharmaceutical industry, $20 billion in herbal supplement sales, and around $3 billion in cosmetics sales, according to a study by the European Commission.”
It’s worth noting, though, that none of those three once-exotic plants (exotic when – twenty-five years ago?) are the source of any major revenue for the pharmaceutical industry, unless you count aloe-vera sunscreen line extensions and the like. Kilham himself has some definite opinions on the value of plant-derived drugs:
Mr. Kilham believes multinational drug companies underutilize the medicinal properties in plants. They pack pills with artificial compounds and sell them at huge markups, he says. He wants Westerners to use the pure plant medicines that indigenous peoples have used for thousands of years.
“People in the U.S. are more cranked up on pharmaceutical drugs than any other culture in the world today,” Mr. Kilham said. “I want people using safer medicine. And that means plant medicine.”
Unpacking those statements is a chore, though. Just to pick a big one, “pure plant medicine” is a tricky concept, as any natural products chemist will tell you. Are we talking ground whole plants here (and if so, which parts, grown where?) Extracts (and if so, which fractions?) Purified single compounds?
Moving to the next difficulties, would these plant medicines somehow not be sold at such huge markups? Take a look at the herbal supplement industry for a reality check on that one. And if we in the drug industry could get such drugs with less trouble and effort than our “artificial” ones, why wouldn’t we do so – especially if they have fewer side effects? (Side effects cost us money, too, you know). Finally, are those natural compounds really safer than the nasty artificial ones? Not as far as I’ve ever seen – they come out the same in genotoxicity studies, for one thing. The whole “artificial” versus “natural” division is generally a sign of lazy thinking, in my experience. There’s no wholesome Gaia-derived goodness to be found in a plant-derived natural products, and they weren’t somehow made for us to use as medicines. Some are harmless, some are toxic – same as everything else.
Then there’s this interesting part:
“So-called bioprospectors can make their fortunes by bringing those advantages to the attention of companies who identify the plant’s active compound and use it as a base ingredient for new products that they patent.
Some 62 percent of all cancer drugs approved by the Food and Drug Administration come from such discoveries, according to a study by the United Nations University, a scholarly institution affiliated with the United Nations.”
Hmm. Examples? The only “bioprospector” that I can recall making a fortune in this way was Russell Marker, the founder of Syntex, who realized that Mexican yams contained an excellent starting material for steroid synthesis. Mind you, that was in 1944. If anyone has a more recent example of an Indiana Jones figure stumbling out of the jungle clutching a profitable wonder root, please do let me know. Whole companies have been founded on the idea of cashing in on active natural products and indigenous medicines. None of them, as far as I can tell, have made any fortunes yet, and some of them have done the reverse. Shaman Pharmaceuticals is the obvious example. I know someone who was right in the middle of their drug discovery effort. It wasn’t pretty, and it sure wasn’t profitable.
Besides, the Times reporter should have asked Kilham himself about cancer therapies. Here's a 2005 interview with him:
"I don't see the cancer herb category becoming a major category any time soon. I believe that the majority of people who get cancer are still going to turn to a conventional medical doctor. I think the greatest majority will. . ."
And that study by the UN doesn’t appear to have dug all that deeply. (It should be noted up front that oncology and anti-infectives are the two areas where natural product-derived compounds are by far the most well-represented). That 62 per cent figure for cancer drugs would seem to come directly from this 2003 paper in the Journal of Natural Products, from a group at the Natural Products branch of the National Cancer Institute. A closer look at the figures show that they list 140 drugs available over the years 1981-2003 (note that many of these are no longer first-line therapies). The 62% figure comes from excluding all the antibodies, proteins, and vaccines (10% of the total) and counting straight natural products (14%), semisynthetic compounds derived from them (26%) and synthetic compounds whose active pharmacophore came from a natural product lead (14%).
You can draw the line wherever you like, but by rigorously crunchy standards only that first 14% qualifies. If we’re going to draw some line between “natural” and “artificial”, everything else is on the other side of it. There’s no denying that natural products are and have been a great source of active compounds and structural leads, of course. But the vast majority of drugs come from us chemists, cranking out the man-made (and man-improved) structures.
The other problem with that number is that, if anything, it may represent a peak. The kinase inhibitors that have been approved in recent years are all completely synthetic compounds, and the antibody and vaccine ranks are swelling, too. Ranked by sales, there are 19 oncology drugs in the most recent top 200 list I can find, and only one of them is a straight natural product (taxol, at #169). Taxotere, at #37, is a semisynthetic derivative of taxol, and irinotecan at 122 is a semisynthetic as well. But to my eyes, that’s about it. Getting data by usage is harder (without paying for it!), but the older natural products would come out looking better ranked by total prescriptions filled. In most cases, though, they’re no longer first-line therapies.
So natural products aren’t dead, by any means. But they aren’t an untouched gold mine, either. Someone tell the Times.
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October 29, 2007
Posted by Derek
There’s been a steady stream of reports in the news about methacillin-resistant Staph. aureus. It’s not a new problem, but (like other nasty infections) it does get a lot of press when the media start paying attention. Works in reverse, too – on the viral front, have you noticed the much reduced number of bird-flu-will-kill-us-all stories this year as we head toward winter? This despite the likelihood of bird flu killing us all being as high (or low) as ever, as far as I can tell.
But the resistant bacteria problem is certainly no joke, and there doesn’t seem to be any reason why it won’t gradually get worse over time. It struck me the other day that antiinfectives, as a drug research field, might be moving toward a similar spot to oncology. In both cases, you have a problem with rapidly multiplying cells, giving you a serious medical outcome - often in cancer, and increasingly with infections. The average tumor is a lot more worrisome than the average infection, of course, but that’s something we can only say with confidence in the industrialized world, and we've only been able to say it for the last sixty or seventy years. As cancer gradually becomes more manageable and infections gradually become less so, the two might eventually meet – or even switch places, which would be bad news indeed. (In some genetically bottlenecked species, in fact, the two problems can overlap, which is fortunately extremely unlikely in humans).
There are, of course, a lot of differences between the two fields, not least of which is that you’re fighting human cells in one case and prokaryotes (or worse, viruses) in the other. But many of those differences actually come out making infectious diseases look worse. The transmissibility of bacteria and viruses make them serious contenders for causing havoc, as they have innumerable times in human history, and they can grow more quickly in vivo than any cancer. It’s only the fact that public health measures allow then to be contained, and the fact that we’ve had useful therapies for many of them, that makes people downrate the infectious agents. If either (or both) of those change, we’re going to be rethinking our priorities pretty quickly.
What this means for drug development is that some researchers will have to rethink their attitudes towards antiinfective drugs. For serious infections, we're going to have to think about these projects the way we've traditionally thought of oncology agents - last-ditch therapies for deadly conditions. Anticancer therapies have long had more latitude in their side effects, therapeutic ratios, and dosing regimes, and antibiotics for resistant infections are in the same position. For some years now, there's been a problem that new drugs in this field would perforce have small markets, since they'd be used only when existing agents fail. That market may not be as small as it used to be. . .
Comments (13)
+ TrackBacks (0) | Category: Cancer | Drug Development | Infectious Diseases
September 17, 2007
Posted by Derek
As I was mentioning the other day, the latest issue of Nature Medicine has the details on a story that doesn’t, on the face of it, do the industry any credit. About twenty years ago, there were reports out of China that a solublized form of arsenic was very effective in treating acute promyelocytic leukemia, a rare (and fatal) form of the disease. Arsenic had been used as a folk remedy for such conditions, as it has been for many others (often with much less justification!), but its most common compounds (like arsenic trioxide) are tremendously insoluble. The Chinese authors had found a way to make that one go into solution where it could be dosed, but didn’t disclose it in their publication.
That left the door open to someone else, namely a small company called PolaRx. They found a way to do the same thing with the oxide (as far as anyone can tell), and got a patent on its use in oncology. Over years, mergers, and reshuffles, the patent finally ended up in the hands of Cephalon, who now market the soluble arsenic trioxide. However, a course of treatment costs about $50,000, which means that for many patients around the world, the drug is totally out of reach.
Even across the entire world, there aren’t that many patients for this therapy, so the price would tend to be high no matter what. It’s worth remembering that production costs are not a major factor in the pricing of most drugs. We’re not indifferent in this business to how much it costs us to make something, far from it, but we try to keep that a small part of the price. So what does set the price? What sets the price is what sets most prices in this world: what the market will bear. A drug that only treats a small number of patients every year is going to cost a lot of money, no matter what it’s made out of. A company will not market a compound unless they can use its profits to help defray the costs of all the things that don’t make it to market at all.
Cephalon is charging what their market will bear, which is their right, but their market is the health insurance organizations of the industrialized world. That’s another thing to remember – drug companies aren’t selling direct to patients most of the time. They’re selling to insurance companies, and first-world health insurance will put up with a lot of things that no one else can or will. There’s a lot of room to talk (and to complain) about this (I think it distorts pricing signals something fierce), but all the complaints have to start with the realization that this is how things are now set up. Cephalon, for its part, says that it’s open to compassionate use of its drug – that is, providing it to people in need who absolutely cannot afford it. With any luck articles like the Nature Medicine one will help to get the word out about that, and we’ll see how well they follow through.
It’s tempting to blame the patent system for this whole situation – after all, the only reason the company can charge these prices is that they’re the only ones who can sell it, right? But perversely, this might actually show the need for more use of patents rather than less. As another piece in Nature has helpfully reminded people, patents not only grant a period of exclusivity. In return for that, you have to tell people how to replicate your invention.
The alternative, in countries that don’t follow this system, is usually secrecy, and I can’t help but think that this is why the original Chinese work didn’t disclose all the details. A strong patent system eliminates a lot of trade-secret grey areas: someone owns a discovery (for a predetermined period of time), no one owns it, or everyone owns it. There’s none of this “someone owns it until someone else finds out about it” stuff.
But my guess is that the Chinese lab, being used to a trade-secret (or government-secret) culture, reflexively held back their important details. If they wanted to make sure that no one could patent anything, they would have (or at least should have) put all the information out into the public domain, where it would have been prior art against anyone attempting to file on it. (But see below - would that have helped get it through clinical trials, or not?) It’s worth noting that if a patent had been filed back in the early 1990s, the drug would not only have come to the world’s markets faster, the patent would also be much closer to expiration by now, opening up its production. The US researcher who formed PolaRx and filed the patent, Raymond Warrell (now chairman of Genta), stands up for it in the Nature Medicine article, and like it or not, he has a point, too, saying that the patent stimulated interest in the compound: "Without the patent, it would have remained a curious Chinese drug, not available to anyone else." I should note that there may well be room to argue about the validity of the patent, from prior-art concerns, but no one (as far as I know) has seen fit to challenge it.
But I can say for sure that without intellectual property protection in the US and Europe, no drug company would have touched the compound. Without industrial input, the drug would have either never reached the market at all (arsenic trials were a hard sell at the FDA), or would have likely come on more slowly. (That ticking patent clock does keep an organization moving, I can tell you). And now its success in the market has other companies working on improved versions of the therapy. This is how our world works, and (for better or worse) there's no requirement that it be aesthetically appealing.
Comments (8)
+ TrackBacks (0) | Category: Cancer | Drug Development | Odd Elements in Drugs | Patents and IP | Why Everyone Loves Us
August 20, 2007
Posted by Derek
As I've mentioned before, advances in molecular biology have continued to make all sorts of brute-force approachs possible - things that would have been laughed at (or, more likely, not even proposed at all) a few years ago.
Another recent example of this is a paper earlier this year in Nature from the group of Michael White at UT-Southwestern. The authors selected a lung cancer cell line that's know to be very sensitive to Taxol (paclitaxel), and looked for possible targets that might increase the drug's effectiveness. (It's a good compound to pick for a study like this, since it's simultaneously quite effective and quite toxic).
So, how do you go fishing for such combinations? These days, you set up 21,127 experimental wells, each one contained some cells and some silencing RNA molecules targeting, one at a time, 21,127 different human genes. And you look to see if knocking down expression of any of those genes increased the potency of a normally ineffective dose of the drug. (There were four different siRNAs per gene, actually, and each one was run in triplicate with and without Taxol, leading to a Whole Lotta 96-well plates. I'm glad I'm not paying for all the pipet tips, I can tell you that for sure.)
As you'd imagine, working up the data from this kind of thing takes as long, or longer, than setting one up. After comparing everything to the control wells and to each other several different ways, they ended up with 87 candidate genes whose knockdown seems to make the drug more effective. Gratifyingly, many of these make one kind of sense or another - there are several genes, for example, that are known to be involved in spindle formation, which is the target of paclitaxel itself.
Even more interestingly, not all the hits were obvioius. Another group of genes code for parts of the proteasome. That part of the cell is targeted by Millennium's Velcade (bortezomib), and it's recently been reported that the combination of Velcade and paclitaxel is more effective than expected. And there's another combination that seemingly hasn't been tried at all: the experiment suggests that inhibitors of vacuolar ATP-ase should synergize with Taxol, and (as it happens) a compound called salicylihalamide A has been looked at for just that target. They tried this experimental combination out on the cells, and it seems to work well - so, in humans?
As a commentary in the New England Journal of Medicine on this work dryly put it, "This hypothesis should be tested." And so it should. I've always had doubts about how far one can extrapolate cell data in cancer studies, but this kind of thing will tell us for sure. If something hits from this work, more such studies will come pouring out - they're getting easier to do all the time, you know. . .
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+ TrackBacks (0) | Category: Cancer | Drug Assays
June 4, 2007
Posted by Derek
We have a new phrase to toss around in in the industry: "Phase Zero". That's what they're calling a recent trial of an anticancer drug from Abbott (ABT-888), which was tested in humans before any safety dosing (Phase I) had been done.
So, how exactly can you do that? By giving extremely small amounts of the drug, that's how, and looking to see if you can detect a change in some marker for eventual efficacy. In this case, the marker was inhibition of the activity of PARP, poly(ADP-ribose) polymerase, which is involved in the cellular response to DNA damage. Inhibiting it should make cells much more likely to die once such damage had been detected, which one of many such signals that cancer cells tend to ignore under normal conditions. Abbott's drug seemed to do the trick, so work on it will continue.
The good part of this is that the drug got into humans more quickly than usual, and that its mechanism of action has now been verified (to a first degree of approximation, anyway - it hits the target). This should make a company a bit more confident about moving on to larger trials, and could potentially weed out losers early in the game.
But there are bad parts, too. For one thing, the patients in a phase zero trial have no hope of benefit from the drug: the dose is just too small. The small doses could give results that (for better or worse) aren't relevant to the later real-world ones, too. Another problem is that reliable biomarkers are thin on the ground despite great sums of money being spent to find and validate them. If you're going to let the future of your drug ride on one of these trials, you'd better be confident that you know what it's telling you. (And if you're not going to let the future of the drug ride on a phase zero trial, why are you running one, eh?)
What would be worth knowing is how many drugs fail because of lack of effect on their intended target, as opposed to those which hit the target but still have no effect. You'd also want to know: of that first group, what portion are going to be amenable to robust biomarker studies. Those two fractions would tell you how much of an impact this whole idea will have. Right now, I think the error bars are way too large to make a prediction. . .
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+ TrackBacks (0) | Category: Cancer | Clinical Trials
April 19, 2007
Posted by Derek
If you want to see a bunch of press releases from biotech companies that you've never, ever heard of in your life, just go over to Google News and type in "AACR", sorting by date. That meeting just wound up, and it was the usual fiesta of early- and late-stage oncology data.
But cancer is an odd field for drug development. There are (relatively speaking) many more targets, since the disease itself is a huge fragmented bunch of different indications. And we don't have nearly enough knowledge to have a good idea - any idea, most of the time - about which of these targets are more likely to work, and against which forms of cancer. The trials themselves tend to be smaller (thus cheaper), since the course of the disease is often so relentless, and if you get a drug to market, you don't have to take out ads on the Super Bowl to promote it to oncologists.
All that means that the entry barrier to the field is lower, and there are plenty of niches. And boy, are they filled by a lot of microscopic companies. I keep up with things fairly well, but there are outfits presenting at AACR that might as well be from the asteroid belt for all I know about 'em. . ..
Comments (5)
+ TrackBacks (0) | Category: Cancer
April 11, 2007
Posted by Derek
Amgen's not getting a lot of good press these days. They're famously the House that EPO built, but (in a familiar story) they may have pressed their lead franchise too far. An excellent backgrounder can be found here at Nature Biotechnology. In short, the company was coining money in the renal market, and looked for new areas where EPO could be of use (and of profit). Chemotherapy-induced anemia looked like a winner, and Amgen aggressively promoted EPO's use in oncology. (Correction - the real extension was into cancer-associated anemia, not just that induced by chemotherapy. See the comments for more - DBL). But (as the editorial details), this whole strategy is backfiring disastrously.
First off, anemia doesn't appear to be a major cause of chemotherapy side effects. If that weren't bad enough, a series of clinical trials have shown that patients receiving standard therapy plus EPO do worse than usual. As of last month, all forms of EPO now have a new black-box label warning. Not ugly enough yet? OK, the company has admitted that it knew about some of this data but didn't talk about it for months. The SEC is investigating them for that decision, and Medicare is looking at whether the company has been overcharging. Their CFO just announced that he's "pursuing other interests".
A sample of the Nature B. editorial makes its point well:
"Amgen does not come out of this well. Although seeking new indications for existing medicines is clearly a valid strategy, the company appears to have miscalculated the balance between expansion and the risks to its existing business—and potentially opened itself to charges that it has recklessly endangered patients' lives. . .
Furthermore, Amgen has surely miscalculated strategically. Any benefits from the commercial push to extend Aranesp into new oncology markets are likely to bring relatively modest returns—Aranesp's 2006 sales in cancer-associated anemia, for example, were approx. $500 million. But the repercussions of failure will be felt not only in cancer but also potentially across all EPO markets. A proportion of the whole $7.1 billion Epogen and Aranesp franchise—nearly 50% of Amgen's total revenue in 2006—is thus under threat."
Amgen isn't the first drug company to have over-reached. Everyone's going to try to make the most of their existing drugs, especially when there aren't all that many things coming along to replace them. But readers with some classical background may well think of Croesus crossing the Halys every time they hear about this kind of thing. . .
Comments (11)
+ TrackBacks (0) | Category: Business and Markets | Cancer | Why Everyone Loves Us
April 5, 2007
Posted by Derek
Cancer drugs have a terrible history in clinical trials. The most definitive figure, from development candidates of the 1980s and up to the mid-1990s or so, was a cold, hard, 95% failure rate. That beat even the central nervous system (CNS) drug category, which is a spacious haunted mansion all its own. One reason for this is that all kinds of things get thrown at oncology targets, because there's so much unmet need in the category. Whenever someone comes up with a new technology - monoclonal antibodies, antisense DNA (or RNA interference), disease-altering vaccines, etc. - you can bet that someone's going to try it out on a cancer target. Not all this stuff is going to work, needless to say.
But I wonder if that figure still holds. Starting later on in the 1990s, and gathering speed ever since, a lot of the small-molecule drug candidates in the cancer area have been kinase inhibitors. Now, back when I took my first pharma job, those compounds weren't in very good favor, partly because the key structural motifs that everyone uses today hadn't been worked out yet. If you mentioned kinase inhibitors in the labs, likely as not someone would spit in the sink and say something rude about staurosporine.
That was one of the early potent kinase inhibitors, a fairly nasty natural product. (Note: outdated web page in that link, which fits the subject). All sorts of people worked on staurosporine-like compounds during the 1980s and beyond, and most all those projects came to grief of one sort or another. It gave the whole field an unhealthy look.
There were also good reasons to think that no really selective kinase inhibitors could be discovered (since the enzymes have many structural similarities), and that the resulting broad-spectrum compounds would have just too many side effects to be useful. But molecular biology was uncovering a role for many kinase enzymes in cancer and other disease states, so people kept taking a crack at the area, and finally some far less ugly compound classes were discovered that broke the field open. Once decent compounds were in hand, it was found that they weren't as toxic as everyone had feared. Selectivity was still an issue, but you could sort of tune the structures to inhibit various groups of kinases over others.
I would not want to hazard a guess as to how many kinase inhibitors have gone into development over the past ten or twelve years. It's a pile, for sure - just look at KinasePro and Xcovery to get the idea. I will guess, though, that they haven't failed at quite that horrific 95% rate, and that a 1995-2010 survey of the field will show an improvement. Mind you, the record-holder in the earlier survey was, cardiovascular area, where only about 85% of the compounds collapsed, so don't think I'm talking about a huge increase. But when only one out of twenty of your drugs makes it, getting up to two in twenty means that you have twice as many drugs.
Comments (11)
+ TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History
April 3, 2007
Posted by Derek
You know, small-molecule folks like me are going to have to learn to deal with immunology. I don't mind saying that it's not my field - yet - but who knows, perhaps it will be. The recent successes of Dendreon and (today) Cell Genesys prompt these thoughts. Both companies have shown useful efficacy with immune-based prostate cancer therapies, good enough to make you wonder how effective these things will eventually be when we understand more about what's going on.
As things stand, there are a bewildering number of possibilities. Both of these vaccines depend on production of GM-CSF secreting cells (a powerful cytokine which stimulates white blood cell production and activity), but they're rather different otherwise. Dendreon's Provenge is autologous, that is, derived from each patient's own cells, for one thing, while the Cell Genesys GVAX vaccine isn't individualized at all (that is, allogeneic). That's just the first choice to make. There are all sorts of options about what kinds of cells to use, which antigens to decorate them with and what proteins to have them secrete, how to administer them to patients singly and in combination with other conventional chemotherapies, and so on. This work has been going on for years now, and I've no doubt that a lot of blind alleys have been followed. And a lot more will get followed, too, but the results so far are pretty impressive. They're beating the small-molecule conventional therapies in the difficult cases, that much is clear. It's important to remember that the patients are still dying of cancer, but they're taking noticeably longer to do it, which is success in our era.
We'll probably see a rush into the stocks of every company that has both "cancer" and "vaccine" in its 10-K filings, but I'd say be careful. For example, if you bought Cell Genesys last week, you're quite happy. But if you bought it this time last year, you're still in the red. Although I find these current results quite interesting, the field is still very young indeed. Companies are targeting prostate cancer because it's a non-essential organ (so it doesn't matter if the immune system trashes it), but they're also going to be going after tumors in rather more vital organs like the lung and pancreas. Development of immune therapies in those areas is going to be full of more excitement than some of the stockholders will be ready for.
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+ TrackBacks (0) | Category: Business and Markets | Cancer
April 2, 2007
Posted by Derek
Here's something that you don't see discussed very often, but it's worth some thought: what kind of personality do you need to have to do drug discovery research? Clearly, any conclusions are going to carry over well to other fields, but drug work has some peculiarities that can't be ignored.
The most obvious one is that the huge, horrible, overwhelming majority of projects never lead to a marketed drug. Many readers will have seen the sobering statistics of 85 to 95% failure rates in the clinic, but (bad as that is) it doesn't get across the number of times that projects get nowhere near the clinic at all. Take it from the top: the majority of targets that are screened for chemical matter don't turn up anything useful (it's not even close). The majority of the ones that do still die on their way to clinical trials. And then a solid 90% of those don't make it to market.
So, if you define yourself as a success by whether or not you've put something on a pharmacy shelf, you've set a very high bar, one that many people in basic research don't reach. It's different for people further down the line, where the field has already narrowed. But if you're working on early med-chem, for example, you're likely to go years between realistic shots at a drug you can claim part of the credit for.
That'll vary by your company's culture, too. Some companies bang out projects like a sawmill spitting out boards - or try to, anyway - while others carefully take their time for years and years. There's no certain advantage to either method, as far as I can see (else the companies doing the best one would have taken over by now and driven other modes out of existence). But you'll certainly have more shots on goal at the first type of company, which might keep your spirits up. Of course, the fact that you're largely going to be getting more chances to fail in the clinic might just depress them again, so you have to take that into account.
It'll also vary by therapeutic area. Central nervous system projects are going to run slower than oncology ones, by and large. In cancer, the clinical goals are comparatively clear, and where the disease is often (and most terribly) progressing at such a pace to give you solid numbers in a reasonably short period. Contrast that to Alzheimer's disease, for example, whose ruinous clinical trials could take years to tell you anything useful. Cancer will also give you more shots per compound, since a drug that does zilch for pancreatic cancer (and most do just that) might be useful in the lung or liver. While what we call cancer is several hundred diseases, what we call Alzheimer's might only be one. Depression and schizophrenia are clearly more complicated and split up, but (as opposed to cancer), there's no easy way to tell how many types there are or what particular one a patient might be presenting with, so the clinical work is correspondingly more difficult.
So, this is the pharmaceutical world you're going to have to live in. If you take each drug project personally, as an indicator of your own worth, you're probably not going to make it. You'll be beaten down by the numbers. As an antidote, a bit of realistic fatalism is helpful, although too much of it will shade into ah-that'll-never-work cynicism, which is the ditch on the other side of the road from prideful optimism. I'd recommend learning to enjoy the upside surprises, and to not be surprised by the failures (while still looking them over to see if there's something you can avoid next time around). You really have to draw a line between the things you can affect through your own talent and hard work, and the things you can't. Most of the crucial stuff is in the second category. A sense of humor about your own abilities and limitations will serve you well. But that goes for a lot of other jobs besides the drug business, doesn't it?
Comments (15)
+ TrackBacks (0) | Category: Alzheimer's Disease | Cancer | Drug Development | The Central Nervous System | Who Discovers and Why
March 26, 2007
Posted by Derek
Amgen served up a nasty surprise on Friday with the results of a trial they're running on their Vectibix (panitumumab) cancer therapy. It's an EGFR inhibitor (same space as Imclone's Erbitux) and this trial was the first to test a "dual biologics" approach to colon cancer. One group got the standard of care (oxaliplatin and irinotecan chemotherapy, plus Genentech's Avastin VEGF inhibitor), and other other got that plus Vectibix.
Unfortunately, in one of those unexpected results that cancer trials are always delivering, the two-protein-therapeutics group actually showed slightly worse survival data than did the standard-of-care group, and that takes care of that. By itself, this result isn't enough to call Vectibix a failure by any means. But its expected rise to overshadow Erbitux has clearly been delayed.
Imclone's stock price reflects this. Does it ever - my modest short position in their stock is now underwater good and proper. Their stock's up 45% so far this year, with a lot of that in just the last two weeks. But these are early days (he said to himself abstractedly, looking out the window with his brokerage statement in his lap). Both drugs are in similar Phase III trials against colorectal cancer (as that first link, to Bioworld Today, details) and eventually we're going to have about as good a head-to-head comparison as you can expect in this area. Whether that'll be enough to decide anything, well. . .
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+ TrackBacks (0) | Category: Business and Markets | Cancer | Clinical Trials
February 12, 2007
Posted by Derek
So, you're asking yourself, "Why do people invest in biotech and small-pharma stocks?" You could especially ask yourself that after reading this New York Times article from Sunday, which describes how Xoma (yep, they're still around) has vaporized $700 million dollars, and counting, in its 25-year history.
Well, here's why: as I write this, Onyx Pharmaceuticals is up a solid 90% on the day. They're partners with Bayer on the kinase inhibitor Nexavar (sorafenib), and the companies today reported positive data in treating hepatic cancer. This wasn't long after the drug had pretty much whiffed on melanoma, so the news came as a bit of a surprise (thus that 90% updraft).
My guess is that it came as a surprise to the people doing the study as well. Liver cancer is a bigger market than anything that Nexavar is approved for, and you'd think that it would have been one of the first trials run if it were considered a high-percentage play. But cancer is tricky, and we don't understand it worth beans. You have to do the experiments, and you have to realize going in that you only have a vague idea of how they might go.
So that's one reason that biotech stocks continue to get buyers - for the same reason that lottery tickets do. It would be interesting to know which one has returned more money over the years, although I'm afraid I already know the answer. But long-term, biotech has the edge, because (slowly and with infinite pains) we're learning what we're doing. . .
Disclosure: I have a financial interest in Bayer stock - I have no exposure to Onyx (damn it all) or Xoma.
Comments (17)
+ TrackBacks (0) | Category: Business and Markets | Cancer
February 5, 2007
Posted by Derek
Here's an interesting press release on a potential new class of anticancer drugs. It has a nice hook ("Lab mistake leads to cancer finding!"), and the work itself isn't bad at all. It's an neat biochemical result, which might eventually lead to something. You have to know a bit about drug discovery and development to spot the problem, though - and not that many people do, which provides the ecological niche for this whole blog, frankly.
The discovery (from the University of Rochester) has to do with PPAR-gamma compounds, an area of research I've spent some time in. I didn't spend enough time there to understand it, mind you - no one has spent enough time to do that yet, no matter how long they've been at it. I wrote about some of the complexities here in 2004, and things have not become any more intelligible since then. The PPARs are nuclear receptors, affecting gene transcription when small molecules bind to them. There are, however, zillions of different binding modes in these things and they affect a list of genes that stretches right out the door. Some get upregulated, some down, and these vary according to patterns that we're only beginning to understand.
The Rochester group found that a particular class of compounds, the PPAR-gamma antagonists, had an unexpected toxic effect on some tumor cell lines. Their tubulin system was disrupted - that's a structural protein which is very important during cell division, and is the target for other known oncology drugs (like Taxol). The PPAR ligands seem to be messing with tubulin through a different route than anyone's seen before, though, and that definitely makes it worth following up on.
But the tone of the press release is too optimistic. (I should turn that line into some sort of macro, since I could use it twenty times a day). It mentions "high-dose" PPAR antagonist therapy as a possible cancer treatment, but take a look at the concentrations used: 10 to 100 micromolar. Even for cells in a dish, that's really hammering things down. And there's hardly any chance that you could attain these levels in a real-world situation, dosing a whole animal (or human). As blood levels go, those are huge.
But how about using more potent compounds? Of the three that are mentioned in the paper, BADGE is pretty dead, but the other two are actually quite potent. Tellingly, nothing happened at all with any of them up to 1 micromolar. These things will mess with other PPAR-gamma driven processes at much lower concentrations, so you have to wonder what's really going on here. And keep in mind that other PPAR compounds whose mode of action is roughly the opposite of these have been suggested as potential anticancer agents, too - this sort of thing happens all the time with nuclear receptors, and reflects their head-grabbing complexity.
This is still worth figuring out; don't get me wrong. There might be a new mechanism here that could lead to something, eventually, although it looks to be a tough problem. But that's the part of this work that's interesting - the level of activity seen here isn't. If I had a dollar for every compound that affects tumor cells at 50 micromolar, I wouldn't need to be sending my CV out these days.
Comments (5)
+ TrackBacks (0) | Category: Cancer | Drug Assays
January 11, 2007
Posted by Derek
If you're on the editorial staff of J. Med. Chem., and you've got one of those "Perspective" review articles to go over, and it's on the very important (and very complex) topic of the binding of kinase inhibitors, something that's going to catch the eyes of lots of people all over the place. . .wouldn't you (and your referees) want to make sure that the paper has the correct structures in it? Even down to the level of obscure drugs like, say, Gleevec? Kinase Pro is just asking. . .
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+ TrackBacks (0) | Category: Cancer | The Scientific Literature
January 10, 2007
Posted by Derek
I've noticed a few stories making the rounds recently about possible new cancer therapies. Johns Hopkins has press-released the work of a group there on, and several news outlets have picked up on a British study on the effect of vanilloid agonists (such as the hot-pepper compound capsaicin) on cancer cells.
And all this is fine, until the word "cure" starts being tossed around. It always is. The number of times you see it, though, is inversely proportional to how reliable your favorite news source is. I wish the Nottingham and JHU people all the best in their research, and I hope that their projects lead to something good. But they have a long way to go, which you might not realize from the "Johns Hopkins Patents Cancer Cure" and "Hot Peppers Can Cure Cancer" headlines.
You see, these studies are all on cell cultures. I've worked on several cancer research programs, and I'm sure that other readers who've done the same can back me up here: unless you've seen cancer drug discovery work at close range, you may have no idea of just how many compounds work against cancer cells in a dish. It isn't that hard. I have absolutely no idea of how many thousands of compounds I could dig up from our files that will just totally wipe out a lot of the common cancer cell lines - in culture, that is.
We don't even bother looking at a compound unless it goes through cultured cell lines like a flaming sword. Problem is, a good number of those compounds will go through normal cells in the same fashion, which isn't exactly what the oncology market is looking for. And of the ones that are left, the ones that aren't hideous toxins - well, a lot of those hit the skids when they go into a live mouse model. Drug candidates that rip through the cell assays but fizzle in the mouse are very easy to come by. Anyone who does oncology drug discovery can furnish you with piles of them, and you're welcome to the darn things.
Now comes the really ugly part. We've ditched the nonselective cell killers, and we've shaken out the compounds that can't cut it in a live animal. How many of these actually work in human beings? Nowhere near as many as we'd like, that's for sure. AstraZeneca's drug Iressa is always useful to keep in mind. That one was going to be a huge hit, back when it was in development. But in real patients, well. . .for the vast majority of them, it just doesn't do much at all. There are a few responders (some of whom we can screen for), but otherwise, you'd have to call the compound a massive failure in the real world. Oh, but you should see it kick through the cell assays, and watch what it'll do for the mice.
Our assays just aren't that predicitive. It's a big problem, and everyone in the field knows it, but so far (despite crazy expenditures of time, money, and brainpower), no one's been able to improve things much. Anyone who does cancer work knows not to celebrate until the human trials data come back, and you'd better be careful even then. So the next time you read about some amazing thing happening to cells in a dish, well - wish the researchers luck. And go back to what you were doing before. There's time.
Comments (11)
+ TrackBacks (0) | Category: Cancer | Drug Assays | Drug Development
November 20, 2006
Posted by Derek
Since I mentioned a little while ago that I'd gone short Imclone stock (at $29 and change), it was heartening to see Gretchen Morgensen make the exact same case against them in the New York Times on Sunday. (Subscriber link). The article makes much of the company's recent patent troubles, and the competition for their lone drug, Erbitux:
But neither the new competition from Amgen nor the legal ruling on the Yeda matter seems to worry the hopefuls who have bid up ImClone shares in recent weeks. These speculators also appear undaunted by results earlier this month from a drug trial in patients with midstage colorectal cancer. ImClone had hoped that the trial would show a survival benefit; it did not.
Two analysts, at Merrill Lynch and Citigroup, predicted that the trial results would mean stagnant market share for Erbitux and growth prospects for Vectibix. Both analysts rate ImClone a “sell.” Bristol-Myers Squibb, which owns 17 percent of ImClone, said in its most recent quarterly filing that Yeda might seek damages for infringement on past Erbitux sales and royalties on future sales of the drug. If Yeda licenses its patent to other companies, Bristol-Myers acknowledged that new competition for Erbitux would arise, but added that it was too early to tell what impact such a development would have on its business.
Investors are going to have to catch up with therapeutic reality here: Erbitux is a drug of limited utility. All cancer drugs are, unfortunately. "Cancer" is a catch-all term for hundreds of distinct disorders of cell division and growth, and no one drug is likely to be efficacious across much of that range. Even in its best applications, though, Imclone's drug is only fair-to-good. Meanwhile, progress in the field (though incremental) is very real, and every slightly better compound that comes along is going to capture a lot of market share.
So when I hear Carl Icahn going on about how he wants the company to step up its marketing efforts, I have to roll my eyes. The thing is, to some extent cancer drugs market themselves. They already sell much more than a purely rational calculation would predict. That's because many clinicians try them all, against all sorts of things, no matter what the label says. And it's not like no one's heard of Imclone or Erbitux, so there's only so much that a whiz-bang selling campaign can accomplish. Icahn is trying to apply the lessons he's learned from other industries to pharmaceuticals, a tempting idea that has sent more than one R&D-based organization rolling off the edge of the table.
I know that I've linked to this post of mine several times - it's the one where I talk about all the times I've told people to sell Imclone. But you know, it's been good advice. After all, I took it myself, and I didn't even own the stock. . .
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+ TrackBacks (0) | Category: Business and Markets | Cancer
October 30, 2006
Posted by Derek
Here's my latest contender for an award in the highly competitive Desperate Press Releases category: Albany Molecular says that it has an anticancer compound. Well, it has one that's going to move into "advanced preclinical testing", and if everything goes perfectly, they'll try to submit an IND by the end of 2007. Which means that the first bit of Phase I testing, the toe-in-the-water look at blood levels, can be realistically expected no sooner than sometime in 2008.
The headline is "Albany Molecular to Test Cancer Compound", which the unwary might suppose means that they're going to test it against, well, human cancer. But who knows when that might happen, because I read the press release to mean that the compound hasn't even gone through real small-animal toxicity testing. Is that a long way from human cancer patients? Is Auckland a long way from Albany?
Now, I understand that AMRI hasn't been down this road too many times before. Looking at this chart, it appears that this project is the most advanced they have, and I don't recall them ever heading for the clinic before. That's because the company has been mainly an outsourcing venture, a place to get compounds and libraries made for you. With that business model under pressure, they've decided to give in to temptation and become a drug company.
It's not an easy living, and they're just getting started at it. The programs they have listed are all at the seedling stage, just barely edging into reality by the standards of people who've seen things crash in Phase III. There are probably plenty of people at AMRI who feel the same way, actually - I know that they have a number of scientists and managers who've worked at other drug companies over the years. They know the score, even if their PR department doesn't.
The compound being trumpeted today is said to be a tubulin inhibitor, which puts it in the same class as the taxanes. That's an interesting cancer target, and it's not always easy to get good chemical matter against it. Still, there have been a lot of compounds reported over the years, many of which have never been heard from again. Here's a recent review (PDF, which may be subscriber-only) on the compounds that are already in the clinic. It's a tough area, and not exactly an uncrowded one.
But really, good luck, guys. I hope the compound makes it through the mice, and the rats, and the dogs, and histopathology and formulation and GMP scale-up and all the rest of the whirlpools. Just try not to press-release the world every step of the way, OK?
Comments (8)
+ TrackBacks (0) | Category: Business and Markets | Cancer
October 9, 2006
Posted by Derek
A few miscellaneous notes this morning: I had an e-mail from a reader who asks "Why is Imclone stock worth anything at all?" He was referring to the competition they're now facing from Amgen, and the managerial turmoil that's been going on for months now. For my part, I think that IMCL is worth something, but I sure don't think it's worth $29.44/share, which is where I went short on Friday. (In the future, if I write about them, I'll make note of that fact each time in the interest of disclosure). I realize that this puts me on the other side of the fence from Carl Icahn, a person whose stock-picking judgment I might normally defer to. But in this case, I think I may know more about cancer therapies than Icahn does. We'll find out.
On an unrelated topic, I have a request. Does anyone know of a commercial source for a library of diverse phenyl carbamates? I realize that that's not the usual sort of diversity library - if I were after secondary amines, the offers just wouldn't stop. I can find scattered examples from various suppliers, but if someone had a bunch already collected, it would be a great time-saver. Any ideas?
But finally, though, physics is more on my mind than chemistry this morning. I'm digesting the unpleasant implications of this map, courtesy of the US Geological Survey. . .
Comments (2)
+ TrackBacks (0) | Category: Cancer | Current Events
September 20, 2006
Posted by Derek
So, it turns out that Imclone doesn't actually own a key patent covering uses of its only money-maker, Erbitux. This case has been dragging on for years in one form or another, a bizarre story well chronicled here at Fortune. This is another case of prior art invalidating a patent:
The trial is the culmination of a strange 20-year saga. It pits three distinguished scientists from Israel's Weizmann Institute against ex-colleague Joseph Schlessinger. . .The scientists accuse Schlessinger of absconding with their idea of combining a monoclonal antibody with chemotherapy, taking it to a corporate predecessor of Sanofi-Aventis, and secretly applying for a patent on it. While the application was pending, Aventis licensed the rights exclusively to ImClone. (Schlessinger denied impropriety and claimed credit for the antibody and the combination.)
ImClone had reason to question who the inventor was as early as 1994, when the U.S. Patent Office rejected its application on the grounds that the Weizmann scientists had published an article describing the combination idea before Aventis filed for the patent. ImClone told the patent office it would provide support for its claim, then dropped the application. The company later refiled, and the patent office relented.
Imclone was never able to back up that claim in the end, so out goes their patent. (The Israeli scientists, as Yeda Research and Development, still have a valid patent of their own which they just licensed to Amgen). This is the sort of thing that I don't think should be patented to start with - I have a big problem with broad method-of-treatment claims - but the prior publication makes that a moot point in this case as far as Imclone's concerned. Analysts are estimating that this loss could cut Imclone's earnings by 10 to 20 per cent, which they certainly don't need.
Carl Icahn, the company's largest individual shareholder (behind Bristol-Meyers Squibb), has seen enough. He was elected to the board of directors today, and lost no time sending an open letter calling for the CEO's head. Icahn's no fool as an investor, but I have to question his judgment in hanging on to his Imclone position with such tenacity. Not that Big Carl cares, but I've been telling people to sell the stuff for a long time now, because I don't like their prospects.
I didn't count on this patent loss, though - I just had them downrated in general. And it seems this opinion is shared by others in the industry. Back earlier this year Imclone announced with great blasts of trumpets that it would entertain offers to be bought. Reaction to this opportunity didn't meet their expectations, though, because in August they took themselves off the block, saying that the offers they'd received had been inadequate. It's especially notable that Bristol-Meyers Squibb didn't see fit to buy them out, especially considering that many of Imclone's stockholding fanatics have always seen that as a safety net.
So if BMS, who know Imclone inside out, doesn't want them, why does Carl Icahn? The stock did make it back to $40 per share after I last stuck my tongue out at it around $34. But now it's at $29. . .
Update: as per the comments, here's an excellent and detailed summary of this litigation from PatentBaristas. There are a lot of odd features to the case - check out the part where the Imclone scientist had a suspiciously good memory of a key conversation from twenty years ago. . .
Comments (10)
+ TrackBacks (0) | Category: Business and Markets | Cancer
September 6, 2006
Posted by Derek
When I tell people that I work for a drug company, they often want to know what disease I'm working on. I've been able to give all kinds of answers over the years, and most of them go over well. Everyone's glad to hear that you're doing research on diabetes, cancer, Alzheimer's or other widespread high-profile problems. Of the areas I've spent time in, cancer probably has the most cachet on this scale, since almost everyone knows of someone who's had serious trouble with one form or another.
The antithesis of cancer's situation is probably obesity. No matter how many headlines come out on its epidemic nature, huge public health consequences, and so on, it still doesn't get you the respect that other indications do. There are several reasons for this, the first of which is the seriousness of the disease, as defined by life expectancy. For better or worse, obesity patients are going to survive for much longer periods than cancer patients.
Scientifically, this actually makes the field more difficult to work in. Frankly, with most of the current cancer therapies, all we can offer is a few more months or (in some cases) years of life for most patients, so until recently long-term side effect issues haven't been a big concern. (Note, though, that this is changing). But obesity therapies are going to be used for longer periods of time. Obesity is associated with a shorter lifespan, true, but the level of obesity that some people are wanting to treat doesn't have that great an effect on mortality, and the survival rate with even morbid obesity is one heck of a lot better than with most kinds of cancer.
Getting back to the seriousness problem, another issue is that for many people, it's hard to shake the image of obesity as something that could be better treated by just eating less food and getting off the couch. I realize that that's not always a fair judgement, and my heart does indeed go out to people who put on weight more easily than the average person. But that said, there can be little doubt that eating fewer calories and doing a bit more exercise would take off untold numbers of pounds nationwide. The question is, as physicians will tell you, is whether anyone is going to do those things. If they can be more motivated by taking an obesity drug along with changing their diet and doing some exercise, then perhaps the drugs will have partially proved their worth. Of course, you could argue that similar effects at that level might be obtained by pills filled with, say, oat bran, billed as wonderful new obesity therapies: Placebatrim, anyone?
No, we're not going to be able to get away with that one. That's a market for the "nutritional supplement" people. An obesity drug from a real pharmaceutical company is going to have to really do something to get past the FDA, and it's going to have to be extremely safe in order to stay on the market. (Thus the current state of the obesity drug market). Anything that meets these criteria will make a huge amount of money. But respect? Fair or not, that might be asking too much. . .
Comments (22)
+ TrackBacks (0) | Category: Cancer | Diabetes and Obesity
June 4, 2006
Posted by Derek
Over the last few years, there's been more attention paid to a problem in cancer therapy that is going to keep us all very busy: drug resistance. Everyone's heard about this topic in reference to antibiotics, and with good reason. But the same thing happens in oncology, which makes sense. Despite a lot of major differences, in both cases we're trying to kill off robust, fast-dividing cells that have a lot of genetic variation in them. Anything that doesn't respond to the drug is going to have an open field in front of it.
The situation in cancer might actually turn out to be worse than in antibiotics, disturbing though that sounds. For one thing, cancer cell lines are often rather genetically unstable, which may well be how they ended up becoming cancer cell lines in the first place. So mutants are pretty easy to come by. Counterbalancing that, they don't have a quick way of transferring genetic material to each other like bacteria do, which means that we don't have to restrict the use of the therapies like we have to with antibiotics. Each patient is an island, fortunately.
The real difficulty is that antibiotics are typically taken for a set course of treatment - you knock the infection down enough to where the patient's immune system can clean up the rest, and everything's done. But cancer therapies, the kind that we're turning out now, are likely going to be more like insulin is for diabetics - you're going to be taking them for a long time, quite possibly for the rest of your life, which gives plenty of time for something bad to happen. It's impossible to know whether all the cancer cells disappear, or whether they're just lying low. So no one's sure yet what will happen ifyou go off of the drugs, and as you can imagine, that's data which is going to be hard to obtain.
Gleevec (imatinib) is a good example. There are all too many patients who have taken the drug for longer periods and have seen it lose its effectiveness, which must be really a wrenching experience. The kinase that the drug targets (Bcr-Abl) turns out to have a number of mutant forms that are unaffected by Gleevec, so any cells that have (or develop) these variants are free to cut loose. Interestingly, it may be the case that Bcr-Abl itself sets up conditions inside the cell that favor development of mutations, which for cancer cells could be something of a survival tool.
The only way around such problems is to make new drugs, just like in the antibiotic field. Two of the most advanced ones are AMN107 (nilotinib) and BMS354825 (dasatinib). Dasatinib had a good ASCO meeting, with an FDA committee recommending its approval, and with new data being presented comparing it head to head with Gleevec. So far, it looks like it's superior to higher doses of Gleevec in CML patients who've started to show resistance, but this is all with blood markers (as opposed to real survival data, which naturally takes longer to come in). But so far, so good.
These might remain useful for longer, since their binding modes are somewhat different than Gleevec, and whole classes of mutant Bcr-Abl forms are still susceptible. But resistance will surely keep cropping up. We're going to be a this for a long time.
Comments (16)
+ TrackBacks (0) | Category: Cancer
June 1, 2006
Posted by Derek
Well, the American Society for Clinical Oncology (ASCO) meeting is almost upon us, and it's time for the annual blizzard of misinformation. I'm not talking about the presentations at the meeting, which are no better or worse than the usual scientific meeting. No, I mean the press releases and subsequent press reports, of which the Reuters item I'm going to highlight today is a depressingly good example.
The headline reads "Big Pharma Expected to Dominate Key Cancer Meeting", which isn't such a good start. Any time you see the industry being divided up into "Big Pharma" and "Biotech", as this piece does, an alarm bell should go off in your head. We need to get clear on what "biotech" means, or dump the term altogether. I'm in favor of the second choice, although that's not going to happen, because all the categories are mixed up, anyway. The tiny-DNA-and-protein versus big-chemical-drug storyline doesn't work so well these days. If Genentech and Amgen aren't Big Something, I'd like to know who is. And on the other end of the scale, was Sugen a "biotech" because they were small (even though they make small organic molecules instead of protein-based drugs?) How about Vertex, or OSI?
My favorite part of the article is this one:
Big pharma's interest in cancer comes about five years after Novartis' launch of the targeted leukemia drug Gleevec.
Gleevec was initially expected to be a niche product, but its effectiveness and benign side-effect profile led to sales last year of $2.2 billion.
Let's take those in order. "Big Pharma's interest in cancer" has, in fact, been pretty constant. It's our success that comes in fits and starts. The article would makes it seem as if we can turn on the clinical research tap at will - when we finally get around to it, anyway. But there are no sudden waves of interest that show up in clinical research meetings - you're seeing the end result of decisions taken eight or ten years ago. When do you think we started the projects that are now being presented at ASCO, anyway?
And as for Gleevec, which is a fine drug that does well by its small intended patient population, let me say (again) that I think that a good amount of it is being wasted. There are, to the best of my knowledge, not enough people with GIST or CML (the two cancers that it's been approved to treat) to account for its sales, not even nearly enough. Gleevec was indeed expected to be a niche product. In terms of the people it can effectively treat, it still is.
It's not for lack of trying. Here are a few attempts from just the last few months: endocrine tumors, renal cell carcinoma, metastatic melanoma, germ cell tumors, refractory myeloma, and advanced hepatocellular carcinoma. In some types of tumor, Gleevec may actually make things worse.
Again, I'm not going off on Gleevec because it's a bad drug,. It isn't. It's pretty typical of what we have to offer these days in cancer: very good effects in a small number of people, some help for a slightly larger number, and nothing much for most. Talk of a "benign side effect profile" is ridiculous for many of the newer agents, because they can only be considered benign with compared to the old ones, which were toxicologically the scourge of the earth. Compared to cisplatin, sure we look good. Who doesn't?
There were surely be more of this kind of thing over the next few days. My advice is to ignore the cancer news until things calm down a bit and we can get a better read on what's really happening. There's going to be too much dust in the air for that this weekend.
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+ TrackBacks (0) | Category: Cancer
April 26, 2006
Posted by Derek
There are all sorts of excellent reasons not to cut down the rainforests of Borneo. Biological diversity, erosion, local climate, sheer aesthetics. . .no one should have to scratch their head for very long. But this isn't one of them, at least not the way it's being sold:
"Plants thought to help treat or cure cancer, AIDS and malaria have been found in the rainforests of Borneo, a report from the Swiss-based global conservation group WWF said on Thursday. . . A promising anti-cancer substance has been found in a Borneo shrub by researchers for an Australian pharmaceutical firm, while a chemical found in latex produced by a tree appears to be effective against the replication of HIV, the report said.
In the bark of another species of tree, the researchers discovered a previously unknown substance which in laboratory tests appeared to kill the human malaria parasite, it added."
Going to the source of the story, one finds more details:
"According to the report, Cerylid Biosciences – an Australian pharmaceutical company – has identified a promising anti-cancer substance in a shrub found in Sarawak. A compound present in the plant Aglaia leptantha has been found to effectively kill 20 kinds of human cancer cells in laboratory tests, including those that cause brain and breast cancer, and melanoma.
“The fact that the compound is very effective against a number of tumour cells, presents a very good argument for preserving the plant's habitat in Borneo,” said Dr Murray Tait, Vice President of Drug Discovery at Cerylid Biosciences."
No, it doesn't. The reason I say this is that we have oh, so many compounds already that will kill off twenty different kinds of human cancer cells in the lab. I mean that - tens of thousands of the damn things. Killing cancer cells in a dish is not as hard as it sounds, unfortunately. Now, killing any of them off effectively in a mouse model, that's another story. We probably only have hundreds and hundreds of those around, maybe a few thousand. And getting these things to work in humans? Well, you already know how many of those we have. It's a rather stiff attrition rate, y'know. I note without comment that Cerylid itself doesn't seem to be doing all that well right now.
Keeping Borneo from being clear-cut is a proposition that can be sold on its real merits. It doesn't need this kind of whoop-whoop. All these arguments do, in the long run, is make the people advancing them look like fools or con artists (Rain forest medicine! Jungle cures! Real soon now!). And it makes people think that discovering cancer drugs is actually not all that hard - just look in the right plant, and there it is. We already have enough people who don't realize how long the road is between some neat result in a culture dish and a real drug, thanks very much.
Comments (16)
+ TrackBacks (0) | Category: Cancer | Press Coverage
April 9, 2006
Posted by Derek
One of the big uses for human gene chips has been the search for biomarkers: genes that are up- or down-regulated in disease states. The hope is that gene expression changes will be the early warning signs of diseases, and could also help refine their diagnosis beyond what can be done by traditional means.
Cancer is the obvioius place to start. As I've said in the past, there's no one disease by that name - just thousands of broadly similar diseases that we don't adequately distinguish between. We'll have to get down to the genetic and protein-expression levels to see the important differences. The process has already begun, as a look at the Iressa story shows.
Nothing good comes easy, though, and the field may have gotten ahead of itself. That's what a new paper in PNAS maintains, anyway. The authors, from the Weizmann Institute in Israel, point out that the various predictive gene lists proposed for different kinds of cancers have a lot of disquieting problems. For one thing, the lists for the same types of cancer don't seem to overlap very much. And in those cases, if you take the two and switch them (applying one group's list to the other group's patients) their success rates fall sharply.
The problems remain after all attempts to massage them away. Some possible reasons for them might be the different gene chips technologies used by different groups or different methods of analyzing the data, but these don't seem to be nearly enough to account for all the trouble. A bigger problem is the dependence of the results of these studies on the particular patients who were entered into them. There seems to be a major problem with unstable results based on the training set used to generate the lists.
This latest paper lays this out in mathematical terms, and the results aren't real pretty. The published gene lists were derived from dozens, or at most a couple of hundred patients. But in order to have an overlap of at least 50% between two lists of candidate marker genes, with a confidence of 95%, the authors calculate that the number of patients needs to be in the low thousands. The existing proposals are almost certainly completely inadequate. The search goes on, but it just got harder, and a lot more expensive.
Comments (4)
+ TrackBacks (0) | Category: Cancer
March 16, 2006
Posted by Derek
Update: More on this issue from Jim Hu here.
The New York Times ran a pretty heavy-duty article the other day on drug pricing. But for once, it wasn't the big companies that were getting pummelled. No, this time it was Ovation Pharmaceuticals getting the treatment, and I'd have to guess that most readers will have the same reaction I did: who they?
Well, they're sort of a specialty generic company. Their business model seems to be taking on ancient medications, which other companies are giving up on, but which still have a small patient population to serve. Their business model is also apparently to raise the price of said drugs, and that's what got them into the papers:
"Last August, Merck, which makes Mustargen, sold the rights to manufacture and market it and Cosmegen, another cancer drug, to Ovation Pharmaceuticals, a six-year-old company in Deerfield, Ill., that buys slow-selling medicines from big pharmaceutical companies.
The two drugs are used by fewer than 5,000 patients a year and had combined sales of about $1 million in 2004.
Now Ovation has raised the wholesale price of Mustargen roughly tenfold and that of Cosmegen even more, according to several pharmacists and patients."
Mustargen is better known to chemists as nitrogen mustard, which was basically the first chemotherapy agent ever used. Cosmegen, for its part, is the brand name for actinomycin D, which goes back almost that far itself. (To give you the idea, the first person to try it out for cancer was Sidney Farber, whose last name still turns up in cancer therapy circles.
These are drugs from the caveman days, that's for sure, and many references (that Wikipedia link to nitrogen mustards, for example, unless it's been fixed by now) will tell you that they aren't used at all any more because of their toxicity. But they're each still useful for the small group of patients the Times article mentions, generally those with very particular forms of cancer that respond well to these agents above all others. To give you the idea, five thousand patients is one fortieth the market size for what the FDA considers an orphan drug, and it's not clear if that's the patient population for both drugs put together. These are orphaned orphans.
This article is of a piece with the recent one on the price of Avastin, which I spoke about here:
The increase has stunned doctors, who say it starkly illustrates two trends in the pharmaceutical industry: the soaring price of cancer medicines and the tendency for those prices to have little relation to the cost of developing or making the drugs. . .people who analyze drug pricing say they see the Mustargen situation as emblematic of an industry trend of basing drug prices on something other than the underlying costs. After years of defending high prices as necessary to cover the cost of research or production, industry executives increasingly point to the intrinsic value of their medicines as justification for prices."
Now we're down to the real question: is this price justified, or not? Ovation is in business to make money, like any drug company, and charging a high price is about the only way to do that when you're talking about a few thousand patients. A company like Merck could carry these things on its books without much harm being done to its bottom line, because the costs of its other medicines would make up for them (not that the Times is too crazy about those other prices, either). But when a small company like Ovation takes them over, they're going to try to make them into profit centers. Over at Blogs for Industry, Jim Hu asks: "I wonder what (the Times) would be writing if Merck just dropped Mustargen and these patients weren't able to get it at all." He's got a point.
For the most part, Ovation seems to be getting the prices that they're asking. One problem is that they're selling injectable Mustagen, which is the approved form, but there's one set of patients that uses the stuff as a topical lotion (which is formulated for them by local pharmacies). It's harder to get insurance to pay for that, since it's not an approved use. (And it's hard to imagine who would be able to go to the expense of getting it approved, either, considering the subset-of-a-fraction-of-an-orphan size of the market). These people are really feeling the price increase, and the Times article accordingly spends most of its space on them. Ovation is apparently lobbying for increased insurance coverage - which is, after all, in their financial interest - but for now, things don't seem to have changed.
The downside, for Ovation and for the industry, is that this kind of thing makes it very easy to write the heartless-price-jackers article. And this is why I think the ban on Medicare using prices as a consideration is a mistake. I know that my industry lobbied hard for it, and it's no mystery why. But I'd rather have Medicare responding to (and giving out) pricing signals, and I think that (for their part) private insurance companies should do so at every opportunity. Says the Times article:
And once a company sets a price, government agencies, private insurers and patients have little choice but to pay it. The Food & Drug Administration does not regulate prices, and Medicare is banned from considering price in deciding whether to cover treatments.
While private insurers can negotiate prices, they have limited leeway to exclude drugs from coverage based on price, said C. Lee Blansett, a partner at DaVinci Healthcare Partners, which works with drug makers on pricing and marketing.
"Price is simply not included in whether or not to cover a drug," Mr. Blansett said.
But why not? It's included as a factor in decisions to pay for all sorts of other things. If that quote were talking about anything other than pharmaceuticals, it would sound weirdly obvious. The same goes for that earlier excerpt: all sorts of things are priced considering factors other than their intrinsic costs. (What the market will pay, for example). Competing on price sounds heartless at first, but consider: if Ovation's raising their prices too high, that should open the door for someone else to step in and undercut them. Pricing signals go both ways. . .
Comments (9)
+ TrackBacks (1) | Category: Cancer | Drug Prices
February 21, 2006
Posted by Derek
There's been a lot of work in the last four or five years using nanoparticles of gold in biological systems. When they're are brought down to this size their electronic properties get quite unusual - in gold's case, the particles become huge absorbers and scatterers of certain wavelengths of light. They're thousands of times better then the kinds of dyes that organic chemists like me can crank out, which gives you potentially huge signal-to-noise in microscopy applications and assays.
Another exotic property these things have is that they convert the energy they absorb very efficiently into heat, and it didn't take long for people to have the idea of using this effect for cancer therapy. Heating cells, after all, kills them. Of course, you'd want to have some way to get the metal particles to stick only on to cancerous cells, and this has been realized by linking antibodies to the surfaces of both hollow and solid gold nanospheres.
The latest advance in this area has come from changing shapes. Rods are predicted to absorb more efficiently and at much different wavelengths than other shapes, and a joint Georgia Tech/UCSF team (who had worked earlier on the solid gold nanospheres) has verified these effects. They were able to grow rods of various sizes and aspect ratios and to conjugate them to anti-EGFR antibodies. EGFR, of course, is a well-known cancer target (via inhibition of angiogenesis), which is hit by several small molecules as well as antibodies like Imclone's Erbitux.
Each of these types of particle has its advantages. The gold nanosphere/antibody conjugates actually absorb at slightly different wavelengths when they interact with EGFR-expressing cancerous cells compared to noncancerous ones, which could make for a useful diagnostic assay. This can really only be done ex vivo, though, in thin preparations, because the wavelengths of light needed are also absorbed by the tissue itself.
The rods don't manage to show the differences between cells, although (as with the spheres) you can see the differences (scroll down on that page) qualitatively in how many particles are bound to the cell surfaces. But they do have a property that's potentially even more useful: their absorbing wavelengths are shifted to the near-infrared, which penetrates tissue much better (up to four inches)! You need green 520nm light for the spheres (with a convenient argon laser wavelength nearby at 514nm), but the rods need red 800nm light from a titanium/sapphire laser. When cell cultures are hit with that wavelength, the heating of the gold nanorods kills them off - and the EGFR-expressing cancerous cells can be killed by laser light of only half the strength needed for normal cells.
That's probably just barely enough of a gap to be therapeutically useful, for several reasons, not least because for tumors inside the body, I think that you'd be dosing the outer skin layers with too much wattage in order to hit the deeper tissues. No doubt work is already underway on widening the window between the two effects. I can certainly imagine some possible next steps as well: simultaneous treatment with conjugates of different antibodies, for example. Since many cancerous cell lines overexpress more than one type of cell surface protein, you might be able to hit them in several ways at the same time.
As much as I love small molecules (and the organic chemistry used to make them) I have to admit: they may not be able to hold their position against ideas like this. We can try to target things like EGFR that are overexpressed in many cancers, but we don't have much of a guarantee of success, because overexpression doesn't make a pathway crucial enough by itself. But overexpression alone is all you need with this technique, and the cellular pathways downstream don't matter a bit. It's a liberating thought. . .
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February 16, 2006
Posted by Derek
So now we come (again) to the topic of cancer drug pricing. The New York Times ran an article on this the other day which has gotten a lot of attention. In it, Alex Berenson points out that prescriptions for the antibody therapies like Avastin and Erbitux cost a huge amount of money.
This isn't news, unfortunately. See this 2004 article by Matthew Herper in Forbes, for example, or see my posts from around that time here and here. What the NYT article makes much of, though, is what it says is a new rationale for the costs:
"Until now, drug makers have typically defended high prices by noting the cost of developing new medicines. But executives at Genentech and its majority owner, Roche, are now using a separate argument — citing the inherent value of life-sustaining therapies.
If society wants the benefits, they say, it must be ready to spend more for treatments like Avastin and another of the company's cancer drugs, Herceptin, which sells for $40,000 a year. . ."
You won't catch me disagreeing about the value of pharmaceuticals. But this argument can only be taken so far, because (as those links from two years ago make clear) drugs like Avastin really only add a few months of life. That's nothing to make light of, but I fear that it's also not much of a basis for Genentech and Roche to talk about how society should be willing to pay for such outcomes. Can you fix a price for two extra months of life? We're going to have to.
The NYT article has an excellent example of someone who's done the calculation for himself:
"Ellis Minrath, who has pancreatic cancer, said he had chosen not to take Tarceva, a drug from Genentech that is approved for lung cancer and has shown promise in pancreatic cancer. He did so after learning that it would cost him about $1,000 a month in co-payments, even though he is covered by Medicare.
"If anybody came out and said, 'By God, this is the stuff. You want to get well, find a way to buy it,' that would be one thing," said Mr. Minrath, who is 87. "But that isn't the case. The forecast of how much it's going to do is not that wonderful. . .
I agree with Mr. Minrath's decision, and I strongly endorse his right to make it. As an 87-year-old with pancreatic cancer, he seems to have studied his situation objectively and realized the odds he faces. He is very, very likely to die within the next few months, and (although we've never met) I'll be sorry to see him go, because he sounds extremely sensible. Personally - and I hope I never have to work this decision out for real - I would lean toward a similar "leave more for my heirs" position. Other patients in different situations may well come to different conclusions, and that's up to them (and in the real world, up to their insurance companies) as well.
What we need, of course, is some cancer drugs that don't make us put prices on months. I'd rather be working out the value of whole years or decades. Therapies which can do that will be the place to make the "society should suck it up" argument, but making it for Avastin and the like seems rather premature. What will we do when we find something that's good?
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+ TrackBacks (1) | Category: Cancer | Drug Prices
January 4, 2006
Posted by Derek
Via Tyler Cowen at Marginal Revolution I came across this post earlier in the year from a blog called EffectMeasure on the use of rodent models to predict human cancer risks. It's a broadside against the American Council on Science and Health and a petition they filed against the use of high-dose rodent carcinogenicity tests.
Quote the anonymous "Revere":
The main rhetorical lever ACSH employs is the use of high doses in the animal studies, doses that are much higher than usually faced by humans. But as ACSH knows well (but didn't divulge) there is a technical requirement for using these doses. If one were to use doses in animals predicted to cause cancer at a rate we would consider a public health hazard, we would need tens of thousands of animals to test a single dose, mode of exposure and rodent species or strain. This makes using those doses infeasible. Thus a Maximum Tolerated Dose is used, one that causes no other pathology except possibly cancer and doesn't result in more than a 10% weight loss. The assumption here is that something that causes cancer at high doses in these animals will also do so at low doses. This is biologically reasonable. It is a (surprising) fact, that most chemicals, given in no matter how high a dose, won't cause the very unusual and specific biological effect of turning an animal cell cancerous. Cancer cells are not "damaged" cells in the individual sense but "super cells," capable of out competing normal cells. It is only in the context of the whole organism that there is a problem. It is not surprising, then, that very few chemicals would have be ability to turn a normal cell into a biological super cell of this type. Estimates are that is far less than 10%, perhaps only 1% of all chemicals that have this ability. Thus western industrial civilization doesn't have to come to a screeching halt if we eliminate industrial chemical carcinogens from our environment.
We know of no false negatives with this process. Every chemical we know that causes cancer in humans also does so in rodents (with the possible exception of inorganic trivalent arsenic, which is equivocal). The reverse question, whether everything that causes cancer in animals also is a human carcinogen, is not testable without doing the actual natural experiment: waiting to see if people get cancer on exposure, an experiment ACSH is only too happy to conduct on the American people to make their corporate sponsors happy."
I've left out (as did the MR post) the part where he called the ACSH "right wing whores", which is the kind of thing that doesn't enhance the statistical arguments very much. Dropping the invective, I want to take up Tyler Cowen's question: is there anything to this critique? My answer: there might be. But there might not be. It's certainly not as clear-cut as the author would like to make it, cancer epidemiologist though he is, which would seem to be one of the criticisms he's making against the ACSH petition.
Here are some complicating details:
1. The effects of high doses of compounds can be due to their effects on cell division. At such levels, test substances cause irritation and inflammation that promotes cell proliferation. The more cells are forced to divide, the more opportunities there are for the defects that lead to cancer. These effects do not scale well to lower doses. It's the opinion of Bruce Ames (inventor of the Ames test genotoxicity screen) that this problem has completely confounded the interpretation of high-dose animal data. (His article in Angew. Chem. Int. Ed. 29, 1197, 1990 is a good statement of this argument).
2. The statement that "most chemicals, given in no matter how high a dose, won't cause the very unusual and specific biological effect of turning an animal cell cancerous" is not accurate. As Revere surely knows, there are many mutations and pathways that can turn a cell cancerous (which is why I keep harping on the idea that cancer isn't a single disease). Somewhere between one-third and one-half of all synthetic chemicals tested in cell assays or in high-dose animal assays show up as possible carcinogens, depending on your definitions. Interestingly, basically the same proportion of natural products (isolated from untreated foods and other sources) show up as positives, too.
Now, if you want to talk confirmed human carcinogens, then Revere may have a point. There are only some three or four dozen specific chemicals that are confirmed as causes of human cancer. Here's the list. If you read through it, you'll note that many of the 95 agents on it are radioactives or broad categories such as "alcoholic beverages." (Mention should be made of things like nickel, all compounds of which are under suspicion. Check your pockets, though, for your most likely exposure). Specific compounds known as human carcinogens are quite rare. But doesn't that fact support the ACSH's point more than Revere's?
3. Revere's statement that "Cancer cells are not "damaged" cells in the individual sense but "super cells," capable of out competing normal cells. It is only in the context of the whole organism that there is a problem" is also inaccurate. Cancer cells are indeed damaged, right in their growth-regulation and/or apoptosis pathways. A car whose throttle is damaged will run at a higher RPM than a normal model, but I wouldn't call it a "super car". And cancerous cells are often quite recognizably problematic, whole animal or not. They divide like crazy in petri dishes, the same as they do in an animal.
4. The majority of the cancers seen in rat and mouse models are in the liver (which supports the idea that these tumors occur through general strain on their metabolic systems). Human liver cancer is much more rare. The most common human cancer in many countries is lung, caused to a great degree by smoking (which is also likely to have constant-irritant cell-proliferation component). Of the agents on that ICAR list in point #2, only three or four are chemicals (or mixtures) known to induce human liver cancer specifically. This is a significant mismatch.
5. Revere states that "We know of no false negatives with this process. Every chemical we know that causes cancer in humans also does so in rodents. . ." But how about false positives? There are hundreds of compounds that seem to cause cancer in rodents that (as far as we can tell) do not pose a risk to humans. I say "seem to", because these are almost always high-dose studies. But I can even think of some compounds (the PPAR-alpha ligands) that cause all sorts of trouble (including tumors) in rodent livers at reasonable doses, but don't do so in humans. Rodent tox is necessary, but it sure isn't perfect.
There, that should be enough to complicate things. It doesn't make for as dramatic a story as the evil henchmen poisoning America on behalf of their corporate masters, I have to admit. But we'll have to try to get along without the excitement.
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+ TrackBacks (0) | Category: Cancer | Toxicology
December 21, 2005
Posted by Derek
Regular readers might enjoy seeing some of the posts from this blog recapitulated in this New York Times story about this week's approval of a new cancer therapy from Bayer:
. . .Although every field has suffered, cancer has had the greatest chasm between hope and reality. One in 20 prospective cancer cures used in human tests reaches the market, the worst record of any medical category. Among those that gained approval in the last 20 years, fewer than one in five have been shown to extend lives, life extensions usually measured in weeks or months, not years. . .Drug companies have been promising for years that gene-hunting techniques would yield targeted nontoxic therapies that melt cancer, but few cancer medicines fit that profile. . ."There are all these myths having to do with cancer drugs," Dr. Steven Hirschfeld, an F.D.A. medical officer with expertise in cancer, said. "That they're very targeted, when in fact all these drugs have multiple targets. That they're nontoxic, when in fact the latest ones have their own set of side effects. And that they're cures, when they are not."
This new compound is the first in a wave of multiple-kinase inhibitors. It's going to be very interesting to see how these molecules work compared to the earlier wave of more targeted therapies. Good luck to everyone involved - the researchers, the companies, and most of all, to the patients.
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December 7, 2005
Posted by Derek
I can recommend this grim but well done article from last weekend's New York Times magazine. It's on the death from cancer of the author and critic Susan Sontag, written by her son.
He spent a lot of time with physicians and researchers during her last illness, and it wasn't time wasted. The article is a very good summary of the current state of the art in cancer research, and doesn't try to paper over the disagreements abpit how far along we are:
". . .advances in cancer treatment and, indeed, in the fundamental understanding of how cancer works have come far more slowly than many people expected. Periodically since 1971, when President Nixon declared his war on cancer, the sense that the corner is about to be turned takes hold. We appear to be in such a moment today. The National Cancer Institute has recently put forward ambitious benchmarks for progress in cancer research and treatment. As its director, Dr. Andrew von Eschenbach, a respected surgeon and a cancer survivor himself (he is also acting head of the Food and Drug Administration), put it recently: "The caterpillar is about to turn into a butterfly. I have never known more enthusiasm among cancer researchers. It's a pivotal moment." The suffering of cancer, he argued, will be well on its way to being alleviated by 2015.
The media have mostly echoed this optimism. It is not unusual to read about the latest "breakthrough" in cancer treatment, both in terms of understanding the basic biological processes involved and with regard to innovative new drug therapies. . . "
Exactly so, and that's one of the things that worries me. I know that it's in the interest of academic and industrial researchers to say that they're making great progress, but let's face it: great progress isn't being made all the time, everywhere, by everyone. You wouldn't know it to look at the press releases, though. It upsets me to see the words "cure" and "breakthrough" thrown around by both scientists and journalists who should really know better. It's understandable that such words should come to be devalued eventually, but we don't have to help devalue them as quickly as possible, do we?
David Sontag quotes Harold Varmus at Sloan-Kettering with some reasonably optimistic statements, but then says:
"Other research scientists seemed far more pessimistic when I spoke with them. Dr. Lee Hartwell, also a Nobel laureate, is president and director of the Hutchinson Center. He has urged that the focus in cancer treatment shift from drug development to the new disciplines of genomics and, above all, proteomics, the study of human proteins. Though he acknowledged the profound advances in knowledge made over the past two decades, Hartwell emphasized a different question: "How well are we applying our knowledge to the problem? The therapy side of things has been a pretty weak story. There have been advances: we cure most childhood leukemias with chemotherapy, for one thing. But the progress has been surprisingly weak given the huge expenditures that we've made. We're spending over $25 billion a year improving cancer outcomes, if you include the spending of the pharmaceutical companies. So you've got to ask yourself whether this is the right approach."
. . .Some researchers are even more skeptical. Mark Greene, the John Eckman professor of medical science at the University of Pennsylvania and the scientist whose lab did much of the fundamental work on Herceptin, the first important new type of drug specifically designed to target the proteins in the genes that cause cells to become malignant, agrees with Hartwell. The best way to deal with cancer, he told me, is to "treat early, because basic understanding of advanced cancer is almost nonexistent, and people with advanced cancer do little better now than they did 20 years ago."
I come down more on this side of things, myself. When we talk about the progress that we've made against cancer, we're almost always talking about the amount of knowledge we've accumulated. Measuring progress by how well we keep people from dying of the disease is more sobering, because the rate of exchange between those two currencies is rather poor. And we should keep in mind that much of the improvement in those numbers is due to early detection, often coupled with surgery. We need to do better.
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October 24, 2005
Posted by Derek
Last week's news about Herceptin made quite a splash, and there are several reasons for that. The main one is the correct one: this is good news for breast cancer patients, and a real advance in the treatment of the disease. The other reasons for all the excitement may not be quite as justifiable, though. In short, while this is significant, it's a long way from a cure.
Herceptin (trastuzumab) is an antibody targeted to a growth factor receptor called HER2 (more background from a previous post here, and from Genentech here. Those are the short version and the long version, more or less). If the cancer doesn't express HER2, it will not respond to Herceptin. The more dependent the tumor is on HER2 for its growth, the better the antibody will work, which is a common theme among cancer therapies. (An extreme version is found with Iressa, where if the tumor doesn't have the rare mutation that makes it dependent on the drug's targets, it doesn't work at all).
So, how many breast cancers express HER2? There are several ways to assay that, and the numbers disagree a bit, but a bit under 20% seems like a reasonable answer. Put more harshly, for about 80% of breast cancer patients, herceptin is of little or no use. This has been proven quite thoroughly, but it's going to be hard to explain to patients who are newly diagnosed and want to know where that cure is that they've read about.
I haven't seen any headlines that have tried to explain that these results are good news for only a certain group of breast cancer sufferers. Many of the press reports get around to mentioning this eventually, although rarely in the first paragraphs - you wonder how many people are still reading when they get to the fine print. The fine print, in this case, would include the numbers that show a twelve per cent increase in disease-free survival after three years. That's big news in oncology, but isn't generally the kind of number that you makes you throw around the word "cure". I hope that some of the people in these news stories have been quoted out of context.
It's true that by the time you add up the taxanes, the estrogen receptor ligands like Tamoxifen, the aromatase inhibitors, and the general advances in surgery and early detection, that breast cancer is a less fearsome disease than it was five (or ten, or twenty) years ago. But advances in this area get overhyped because - and I hate to bring this up - the disease itself is overhyped. Don't get me wrong - it's bad. But it's far from the worst.
The rate of breast cancer, like many other cancers, appears to be declining (PDF), measured both by incidence and by death rate. It's well behind that of lung cancer in the female population, which moved into first place nearly 20 years ago (see the graph on page 5 of this PDF), but it gets easily ten times the press, and surely generates ten times as much worry. Lungs, though, are not visible manifestations of femininity, and come with no cultural or political meaning attached. I'm sure that there's a ribbon color for lung cancer, although I don't know what it is, and I don't know when their Awareness Month might be. This is especially odd when you consider that most of the high incidence of lung cancer is from a completely avoidable cause. . .
(I see that Medpundit has a very similar take on this: "Don't sell the house" is her advice.)
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August 17, 2005
Posted by Derek
Are we going to "eliminate the suffering and death due to cancer" by 2015, a goal set by the National Cancer Institute? Unfortunately, I greatly doubt it. Will we speed up the timetable, as Senator Arlen Specter has apparently asked, and do it by 2010? Absolutely not, and here's why.
There's a widespread myth at work here: that there's a disease called cancer. Cancer is actually the end result of what are probably hundreds (thousands?) of different diseases. We have confused ourselves by giving them the same category name - it's like the old-style classification of infections as various "fevers." There are many, many ways that a cell can end up with (and maintain) the deranged growth profile that we think of as cancerous, and it's going to take a lot of different treatments to do anything about them. (See this post and this one for some of the consequences of that for the drug industry.)
Look at the situation today. Every type of tumor has specific front-line treatment regimes, and they don't overlap that much. The best agents for some types of cancer are totally useless against some of the others. It's possible that some of those multikinase inhibitors that I was writing about the other day could have a broader spectrum of activity, but even if that pans out, it's likely that different kinase "fingerprints" will be needed for different varieties of tumor.
Actually, there are two myths at work in Senator Specter's question. The other one is that research can be sped up to any degree desired. Although more money is always nice, thanks, there comes a point where it's not sufficient to buy you better results. In the case of the various cancers, it's for sure that there are many, many important details that we don't even know about yet. And, as usual, a good amount of the things that we do already know are going to turn out to be wrong. Time, money, intelligence, luck, and hard work are all going to have to be tossed into the pot in great quantities, and there are no other ingredients that can substitute for any of those.
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August 11, 2005
Posted by Derek
One of the comments to the last post mentioned that a way to provide the benefits of a combination therapy is to make a drug that hits more than one target. For a while there, this idea was a bit out of fashion, but I think it's been making a comeback.
There are a number of multiple-target drugs on the market already, and the list even includes some where this profile was arrived at deliberately. (That was a joke. I think.) Examples of the planned category include Tracleer (bosentan), a dual endothelin receptor antagonist for pulmonary hypertension, rupatadine, a dual histamine/PAF antagonist for allergy (not yet approved in the US, I think), and Cymbalta (duloxetine), an antidepressant which affects both serotonin and noradrenaline reuptake.
Examples of the non-deliberate class include all sorts of drugs marketed before the 1980s or so. (That's about the time that target-based drug design really took over, as opposed to "see what it does in vivo".) In some therapeutic classes, this is the norm - the activities of CNS drugs in general are known to be extraordinarily messy. The antipsychotics, for example, hit so many receptors that it's basically impossible to figure out just how they work. A more recent example is the cardiovascular drug Pletal (cilostazol), which is both a PDE-III inhibitor and an adenosine uptake inhibitor. Other PDE-III inhibitors didn't work nearly as well, so there was clearly something else pitching in. (There may well be something similar at work with Lipitor, to pick a drug that everyone's actually heard of, although no one's quite sure what the extra activity is.)
There are all sorts of other dual-acting drugs being looked at in earlier phases of development. For the most part, they're going after similar receptor subtypes or related enzymes, since that's where you're most likely to get the cross-reactivity. (A good example would be the PPAR alpha-gamma ligands that many companies have been trying to develop for diabetes.) But the biggest area of multiple-action drugs now is cancer.
You might not know it from reading the popular press, though. A lot of reporters are still a generation behind, going on about the new breed of incredibly selective targeted cancer drugs. Problem is, it's turning out that some of those incredibly selective drugs work only on incredibly small numbers of cancer patients, which is not what everyone had in mind. Over the last few years, efforts have shifted to making drugs that hit a slew of potential cancer targets simultaneously, in hopes that this will show more efficacy, and these are just coming to the FDA now.
Many, many cancer targets are from a large family of broadly similar enzymes (the kinases), so getting multiple activities isn't really all that hard. In fact, getting selective kinase inhibitors was the hard part - looking back, had we but known, we all could have probably skipped that step and gone right to the blunderbusses. But the fear was that these compounds would be too toxic (yeah, even for cancer therapy), so selectivity got priority. Now that it turns out that we don't need to be so picky, it's also becoming clear that the multiple-kinase drugs are tolerated a lot better than we thought. You'll see the word "targeted" thrown around when these agents are discussed, but it should have quotes around it.
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+ TrackBacks (0) | Category: Cancer | Cardiovascular Disease | Drug Development
July 28, 2005
Posted by Derek
After presenting some disappointing data at the spring ASCO meeting, Novartis and Schering AG's tyrosine kinase inhibitor for colon cancer (PTK/ZK) looked to be in trouble. The "CONFIRM-1" trial showed no real benefit from using the drug on top of standard chemotherapy, but "CONFIRM-2" was also underway. That one looked for efficacy in patients who had already failed first-line therapy, and the results are now in: no survival benefit. The financial markets weren't happy, but weren't too surprised - that second trial was a tougher one to reach significance in, given the nature of the patient population.
It's a real whimper of an ending for a drug that some were once touted as the next Avastin. Schering AG kept tossing billion-dollar sales projections around for a while there, and kept trying to put the best face on things even as the bad news started coming in. Their earlier press release on the CONFIRM-1 data, for example, is a model of the Power of Positive Thinking, and is worth a look in light of today's announcement.
It started off with the headline "First results from PTK/ZK CONFIRM 1 trial. . .show positive drug effects in advance colorectal cancer." As you read further, you got to a figure of 17% reduction in risk of disease progression for the combination therapy, as opposed to the standard regimen, "as assessed by investigators." "Assessment by central review," however, showed a 12 per cent reduction, which didn't even reach statistical significance. Halfway down the first page, and the wheels have come off completely, but you'd never know it from reading the bold print at the top.
The chances of PTK/ZK reaching the market have to be close to zero. I know that at one point the companies were looking to go into non-small cell lung cancer, but I wouldn't hold out much hope there, either. As usual when a heavily studied drug candidate goes into the trash, I'd like to remind everyone that all the money that Novartis and Schering AG spent on this, and it was surely a lot, is burned up and gone. This was a Phase III failure, about as expensive as it comes. That cost will be reflected in the price of the next things that either company gets to the market, depend on it. They'll have to make it up somewhere; it's the nature of our industry.
As fate would have it, some other negative clinical data came out today. A study in the New England Journal of Medicine has shown, rather definitively, that the popular herbal supplement echinacea seems to have no effect on colds at all. That's rather in contrast to the signage over on the herbal medicine shelves at my local pharmacy, when I think about it.
Ah, but now that this trial has been run, what are the chances of my being able to go to that drug store next week, next month, next year, and see echinacea promoted as being good for colds? Do I hear. . .close to one hundred per cent? Of course! Herbal medicine companies are made of sterner stuff than we are over here in the artificial non-holistic world. They won't let a little thing like lack of efficacy slow them down.
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June 28, 2005
Posted by Derek
Time for another public-health issue that someone has done an excellent job covering. That would be Colby Cosh, taking on a fuzzy-minded editorial on cancer rates. This is a fine example of going to the data to see if someone really knows what they're talking about, and I could only wish that all journalists were as handy with a graph as Colby is. Quoth Cosh:
"The effort to play on the emotions--and there is no more emotional topic in Western life than cancer--is so poorly disguised; the contemptuous attitude toward reason is so transparent. I believe this has become more widely known, and pieces like Mr. Anderson's are now commonly regarded by newspaper readers as mere static. And no one thinks there is any harm in having it about, right up until the moment we completely lose the ability to communicate candidly with one another, or to persuade by any means but sheer amplitude."
His further thoughts on non-Hodgkins lymphoma, which actually does seem to be rising, are well worth checking out, too. All this is accented by a well-publicized recent survey of beliefs about cancer, whose full text is available here. The one that particularly gets me is "There is currently a cure for cancer but the medical industry won't tell the public about it because they make too much money treating cancer patients." Actually, you could probably have substituted just about any disease in that question and found the same distressingly high agreement.
The percentage of people agreeing with that place a lower bound on the number of survey respondents who know nothing about economics. (We'll leave knowledge of biology out of it for now.) How much money would people pay for a cure for cancer, compared to current therapies? More, possibly? Would there be any incentive to offer one, then, especially considering that new cancer patients come along all the time? And just when did we pharma companies all get together to share our secret cancer cure, anyway? Why wouldn't a company decide to break ranks and blow its competitors completely out of the market? And who was it that decided that they didn't want a Nobel Prize and the everlasting gratitude of millions of suffering people? Oy.
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June 7, 2005
Posted by Derek
Placebo-controlled trials are usually considered the standard (and most stringent) measure of a drug's efficacy. It's a surprisingly high hurdle to clear. All sorts of things that people swear by, and all sorts of new things that you'd be sure would work fail when they're up against a similarly sized and colored dose of sugar.
But you can't always run a placebo group, because it isn't always ethical to do so. For a life-threatening condition, the comparison group has to be the current best standard of care (which, after all, is what you're trying to beat.) For lesser diseases, a trial against a known therapy can also be appropriate, although it's usually done after a placebo-controlled one has already been run.
But there's one situation where you can run a placebo control for a deadly condition: when the best standard of care is nothing at all.
Several forms of cancer fall into that category. Pancreatic, renal, and hepatic cancers, for example, exhaust their best available treatments very quickly. Some of the patients in that situation then offer themselves as subjects for clinical research, for which we in the drug industry are extremely grateful. With any luck, we'll be able to find something that works well enough to unblind as quickly as possible.
And when that happens, the disease is no longer in the "placebable" category. There's now an active agent, a possible treatment, and thus a new standard of care. Several cancers have moved off the list in recent years, and here's hoping that the process continues.
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June 5, 2005
Posted by Derek
There's a recent piece in Business Week Online that says nice things about the biotech and pharma industries, and I should be happy about that. But there are so many misconceptions in it that I'm going to fisk the darn thing instead.
After a lead-in which discusses a patient who responded to the Sugen/Pfizer kinase inhibitor for kidney cancer, the BW pieces says that cases like this:
". . .have convinced many doctors that medical care is reaching a tipping point. Not that most patients will be healed right away -- the vast majority of sick people continue to dose themselves with tiny bits of chemicals, otherwise known as pills, that represent medicine's Old Guard.
But the times are changing. The past 30 years of biological discoveries, insights into the human genome, and exotic chemical manipulation have unleashed a wave of biological drugs, many of them reengineered human proteins. These molecules have the power to change the prognoses for a huge range of diseases all but untreatable just five years ago. "
Well, first off, Malcolm Gladwell should ask for royalties for use of the phrase "tipping point." But as he doubtless knows, and the authors of the Business Week article should, the drug industry doesn't quite work that way. This isn't a marketing campaign. Advances come on independently, each at its own pace and with its own problems. If several come at roughly the same time, coincidence is as much a factor as anything else. And it's worth remembering that this particular inflection point has been proclaimed about every ten months since the mid-1980s.
Second, the Sugen/Pfizer compound is nothing more than one of those "tiny bits of chemicals" (known as pills, it seems) straight from the Old Guard. It is nothing even close to a reengineered protein. No exotic chemical manipulations are required to make it; a talented undergraduate could whip up a batch (although I wouldn't recommend that to any talented undergrads who might be reading this.) That's just how we folks in the Old Guard like our compounds to be - not terribly expensive to make.
Later on, we get into the academia (good!) versus the pharmaceutical industry (bad!) debate:
""What's interesting is that it is really the academic researchers that pushed biotech forward, not corporate research and development," says Allan B. Haberman, principal of pharmaceutical consulting firm Haberman Associates in Wayland, Mass.
Academic researchers, unlike traditional drug companies, were willing to champion biotech approaches to drugs even when they were long shots. ImClone Systems' (IMCL) Erbitux, a colon-cancer treatment approved last year, would not exist today if not for the efforts of its discoverer, Dr. John Mendelsohn. The scientist-clinician spent 20 years working to find a company willing to commercialize his discovery that some tumors could be stopped by blocking a certain growth enzyme.
Even Gleevec, the most effective cancer drug of the past decade, was almost abandoned by Novartis (NVS). An outside cancer specialist, Dr. Brian J. Druker of Oregon Health & Science University, coaxed the company into pursuing its development."
Let's take those one at a time. It's true that many of the basic discoveries that have led to the current biotechnology industry came from academic research. That's just as it should be. But none of it would have been turned into human therapies without that "corporate research and development." Allan Haberman's statement makes it sound like the industry just sat around while the universities cranked out all the gold, which is untrue. [Note: see Haberman's own take on this in the comment section.]
The examples that follow help prove the point. The thing is, for every Erbitux and Gleevec story, there's a Cell Pathways counterexample - scrappy outsiders who pushed long-shot drugs with all their might, and all the venture-capital and equity funding they could get, only to find that they didn't work. Only the success stories are remembered, it seems. If the Cell Pathways drug had worked, it would be in this story, too. But it didn't, and it wasn't because it wasn't "biotechy" enough, either.
And it's not like Erbitux is that great a drug, either, frankly, as I've pointed out here numerous times. Imclone has been just fantastic at generating headlines, some of them inadvertent, so Erbitux is one of the things that people think of first. But it's hardly the stuff of a revolution. And Gleevec (another one of those small chemicals, by the way) is only "the most effective cancer drug of the last decade" if you have the rare cancers known as GIST or subtypes of CML. But if you don't, it's basically useless, not that that's stopping thousands of desperate people from trying it out. The reason Novartis didn't want to push the compound was that they thought that its potential market was just too small. They didn't realize that they were developing the world's first billion-dollar orphan drug.
Then comes this whopper:
"Traditional pharmaceutical companies shied away from biotech for years, unwilling to bet on unproven technologies. It didn't help that biotech's earliest accomplishments met with setback after setback in the 1980s and '90s.
Today, Big Pharma is paying for its risk-averse stance: Major players have few promising products in their development pipelines, and most are stuck with a business model heavily dependent on blockbuster drugs. Boston Consulting Group estimates that, as a result, biotech firms produced 67% of the drugs in clinical trials last year but shouldered only about 3% of the $40 billion that the drug industry spent on R&D."
Shied away from biotech for years? We pumped uncountable billions into it, much of which we never saw again. And as for that business model, the one heavily dependent on blockbusters? That's what we logic choppers call post hoc, ergo propter hoc. Once a company finds a huge winner, it becomes dependent on that revenue by default. And I have trouble imagining anyone saying "You know, this drug could sell two billion dollars a year. We'd better drop it. I don't think we can handle that kind of money."
Later, the article takes a look at some specific therapeutic areas, such as cancer. The next excerpt contains a couple of nearly unnoticeable palmed cards - see if you can spot them:
"Unlike heart disease, where patients choose between seven nearly identical cholesterol-lowering statins, targeted cancer therapies come in many forms. There are drugs that block tumor-growth factors, starve the tumor by inhibiting blood-vessel growth, combine radioactive isotopes with tumor-seeking proteins, and use vaccines to train the body's immune system to attack cancer cells.
There is even a next wave of multitargeted drugs that could start winning FDA approval as early as next year. Sutent, the drug keeping Julia Barchitta alive, is a member of this emerging class, known as multi-kinase inhibitors. They block blood-circulating proteins that are responsible for both tumor growth and blood vessel creation. Other closely watched candidates in this class include sorafenib, developed by Bayer (BAY) and Onyx Pharmaceuticals (ONXX) for kidney cancer, and lapatinib, a breast cancer drug from GlaxoSmithKline (GSK). These multitargeted therapies seem particularly effective against the hardest to treat cancers, giving hope to some of the sickest patients."
The idea that "cancer" is a single disease category just like "heart disease" is ridiculous. And note that "heart disease" is being defined as equivalent to "high cholesterol" - thus the mention of the statins. But Pfizer has gone to great lengths to prove that Lipitor is actually different from the other statins (and other companies have gone to great lengths only to end up proving the same thing, to their sorrow.)
Cancer is a constellation of hundreds of diseases, all characterized by uncontrolled cell growth. The complexities of the pathways involved give us plenty of potential mechanisms to target, and there we have the second switcheroo in this section. Those wonderful drugs that were being held up as examples earlier in the article - Erbitux, Gleevec - are targeted to only one or two of those mechanisms. And although that was their big selling point at the time, that's probably why they don't work very well. Those "multitargeted" drugs are not a refinement on this idea, they're the opposite idea.
The popular press is having quite a time catching up with this. You still see articles extolling the bold new era of tightly targeted cancer drugs, but they're being overtaken by the articles extolling the bold new era of messy blunderbuss cancer drugs. It's true that these compounds aren't in the same side-effect league as, say, the old cytotoxic agents like cisplatin, but they're a long way from the lasering-in-on-the-single-important-factor storyline from a few years ago.
The rest of the article focuses on stem cell therapies, and that will have to wait for another long post all its own. The cancer section closes out with a quote from Judah Folkman, who is an honest man:
". . .cancer specialists are hopeful that, as more targeted therapies come on line, they can be combined into cocktails that will keep cancer patients alive for years. Renowned cancer researcher Dr. M. Judah Folkman of Children's Hospital in Boston says the most important thing is that the drugs give patients hope: "We have something to offer [patients] now, and if it keeps them alive a little longer, something else might come along."
That sort of deflates the buzzing balloon that the rest of the article represents, doesn't it? Try turning that quote into a headline, won't you? But it's the truth. . .
Comments (9)
+ TrackBacks (0) | Category: Cancer | Drug Industry History | Press Coverage
May 22, 2005
Posted by Derek
Here's a nice article over at Forbes which highlights a tough question: what's the best indicator of efficacy for a new cancer drug? One of the easiest things to measure is tumor shrinkage, and you'd think that would be a good sign. Common sense can only take you so far, though:
"But now doctors are finding that tumor shrinkage, on its own, isn't necessarily a good reason to use a drug, because it's entirely possible to shrink a tumor without helping the patient. More important measures of efficacy are how long it takes for the cancer to start worsening and how long patients live. If a drug increases survival time, its efficacy clearly outweighs any side effects."
Survival, of course, takes a lot longer to measure, and time is nowhere more equivalent to money than in a clinical trial. If we're going to start moving away from the classic response rate - number of patients with 30% or more shrinkage - then we're going to be spending a lot more to evaluate our drugs. It's true that the article linked above quotes someone who doesn't buy this logic, but he's talking about using some genetic marker as a surrogate. This is a very nice idea, but we're back to the same problem: it also takes years to prove that these things are linked to survival, and that'll always be the real standard. Who cares what your cancer is up to if it kills you on the same schedule?
No, using survival as the endpoint will almost always cost more. But I think it'll be worth it. I've never understood the benefit to desperate patients of giving them something that's just going to make them spend their last months being jerked around.
Comments (6)
+ TrackBacks (0) | Category: Cancer
May 13, 2005
Posted by Derek
Well, today is the start of the ASCO meeting, which as I've mentioned is an interesting, important blizzard of hype and spin. A number of companies (Imclone, Merck KGaA, Bayer, Genentech, Pfizer and others) have presentations that will be watched closely. Some of these will take place over the weekend, which will at least keep a few stocks from having to halt trading (unless there are some big order imbalances come Monday morning, that is. . .)
It's hard to keep a proper perspective on this sort of presentation. One thing to remember is that everyone involved realizes the spotlight that they're under, and has planned accordingly. I've long thought that scientific meetings, as they've come to be run, are one of the worst places to discuss scientific results. I'm sure that many of the interesting and important conclusions are things that would only become clear after sitting down with the complete data sets for a few days (or weeks). Distilling all of it down to a meeting talk, even assuming (charitably) that you're not trying to sell something or divert attention, is going to degrade the information.
So, enjoy the news bulletins, and good luck with the stocks prices. But don't take ASCO more seriously than it deserves.
(By the way, another preview of the conference can be found here. Can anyone tell me what the author means in her last sentence, "The financial component is one area that is sorely lacking in research"? Here I thought that we were getting beaten up on for making the "financial component" too darn important. . .)
Comments (2)
+ TrackBacks (0) | Category: Cancer
May 6, 2005
Posted by Derek
Just a brief note this morning. Starting late next week we have that fiesta of spin known as the American Society of Clinical Oncology meeting. A good preview article can be found here. Reading that one, see if you can imagine making investment decisions based on the abstracts of a meeting. How long ago do you think those were written, you itchy investors, and just how much detail do you think anyone is going to include in them?
Comments (0)
+ TrackBacks (0) | Category: Cancer
April 18, 2005
Posted by Derek
Another step down into oblivion: AstraZeneca's Iressa, which was a great hope for them a few years ago, was approved contingent on more studies being completed. As everyone who's been following the story knows, those studies came in a few months ago with terrible news for A-Z and the patients who had been hoping that the drug would help them: no effect on survival, none at all. They pulled the drug from European consideration, and have stopped marketing it here.
Now it appears that another ongoing Iressa trial, a National Cancer Institute study on patients with stable disease after treatment for lung cancer, might be halted based on the negative results of the earlier one. I can see their point, because the data were pretty convincing, in a way that no drug company likes to see. What are the chances that this one will make any difference? Is it ethical, at this point, to continue giving patients the drug?
By the way, does anyone remember, back when Iressa looked like a promising therapy, that the Wall Street Journal (among others) had fits about the FDA's delay in approving it? Here's a piece I wrote about the situation at the time. As it turns out, the less-than-convincing data available back then was about the best that Iressa ever had to offer. If the Journal has offered a follow-up editorial to apologize for pointlessly raising the hopes of cancer patients and wasting their time and money, I've missed it.
And that's the problem that I have, still, with the idea that we should just allow drugs on the market after they've proven safety in Phase I. People get their hopes up. They'll throw their life savings at something if they think that it could help, and it wouldn't surprise me if some folks threw theirs at Iressa. To what end?
Comments (9)
+ TrackBacks (0) | Category: Cancer
March 28, 2005
Posted by Derek
More pre-ASCO-meeting oncology trial news, this time from Ligand: their Targretin (bexarotene) failed all its endpoints for lung cancer. Two Phase III trials both came up empty for a survival benefit, sending the stock down a good 25% or so. (As you can imagine from that cliff dive, Targretin is a big part of Ligand's fortunes.)
And it must have been a rough place to work for the last year or so. Last spring, the mood was a lot more festive - see this story from the San Diego media. Let's take a painful trip back in the time machine:
"Three separate studies showed that combining Ligand's Targretin with the widely used Taxol (paclitaxel) prevented or reversed acquired tumor cell resistance to Taxol in non-small cell lung cancer (NSCLC) and advanced human breast cancer cell lines. . .In the Ligand studies of NSCLC and breast cancer cell lines, when Targretin was combined or used concurrently with the chemotherapy, it resulted in superior reduction of tumor growth than did chemotherapy alone. . .Earlier this month, the biotechnology firm reported its first quarterly profit ever. Ligand shares (Nasdaq: LGND) gained $1.40, or 7.3 percent, to close at $20.56 today after notching a 52-week high of $20.85 during intraday trading. The firm has a market cap of $1.51 billion. Trading was heavy, nearly triple the average daily volume of 1.5 million shares. The stock has more than tripled in price in the past year, after hitting a 52-week low of $6.20 on March 31, 2003."
Contrast that to the company's home page today, whose downer headlines are "Targretin Fails to Meet Primary or Secondary Endpoints in Pivotal Trials" and "Ligand Announces Delay in Filing of 10-K". And the stock has round-tripped back to the six-dollar price. How did this happen?
Well, Targretin an interesting and risky drug, in an interesting and risky therapeutic area. It's an activator of the RXR nuclear receptor, which is at a huge multilane intersection (PDF file) of gene expression pathways. I've worked in this area myself, and it's an exciting mess. There are surely thousands of genes whose expression levels can be sent up or down by changes in RXR, and it's a safe bet that we don't know what many of them are. While we're at it, it's a safe bet that we don't understand a lot of crucial things even about the ones we've heard of. It's a real monkeywrench of a drug, which puts it in the same position as many other oncology therapies.
The drug was approved several years ago as a second-line therapy for small indications like cutaneous T-cell lymphoma, and since then Ligand has been trying to break it through into the larger markets like lung cancer. They still have a number of other combination trials going on, as they should, but these results have to hurt. In today's press release, you find only the echoes of last spring, phrased in the saddest verb tense there is:
"The initial daily dose of Targretin in both trials was similar to that used in prior phase II studies in which a positive trend in survival had been observed. . ."
Comments (1)
+ TrackBacks (0) | Category: Cancer
March 23, 2005
Posted by Derek
Charly Travers is a very clear-eyed observer of the pharmaceutical investment world, and after mentioned Bayer and Onyx yesterday, I'd like to recommend his take on the situation:
"So while sorafenib looks like a promising therapy for kidney cancer, I'm not sure there is much upside remaining for investors looking to buy into a good drug program on the basis of this market alone. With approximately 35,000 new cases per year in the United States, this is a small market. Because profits are split with Bayer, those profits retained by Onyx may not be sufficient to increase the value of the company to a degree that warrants the risk inherent in biotechs at this stage.
The wild cards here are that sorafenib is also in late-stage trials for liver cancer and melanoma. If those trials come out positive, then Onyx is very likely going to be a long-term winner. Cancer drugs often don't work in all cancer types, so despite the encouraging results in kidney cancer, success in these other indications is far from a sure thing."
All true, although there is that factor we were speaking of yesterday, of off-label use. But is that something you want to bet the farm on? It's very important, if you're an investor, to decouple a company (and its drug portfolio) from its stock. They don't always move in synch. I've never been a fan of investing in something just because it's going up, and you have to decide if a company's shares already have most of the good news priced in.
As Travers goes on to point out, you're better off owning smaller companies with earlier-stage drugs that haven't gone up yet. Of course, you really need to own several of those guys, because it's for sure that a majority of them aren't going to work. But that's the kind of portfolio we own inside each drug company, with our own development candidates. Welcome to the club!
Comments (0)
+ TrackBacks (0) | Category: Business and Markets | Cancer
March 22, 2005
Posted by Derek
Speaking of cancer trials, I mentioned the other day how they tend to be smaller than those for many other diseases. But that doesn't mean that they're always easy to run, as a search for "clinical trial design oncology" will show. Note the number of people offering to help you out, via seminars, consulting visits, books, and entire journals devoted to the topic.
The problems start early. Patient recruitment is a big problem for many of the less common types of cancer, and it's getting to be a problem for the better-known ones, too. If you look at all the therapies that are being aimed at breast cancer, for example, and run the numbers, it looks like there aren't enough breast cancer patients in the US to fill out all the trials that would be needed. Cost is, of course, a big reason why a lot of clinical trial work is being done overseas these days, but access to a new pool of patients is a factor, too.
Which brings up another complication - do you want patients who've tried other drugs? That depends on where you're targeting your therapy. If you hope for it to be a first-line drug, you probably want patients that are newly diagnosed. There's a steady supply of those, but not everyone who's newly diagnosed is going to be willing to participate in a clinical trial, not when there might be more proven treatments available. The worst case is when you're looking for drug-naÔve patients with advanced types of cancer. That's feasible (in theory) for some of the ones that creep up on you (like colorectal cancer), but next to impossible for some others.
But if your drug is going to be a second-line therapy, then you should go ahead and see how it performs in patients who've already been through the first-line stuff. There is, unfortunately, a steady supply of those people, too, and they're often more willing to take a chance.
Your clinical trial design will also be influenced by the kind of cancer you're hoping to treat. If you're looking at a very specific type or two, as is the case with Novartis's Gleevec, you may have to cast the net pretty widely to round up enough people. (We'll ignore the fact, for now, that Gleevec sells a billion dollars a year, which means that a lot of people are getting it when it has very little chance of doing anything for them.) If you have a new mechanism that hits all kinds of cancer cells, then you may want to dip into all sorts of different patient populations to see if one of them looks like a good place to take your stand in later Phase II and III trials. The danger in doing that is that your patients may be such a mixed bag that you can't get good statistics on anything.
Ah, statistics. You'll have noticed that I'm referring to cancer patients as if they were so many terms in an equation, which from the standpoint of drug development is exactly what they are. That comes across, to those outside the medical and scientific areas, as a pretty cold way to talk. Guilty as charged - but keep this in mind: people who work for drug companies get cancer, too, as do our friends and relatives. And we're just as upset as anyone else when that happens. But without the icy numbers, and lots of them, we're not going to be able to do anything to help.
Comments (6)
+ TrackBacks (0) | Category: Cancer | Clinical Trials
March 21, 2005
Posted by Derek
Get ready for the clinical trial season for anticancer therapies. The American Society for Clinical Oncology meeting is in May, and everyone who's going to present new trial data is starting to work on their PowerPoint slides. ASCO (famously) embargos the presentations themselves, but the run-up to the meeting is out there in plain sight.
For example, Bayer and Onyx will be talking about their drug, sorafenib. Promising interim data was released today - well, a summary was, anyway - which means that this will be an eagerly awaited ASCO talk. Meanwhile, Schering AG and Novartis were planning to make a big splash with one of their therapies, PTK-787, but the bad news came out on that one almost simultaneously. They'll still be presenting, but the mood will be quite a bit more somber.
All these trials have surrogate endpoints and real endpoints. The real ones are the ones that matter, but you have to wait until the end of the trial for them. Surrogates are designed to be read out more quickly. In the case of these drugs, the surrogate marker is whether the drug seems able to delay progression of the cancer. As time goes on, you'll get actual survival rates, which are the real story, but investors are desperate for news and will take whatever they can get. For their part, the companies will use good surrogate data as a signal to go ahead and start putting the FDA package together, which saves time. Competition in this area is such that time equals money even more than usual.
The problem with surrogate markers is that you can get fooled. It's possible for a drug to look like it's delaying cancer progression, but in the end to not have much effect on survival rates. (Just to really drive everyone nuts, the opposite situation is possible, too.) That's where AstraZeneca's Iressa ran into trouble. As the long-term data starting coming in, it became clear that the drug really didn't help with survival. And if your drug doesn't do that, the patients and insurance companies would like to know, quite correctly, just why they should pay for it.
Comments (1)
+ TrackBacks (0) | Category: Cancer
January 24, 2005
Posted by Derek
So what are these cancer animal models that I was speaking of so poorly? On the face of it, they actually seem like they'd be pretty good, other than being rather disgusting. (That said, it's important to keep in mind that they're not as disgusting as watching people die from cancer when you could be doing something about it.)
What you do is take human cancer cell lines and implant them in a mouse, a process called xenografting. When they form a tumor, then you treat the mouse with your drug candidate and see if the growth rate slow, stalls, or reverses compared to untreated controls. Sounds pretty simple.
But the complications show up very quickly as you look closer. For one thing, these human cancer cells are often cell lines that have been propagated for a while in vitro, and there's room to wonder about how much they've changed since their days as primary tissue. There's also the issue of the number of different cancer cell types you could use - hundreds, thousands, more? We know what tissue they came from, and we know some of the biochemical differences between them, but nowhere near all. Not even most of the important differences, if you ask me, since we don't even know what some of those important differences are yet.
What we have are characterizations like "Cell line such-and-such, non-small cell lung cancer, resistant," or "colon, slow-growing, responds to everything." Each cell line has its own reputation. At least the fact that these reputations are pretty constant gives you some confidence that we're all talking about roughly the same cells, which is no small thing. (More than once in the history of cellular research, people have realized that cell lines which were all supposed to be the same thing had drifted apart.)
Another level of difficulty is that these things are implanted, rather than growing in situ in the tissue of interest. Any cell biologist will tell you that the matrix a cell grows in is one of the fundamental variables of cell culture. Now, once the tumor has formed, the cells are surrounded by other cancer cells, which is closer to the real situation. But they're still being vascularized by mouse blood vessels, which obviously respond to mouse signals and carry mouse blood. That's the fundamental animal model problem, and it's a tough one.
Finally, these aren't any old mice. In order to get the cells to "take" when they're injected, these mice have a severely compromised immune system. They mostly have no thymus, for starters (and no hair, either, as a side issue.) Here's one - if you find hairless dog and cat breeds cute, you probably won't mind these guys, either. They don't make very good pets, though, because (as you'd imagine), they will catch every disease available, and likely as not die from it.
At bottom, these models are probably too permissive. As I mentioned the other day, they can make compounds like Iressa look just fine, when we now know that they confer no real benefit in humans. (If our market were nude mice with good health insurance, we'd be set, though, as would the mice.)
So what good are they, and are we really doing a good thing by running them? Well, it's hard to imagine that your compound is going to do any good in humans if it doesn't at least work in the nude mice, so they serve a screening function. It's true, though, that for some years now, if the compound hasn't worked in the mice it's never gotten to humans, so we don't have as many checks on that idea as we'd need to be sure of that assumption. But we see a lot of disconnects like Iressa, which argues for false positives being more of a problem than false negatives.
And I'm not sure how good the models are at rank-ordering compounds, either. I can justify their use as a pass/fail, but that's about it. We should be doing better, and people are trying to. And a lot more are trying behind closed doors - better animal models would simultaneously help large numbers of desperate patients and save the drug industry about a billion dollars. More on all this in another installment.
Comments (5)
+ TrackBacks (0) | Category: Cancer
December 17, 2004
Posted by Derek
And while we're on the subject, here's the latest example of bad news coming in great squawking flocks: AstraZeneca's Crestor is under suspicion, their new Exanta clotting drug is in major trouble, and now some terribly unimpressive clinical data comes out for Iressa in its ISEL trial.
Note that Tarceva, which I was blogging about a few days ago, would seem to have a big opportunity here. OSI's shareholders sure seem to think so. But I'm still not convinced that the two drugs are that different. We'll see as it goes into more general use. . .personally, if I were an OSI shareholder, I'd sell. Not the first time I've made the recommendation, come to think of it. . .
Update: Colby Cosh picks up on the "Black Friday" theme and adds some interesting comments on the terms under which Iressa came to the market in the first place.
(By the way, readers may have noticed I'm blogging this during the day today, which is a bit unusual. It's not going to be a regular feature, though - unfortunately for the blog and fortunately for me, the day job usually precludes it. But just for today, I feel like Glenn Reynolds. . .)
Comments (1)
+ TrackBacks (0) | Category: Cancer
December 14, 2004
Posted by Derek
I've had a number of comments on my post below about the changing cancer market, and they deserve some follow-up. One very good point that was made is that this change is really a race between several factors: the narrowing of individual markets as we find out the reasons for efficacy could be balanced out by the ease that this could bring to the design of clinical trials. After all, it should be easy to get good data if you have a clearer idea of which patients are most likely to respond. (Every major drug company is plowing money into biomarker research for just this reason.)
But if you design your trial on the basis of a specific biomarker, I assume that you'll get a specific approval based on that, too. You're trading larger market potential for a higher clinical and regulatory success rate - and believe me, I'm far from suggesting that that's a bad trade. But it'll be an interesting decision in some cases. In the short term, I would expect to see some companies forgoing the use of narrow biomarker-driven trials in an attempt to go for the bigger money. But as the everyone-prescribes-for-everything model for the oncology market breaks down, that'll become less and less of an option.
How many years is that breakdown going to take? It's hard to say. Some areas are going to be way ahead of the rest of the field - for example, it might be happening right in front of us with Iressa, but in other markets we don't have a clue. In general, I'd say that twenty years will see the transformation well underway, but I could be off in either direction. Along the way, there are going to be some nasty surprises for the companies involved as they find that their existing or in-development drugs have suddenly contracted to much smaller roles.
Another thing to think about is how many new drugs we're going to need, versus combinations of existing ones. You'd think that the latter option would cover a lot of ground, but I think that the emergence of resistant tumor lines will keep everyone searching for new compounds. Oncology could end up looking a bit like anti-infectives, although the big difference is the individual occurrence of resistant tumors, rather than the far more challenging spread of resistant organisms.
So you'll end up with courses of treatment that look like this: sequence the patient and a sample of their cancerous cells, which will suggest the first-line therapy. Then if that doesn't knock everything down, you move to the next ones on the list (which will look slightly different under each of those first options), and switch to that, keeping an eye out over the next few years for the need to switch to a third agent or combination, and so on.
How will drug companies deal with these changes? A colleague of mine suggested that the larger outfits will probably fare better, because they'll be able to hold a portfolio of cancer drugs that will add up to something. The risk of changing market sizes will be spread out across several agents. Smaller companies may have to explicitly target smaller markets, which you'd think would lead to fewer stock-market skyrockets like Imclone and OSI. These would also seem to be good candidates for in-licensing from the bigger companies looking to fill gaps in their holdings.
Comments (12)
+ TrackBacks (0) | Category: Cancer
December 7, 2004
Posted by Derek
Here's a post from back in the spring which goes into why I think that the cancer drug market is in the process of changing. As we figure out which patients will respond to which drug - which will happen, albeit slowly - the standard industry assumptions about market size will have to be rethought.
For now, we in the business can continue to assume that everyone will be given most everything for most everything. That's why Gleevec sells at the level it does - it's really an orphan drug which has benefited from the let's-give-it-a-shot mentalily more than anyone thought possible. The thing is, most of the people who've received the drug (and the other new agents) for totally different kinds of cancer than they're known to treat have wasted their time and hopes, and their insurance companies have wasted their money. It's true that this kind of clinical practice can lead to new treatments (there are always some surprises), but it leads to a lot of lost effort, too.
But as we move into the world where we know more about what we're doing, that's going to change (see that post linked above for details.) Cancer is going to slowly turn into a constellation of hundreds (thousands?) of orphan diseases, each of which will have its own particular preferred therapy. We won't need new drugs for all of them - many of these will be particular combinations of known agents - but we'll need a lot more than we have now. And the market size for each of them might be at least an order of magnitude smaller than we'd like.
That, naturally enough, will mean that the prices of these drugs will go up, because they're probably not going to be any cheaper to develop. So we'll have a lot of drugs, each of which can do great things for a small set of patients, and each of which will cost a heap. Doctors will have no problems with this, and patients will adapt to this world without many complaints. We'll adapt to it in the drug industry. But think about how this is going to look to an insurance company or HMO. . .
All of their cancer-patient customers will be taking highly expensive medications - different ones, true, but the bottom line will be the same. And they'll all have to stay on them for a long time, since we still don't know how to make cancer reliably go away very well - we can just keep it in check. How's that sound over on the insurance side of the street, guys? Guys?
(For those who are interested, I wrote a few other posts on the issue of cancer therapies (and their prices) back in the summer - try here and here if you haven't seen them.)
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+ TrackBacks (0) | Category: Cancer | Drug Prices
December 6, 2004
Posted by Derek
From Forbes, I find that CSFB has lowered its target price for OSI Pharmaceuticals, co-owner (with Genentech) of the new cancer therapy Tarceva. This is a HER1/HER2 compound (more the former than the latter), which makes it rather similar to AstraZeneca's Iressa.
Tarceva has lived in Iressa's shadow throughout its development, and OSI's stock has moved in response to market perceptions about how much better (or worse) their drug is in comparison. Here's a chart for the last year - take a look at that mighty jump in late April. That's when clinical results were announced that made Tarceva look like it would perform better than Iressa when it hit the market. As you see, people got a bit enthusiastic.
But check out that recent dip, which is a reponse to Genentech's attempt to inject some reality into the expectations of shareholders since the drug was launched last month. Their estimate for the number of Tarceva patients wasn't what the stock's cheerleaders wanted to hear, and it's not quite what OSI's been putting out, either. It's not often you see two companies disagreeing so publicly over their shared drug's profit potential.
There's pressure on the other end of the expectations game, too. The conclusions from a large Iressa clinical study, ISEL, will be released soon - AstraZeneca has said by the end of the year. It's widely thought that this one will make Iressa look a bit better than it does at present - that is to say, pretty much like Tarceva looks now. Quoth CSFB:
"We expect ISEL (Iressa Survival Evaluation in Lung Cancer) to meet its primary endpoint of survival," the research firm said. "A statistically significant result will reinforce existing physician impressions of the two drugs as clinically comparable--despite likely Wall Street squabbling over percentage differences in survival and inevitable differences in subset groups."
But, as mentioned in that last link, Morgan Stanley is sticking with the rosier view:
"The company made an effort to clarify what it considers a market misunderstanding. . .Management's comments were more in line with our thinking and contrary to what we believe were highly conservative comments by development partner, Genentech. . .We expect Tarceva's broad label will allow OSI and Genentech to market Tarceva to a broad patient population. . .we believe that the Street is underestimating the profitability of this drug to OSI."
Well, I'm not being paid to render an opinion - at least, not as much as those folks on the Street, anyway. But for what it's worth, I'm with CSFB on this one. (Some readers may recall that when OSI jumped back in April that I said that if I owned it "I'd have been knocking things over on my desk to get to my phone to sell. . .") In the end, I'm not sure how different these two drugs are going to be. It's a case of near-simultaneous development, the kind I was talking about the other day, and those don't always work out too well. And there's a longer-term problem which is going to affect the whole oncology market: I think that the days of being able to market all kinds of cancer therapies to everyone are beginning to disappear.
But whether Tarceva turns out to be different from Iressa or not, it's still probably not good news for Imclone, whose Erbitux targets the same pathways - just much more expensively, and perhaps not to much more benefit, if any. I took a pile of abuse back in April in that same post where I talked about selling OSI, advising IMCL shareholders to get out at $70. They should have. Hey, there's still time!
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August 16, 2004
Posted by Derek
When a drug makes it into the bloodstream (which is no sure thing, on my side of the business), it doesn't just float around by itself. Blood itself is full of all kinds of stuff, and there are many things in it that can interact with drug molecules.
For one thing, compounds can actually wander in and out of red blood cells. This usually isn't a big deal, but once in a while a compound will find a binding site in there, which had flippin' well better not be on the hemoglobin protein. Depending on the on- and off-rates, this can either add a welcome time-release feature to the dosing or it can be a real pain. I haven't heard as much about interactions with white cells, but since they're a much smaller fraction of the total blood it's not something we'd be likely to notice.
More commonly, drugs stick to some sort of plasma protein. The most common one is serum albumin, and another big player is alpha-1 acid glycoprotein, or AGP. Albumin's found in large amounts and has several distinct binding sites. Acidic drugs are well known to hold on to it. As far as I'm aware, no one's absolutely sure what it's there for, but it must be pretty important. The multiple binding sites make it seem like could be some sort of concentration buffer for several different substances, but which ones? (I've never heard of an albumin knockout mouse - I assume that it would be lethal.)
The same comments about good and bad effects apply. A lot of effort has gone into schemes to predict plasma protein behavior, with success that I can charitably describe as "limited."The real test is to expose your compounds to fresh blood and see if you can get them back out. Some degree of protein binding is welcome, and you can go on up to 99% without seeing any odd effects. But at 99-and-some-nines you can start to assume that something is wrong, and that the interaction is too tight for everyone's good.
But when you're doing your blood assay, you had better make sure to try it with all the species that you're going to be dosing in. There's a kinase inhibitor from a few years back called UCN-01 that provides a cautionary tale. It was dosed up to high levels in rats and dogs, wasn't bad, and passed its toxicology tests, and went into human trials. They started out at one-tenth the maximum tolerated rat dose in the Phase I volunteers, which should be a good margin. But when they got the blood samples worked up, everyone just about fell out of their chairs.
There was at least ten times the amount of drug circulating around than they'd expected, because it was all stuck to AGP and it just wasn't coming off. A single dose of the drug had a half-life in humans of about 45 days, which must be some sort of record. Well, you might think, what's the problem. A once-a-month drug, right? But it doesn't work like that: the compound was so tightly bound that it would never reach the tumor cells that it was supposed to treat. All it was doing was just riding around in the blood. And the clinical program really dodged one from the safety perspective, too, because as they escalated the dose they would have eventually saturated all the binding that the AGP had to offer. Then the next higher dose would have dumped a huge overage of free drug into the blood, and all at once. Not what you're looking for.
The compound is still being investigated, but it's having a rough time of it. It's been in numerous Phase I trials, with all sorts of dosing schedules. A look through the literature shows that the compound is mainly being used as a tool in cell assays, where there's no human AGP to complicate things. With so many kinase inhibitors out there being developed, it's going to be hard to find a place for one with such weird behavior.
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+ TrackBacks (0) | Category: Cancer | Pharmacokinetics
July 25, 2004
Posted by Derek
Continuing on the latest issue of the New England Journal of Medicine and its articles on cancer therapies, there's the Perspective article, from Deborah Schrag at Sloan-Kettering, which points out that:
"In the wake of the optimism generated by recent trial results, patients experience sticker shock when they encounter the prices of chemotherapy drugs. Physicians find themselves in the undesirable position of having to help patients make decisions about whether the potential clinical benefits warrant the financial strain that even the copayments for these medications may create."
I don't doubt it. She has a chart for a typical patient's eight-week therapy on various regimes. Drug costs for the classic fluorouracil-based therapies will run from $60 to $300 for that period. Throw in irinotecan, the standard since the mid-1990s, and you're looking at about $10,000 for the same eight weeks. An Avastin-based treatment will double that, and an Erbitux-based one will triple it. And those are just wholesale drug costs; they neglect support, labor, wastage, and so on. Avastin and Erbitux are harder to store and administer, so their costs will be still higher. And even if you take the statistics in the latest paper at face value, median survival is increased by less than two months with Erbitux. That brings us to a terrible question: how much are those two extra months worth, and who should pay for them? Everyone's trying to offload that decision onto someone else, and I don't blame them a bit.
We're back to where I was discussing this issue a few weeks ago. As I said then, I think that the solution is that many people won't (and shouldn't) take these therapies, because they're just not worth it. But that's a hard thing to convince someone of, and I'm glad that I don't have to try. My attempt to pass the buck is to point out that none of us in the industry is trying to develop a hugely expensive drug that only prolongs survival by a couple of months - that's just how the damn things come out after we've already spent the time and money. We're trying to hit home runs over here, but the pitching is too strong for us.
The article gets its shots in at the drug industry, though:
"Early scientific work that led to the discovery of bevacizumab (Avastin) and cetuximab (Erbitux) was financed with federal dollars. The pharmaceutical industry translated these fundamental insights into the development of commercial products. The rising stock prices of the publicly traded companies that manufacture these drugs reveal that, development costs notwithstanding, the risk-adjusted return on pharmaceutical products is very high indeed. The drug costs that support these stock prices threaten to overwhelm our ability to pay for health care."
Well. . .let's dispose of those in order, then. The first part is the old drug-companies-rip-off-NIH canard. Allow me to point out that no academic labs were attempting to turn antibodies against the growth factors receptors into new drugs, so why is industry to blame for trying? "Translating fundamental insights into the development of commercial products" is exactly what the drug industry does. It's very hard to do, it's very risky, and it costs a hell of a lot of money. You have a problem with that? If Dr. Schrag believes that she can do it more cheaply and efficiently, I invite her to raise the money and come on down and try it. Many people have done just that, and it's an education, all right.
And as for drug costs overwhelming "our ability to pay for health care", has Dr. Schrag considered that the total contibution of drug costs to health care is below 20%? Isn't there any overwhelming being down by the rest of the business, or are they just standing around in awe of our mighty powers?
And let's see. . .the rising price of the stocks, yes. Please note that I think that Imclone's stock is already too high. As high as Erbitux's cost is, I still don't think it can support Imclone's current price. I think that Bristol-Meyers Squibb overpaid for their share of the drug, and I'm not sure they're going to end up with much of a return. Note also this post about the amount of money that the biotechs have lost over the years - on average, biotech investors have lost money and they continue to lose it. For some years now, anyone investing in the stocks of companies I've worked for has been taking a bracing bath indeed. Believe me, although there are some good investment opportunities, the drug industry only looks like a money machine to the unwary.
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July 22, 2004
Posted by Derek
Since I last wrote about Imclone, the stock has had a rather difficult time. That's largely the fault of the Imclone fan club: Erbitux sales have exceeded some of the responsible projections, but still haven't caught up with the fantasies of some of the stockholders.
And now comes a study in the New England Journal of Medicine (about as high-profile a place as you can publish this kind of thing) confirming that Erbitux does shows activity in late-stage colon cancer, when added to the standard irinotecan therapy. Good news, eh? But in the end, the publication may do as much harm as good to Erbitux's prospects, because the same issue has a rather sceptical editorial comment on the study, and a longer perspective piece on the costs of such treatments in general. (Full text isn't available to nonsubscribers - the beginning of the editorial is here and the beginning of the Perspective is here. I'm going to cover that one in the next post for Monday; it makes this one too long and unwieldy when they're combined.)
The editorial, from two physicians at the Mayo Clinic, isn't kind. It's enough to make you wonder why they accepted the study for publication in the first place: ". . .the findings clearly support the notion that interfering with EGFR signaling can overcome the resistance to irinotecan. Nevertheless, the appropriateness of the authors' reporting methods warrants discussion." They point out that the trial was statistically underpowered to detect some clinically meaningful differences, and question whether the reported response rate can justify using Erbitux as a monotherapy. The authors attempted to test the patients for EGFR expression, but it's unclear if they did this in the right way (it's not as simple as you'd think.)
Even if you take the statistics as they are, Erbitux added less than two months to the lives of patients, on average, compared to the current standard of care. The authors' verdict: there may well be clinical settings or treatment regimens where Erbitux is more useful in such colon cancer patients, but we don't know what they are yet. The addition of Erbitux to the list of treatments, they say, "must be tempered by the small advances that it offers in terms of the time to progression and the response rate and its uncertain effects on survival. . ." Not to mention the cost, which we'll take up in the next post.
In light of all this, I'd like to take a moment to address the Imclone-boosting stock cult, those few of them who might have read this far, anyway. Get out. Take the money and run. The alarm bell has sounded, and more than once. If you bought Imclone when it was in the dumper, you've had a great run. Celebrate and cash in! But if you bought it when I was ranting on the subject back in late June, you're in the red, and I fear that it's going to be even worse in the long run. Flee!
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July 19, 2004
Posted by Derek
The PPAR family (known in the US as alpha, gamma, and delta, for obscure historical reasons) is one of those biological jungles that keep us all employed. They're nuclear receptors, and thus they're involved in up- and down-regulation of hundreds of genes. Like most of the other nuclear receptors, they do that by responding to small molecules, which makes the whole class a unique opportunity for medicinal chemists.
Normally, we can't do much about gene regulation, because it's all handled by huge multicomponent protein complexes, terrible and unlikely candidates for intervention with our drug molecules. But when the whole thing is set off by binding of a small ligand, well, that's all the invitation we need. To pick a well-known class of small ligands, the best-known members of the NR superfamily are the steroid receptors, which should give you some idea of how powerful these things can be.
For their part, the PPARs are all major players in cellular energy balance and fuel use, the handling of fatty acids and other lipids, the generation and remodeling of adipose tissue, and similar things. That lands them squarely in some very important therapeutic areas such as diabetes, obesity, and cardiovascular disease. But more recently, it's become clear that they're also involved in things like inflammation and carcinogenesis, which brings in another huge swath of the drug industry. Every large drug company is working on them, for one indication or another. Heck, you could run an entire drug company on nothing but PPAR-related targets, that is, if you weren't terrified by the insane risk that you were taking.
Problem is, the biology of nuclear receptors is powerfully complex and murky. We know a lot more about them than we did five or ten years ago, but it's obvious to everyone in the field that we still have very little idea of what we're doing. Take a look at the three PPARs: there are two diabetes drugs on the market that target PPAR gamma (Avandia and Actos, aka rosiglitazone and pioglitazone), but no one has been able to get anything significantly better or safer than either of those. PPAR alpha is supposed to be the way an old class of lipid lowering drugs (the fibrates) work, but no one's really sure that they believe that. Several companies have been working on PPAR alpha drugs for a long time now, and nothing's made it deep into the clinic yet, which isn't a good sign. And no one really knows what PPAR delta does - it seems to have something to do with lipid levels, and something to do with wound healing, and something to do with colon cancer. The clues are rather widely scattered.
I've mentioned that several companies have been working on combination diabetes drugs that would hit both PPAR gamma and alpha. The idea is that they'd do all the glucose lowering of a gamma-targeted drug, and lower lipid levels at the same time - a worthy goal for the typical overweight Type II diabetic patient. But Novo Nordisk, racing along with a compound they licensed from India's Dr. Reddy's (the evocatively named ragaglitazar) hit the banana peel when long-term rodent testing showed that the compound was associated with bladder cancer. Then Merck, which had a compound from Japan's Kyorin in advanced trials, pulled it when another rare cancer showed up in long-term rodent studies. Screeching halt, all over the industry.
Now the FDA has jumped in, with a requirement that any new PPAR drugs go through two-year rodent toxicity testing. That's an unusual requirement, but (as the two examples above show) it's something that companies were already doing on their own initiative. Bristol-Meyers Squibb and AstraZeneca have already done theirs, for example, and are plowing on.
The feeling has been: no one really knows what to expect from new PPAR compounds, so you'd better test the waters extensively. The thought of putting a compound on the market that turns out - years later - to be linked to increased risk of something like bladder cancer is enough to give everyone nightmares. I should mention that nothing bad has been seen from the two marketed PPAR gamma compounds I mentioned. But everyone remembers that there was another one, troglitazone, the first to market and the first to be pulled. It showed liver toxicity, but that seems to have been compound-related rather than mechanism-related.
Here's an article from Forbes on the subject, one of the few outlets that covered this story in any detail. It's pretty good, although it glosses over a lot of things. For example, the article quotes Ralph DeFronzo of UT-San Antonio saying that the fibrate drugs have been targeting PPAR-alpha for years, so why is the FDA worried about that subtype? What that ignores is that the fibrates are actually very weak drugs at alpha, which is why I mentioned the doubts people have about the whole mechanism. The drugs being developed now are thousands of times more potent. And look at the alpha-gamma combinations: why did all the trouble start only when alpha was added to the mix?
Well, we've got plenty of work to do. Unraveling the biological effects of the PPARs is going to take many, many years. And we're going to have to do it in rodents, in dogs, and in humans, at the very least - all the major species that are tested for toxicity. We already know about some significant differences between the species in the way that these nuclear receptors work. Will these cancer problems be another one? Are humans going to be just fine? Or will we react in even worse ways, given enough time? We just don't know. Everyone's holding their breath, waiting to see what comes next. . .
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+ TrackBacks (0) | Category: Cancer | Diabetes and Obesity | Drug Development | Toxicology
June 23, 2004
Posted by Derek
Over at Slate, NBC's Robert Bazell takes on the drug pricing issue, focusing on the newer oncology therapies. There's no denying that some of them are really costly, and that this is a situation that probably can't continue under the current system (which, to exaggerate only slightly, works like this: every cancer patient gets to try everything, and insurance/Medicare pays for it no matter what.) But the problem with Bazell's article is that it bungles enough other points that his main ones are obscured. One of them goes like this:
"Why are these drugs so expensive? It's hard to know exactly, since drug pricing is a sacred prerogative protected by acts of Congress and the details remain shrouded in trade secrets. But the simplest answer is that drug companies can charge whatever price they want. "
Ahem. That's as opposed to the perfectly transparent pricing mechanisms for, say, cars, toothpaste, and fish sandwiches, I guess. And those aren't even "sacred prerogatives"! Imagine what those things would cost if the businesses that provided them could charge whatever prices they wanted to! Good thing we don't let them. (And yes, I know that cancer drugs aren't exactly discretionary purchases - we'll come back to that one.) Bazell goes on:
"Erbitux and Avastin are both laboratory-produced antibodies (Erbitux blocks a chemical signal that tells cells to grow; Avastin cuts off blood supply to tumors). True, these antibodies are more expensive to produce than most pills, but only slightly-the technology can be replicated in any college biology lab. Production costs amount to few dollars a dose at most."
I hate to put myself in the position of defending Imclone and Erbitux, but this argument is exaggerated to the point of nonsense. I know what he's trying to say - that making monoclonal antibodies is an established technology - and up to a point, it is. But Bazell makes it sound like a bunch of undergraduates could whip up a batch of Erbitux for fifty bucks or so, and that is, to use a term of the pharmaceutical art, complete bullshit. Antibodies are actually a lot more expensive to produce than small molecules. Getting reproducible purity and performance from them is a completely different problem than with small synthetic molecules, and once made, they're significantly harder to formulate, store, and handle. (That's one reason why Iressa, for example, is cheaper by a factor of ten than Erbitux.)
Here's a challenge for Robert Bazell: Let's pick a random college biology lab or two by riffling through a directory, and see if they could produce a steady supply of GMP-grade doses of Erbitux (or any other antibody therapy). Let's just call them up and ask them! Anyone want to put some money down on the results? Bazell goes on:
". . .Like all pharmaceutical companies, BMS and Genentech cite research costs and the huge risks involved in drug development (many drugs fail; clinical trials are expensive ... but haven't we heard it all?) as explanations for the high prices of their drugs. But the real reason is that market forces do not apply to drugs."
I'm sorry that we're boring him. Unfortunately, those explanations get trotted out over and over again because they're true.
"Few individuals purchase these drugs as they would a head of lettuce, say, or a refrigerator. In the case of cancer drugs, health-insurance companies are the consumers. For those lucky enough to have insurance, their plan might pay; and indeed, oncologists say that, surprisingly, so far few have balked."
Now we're down to that nondiscretionary spending issue. It's a real one, and it applies not just to pharmaceuticals, but to every sort of health care. People value their health very highly, as they should. And it's not that market forces don't apply to drugs, it's that no one seems to want them to. If they did so more directly, insurance companies would indeed start to balk, and drug companies would have to decide if they could lower the prices of their new therapies coming through the research pipeline. And if they couldn't, they would have to decide not to take them through clinical trials at all. We would end up with fewer therapeutic options than we have now.
But a therapy that no one can afford is arguably about the same as no therapy at all, so that's not as much of a tragedy as it sounds. And it's certainly true, as the article goes on to point out, that many of these new cancer treatments aren't as effective as everyone would like. Unfortunately, the only way to find that out was to go ahead and spend the money and time to develop them, and take them all the way through clinical trials and regulatory approval. That's when you find out that your wonder drug isn't as wonderful as you'd hoped. But I'll stop right there; I can hear Robert Bazell starting to yawn. Here he comes again:
"But even the current meager benefit will encourage all cancer patients to seek (these drugs), and those who cannot get them, because they lack health insurance or their plan won't pay, to feel cheated. And a marketplace with absolutely no price control will only propel the drug companies to charge even more for future drugs, some of which may offer even less benefit."
Why, exactly, would we enter the market with something that's demonstrably worse than what's already out there? I know that the industry gets hammered for me-too drugs, but those work at least as well as the existing therapies, and they need some selling point that lets you argue that they're even better. I can testify, from personal experience, that projects get killed all the time in the drug industry because we can't beat the competition, either what's already on the market or in clinical trials. I've helped kill them. This hasn't been as big an issue in oncology, but it does happen, and it's going to be happening more often.
And the answer to all this, presumably, is price controls. Hard to say, since that's where Bazell's article ends, but that seems to be the prescription. I can just imagine what kind of price a group of elected officials will decide what is fair. We'll be tied up, top to bottom. It's not clear to me - it never has been - how forcing companies to earn less money from their drugs will cause them to produce better ones. (Think how much Imclone could charge if Erbitux actually worked better than it does.)
If you want a more detailed take on the cancer drug pricing issue, go back a couple of weeks to Matthew Herper's article in Forbes. It covers the same ground, but in a clearer fashion. Ultimately, I think what's going to happen is that there will be patients who will not get some of these drugs, largely because they won't do very much good - or none at all. If we get past the treat-everyone-with-everything style in oncology, it'll force us in the drug industry to modify our projections of market size, and we'll have to come up with a way to deal with it. Pushback from the insurance companies and physicans is a better check on the drug industry, to my mind, than a Central Office of Pharmaceutical Pricing could ever be.
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June 7, 2004
Posted by Derek
I wasn't planning on returning to this topic today, but tonight's e-mail seems to deserve a speedy reply. Says a loyal reader, one "Busterbuckeye":
You gave me a very impolite back hand slap in the above referenced blog. . .(on May 12) I posted in response to your April 28 blog in which you quoted Travers with approval: "Travers did indeed estimate Erbitux revenues at "peak" based solely on its one current crc indication. Your own April 29 response admits at least the possibility of other indications. After careful thought and perhaps after this coming ASCO, I invite you to reconsider adopting Travers' "peak" revenue estimates, and perhaps one of us (sic) my dine on crow."
In light of IMCL's ASCO data on Head & Neck, nsclc, and pancreatic cancer, you should be prepared to abandon Mr. Travers "peak" estimates and apologize for your rude treatment. . .
Let's take these points one at a time, skipping (for the moment) the back of the hand. Charley Travers of the Motley Fool did run his numbers based on the colon cancer indication. And in my April 29th post, "Yahoots", I did mention the possibility of other indications.
But take a look at the context in which I mentioned them. Here's the key part:
". . .don't let those shimmering waves of greed blind you to the facts: in their clinical trials, Imclone, BMS, and Merck-Darmstadt carefully picked the tumor types that would be expected to give the most robust response. That's how you get a drug approved, by going to the agencies with the best data you can get. Erbitux has already been tested in the areas where it's likely to gain the most market share and make the most profit."
Head and neck cancer, for example, is one of those carefully picked areas I was referring to. There's a good chance of a therapy targeted against EGFR showing efficacy against that kind of tumor, and it's an underserved patient population (although not an especially large one.) That's why they picked it for the clinical trial. It's not a new indication out of the blue.
So, let's remedy the situation. The numbers I linked to in yesterday's post speak of an SG Cowen estimate of a "$150 million market" for Imclone in head and neck cancer. It's unclear if that's the total market size, or the net to Imclone after they pay their royalties to BMS and Merck-Darmstadt. Let's be generous and say it's the latter. And let's double that figure, just to get in that optimistic frame of mind.
So, adding another $300 million means that it doubles the sales numbers that Travers estimated. The trouble is, by his figures, Imclone stock was already between 50% and 100% overvalued when he wrote his piece, and it's gone up more since then.
I'm prepared to modify my views, then: instead of saying that Imclone is that much overvalued, I'll put on my rose-colored glasses and say that under current conditions, it's valued about where it should be at its peak sales - a few years from now, mind you. Now, Imclone can pick up some sales in the more competitive NSCLC market, and some in pancreatic cancer too (a small market, but a cruelly underserved one.) But long before then, you Imclonites will have pushed the stock price up to take care of that slack, too. Hey, what am I talking about? You'll have the share price up there next week at this rate. Sell!
From a drug-company perspective, you're working on the assumption that everything will go perfectly. There will be no safety problems in any of these new indications, and no manufacturing or regulatory hitches. And you're choosing not to think too much about other new compounds hitting the market over the next few years. Some of them will take some market share, you know. For one thing, they won't cost $10,000 a month.
Now for the last point, that "apology" for "rude behavior". It's not happening. For one thing, my behavior was the expression of an opinion about the stock price of Imclone, and of those people who are willing to pay it. If you've made money on Imclone, that should be all the compensation you could ever want. I've lost money on them, myself, and believing that I'm right is of only limited consolation in such situations.
I have my opinions; you have yours. You don't have to read (or comment on) mine, and I probably wouldn't read yours on a salary. Perhaps you should start an Imclonocentric blog of your own - you'd probably get more traffic than I do, considering the fanatic following the company has.
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June 6, 2004
Posted by Derek
The American Society of Clinical Oncology meeting is taking place as you read this. ASCO is a pretty high-pressure venue, because key clinical results for cancer therapies are often unveiled there. The audience has a much higher percentage of journalists and financial analysts than you'll see at most meetings. It's a sandstorm of hype, all right - try this news search for a blast of it.
The Imclonites have already started filling my inbox, since I'd taken a crack at the company's stock valuation a couple of months ago. Imclone's just presented data at this ASCO showing that their antibody extends survival time significantly in patients with head and neck cancer. That's good news for the patients, who could use some, and I'm sure that IMCL shareholders figure it's great news for them, too.
But that market is in the low tens of thousands of patients. Even with sizable market penetration, I still think that Imclone stock is no bargain at 70-odd dollars a share. Mind you, that's what it was on Friday. It'll be worth taking a look during Monday's trading to see what it's been inflated to since this news came out. My advice to IMCL shareholders continues to be: cash in and run laughing to the bank. That's what Carl Icahn is doing, guys.
But feel free to ignore me, of course, and go take the other end of Icahn's trades for him. And don't forget to write and tell me what a knuckle-dragging throwback I am. It's not like I catch any abuse at work - I have to depend on my weblog to generate some, don't you know.
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+ TrackBacks (0) | Category: Business and Markets | Cancer
May 19, 2004
Posted by Derek
Closely related to the patenting of biochemical pathways is the patenting of genes. I'm not completely thrilled with that, either, but it still makes a bit more sense to me. With these patents, you own the gene and uses for it, but you don't get to claim everything else downstream of it (like the protein it codes for!) In the first genomic gold rush, the USPTO was swamped with gene applications, and granted quite a few of them without too much in the way of defined utility. Since then, they've tightened up, and you're really supposed to spell out what a gene is good for in order to patent it. Generally, that means using the gene as the basis for a diagnostic test.
In that vein, Myriad Genetics holds lucrative patents on the BRCA1 and BRCA2 breast-cancer susceptibility genes (background here), on which it makes plenty of diagnostic revenue. But it's been losing protection in Europe. Earlier this year, they lost their European patent for BRCA2, and now their BRCA1 patent is history, too.
In general, it's harder to get and hold on to such patents with the European Patent Office, but these decisions seem to have been taken on good old prior-art grounds rather than any finer points. It turns out that a British cancer charity research foundation had applied for BRCA2 before Myriad, which would seem to indicate that the latter's patent never should have even been granted. As for BRCA1, New Scientist reports that the Myriad amended their claims for it in 1995, correcting a few base pairs months after their first filing, during which time the sequence was published in the open literature. Whoops! Can't get a patent after that happens.
Myriad seems to have pretty much given up on the European market for these patents some time ago, what with all the legal trouble. But you have to assume that they're going to continue to pump the US market for all it's worth. Meanwhile, Canada (well, Ontario at least) is just ignoring these patents, according to the New York Times.
A question now is whether Myriad's claims are going to hold up over here. If this were a high-level question about the patentability of genes, the arguing could go on for a long time. But if we're just talking prior art, then it just comes down to some relatively simple issues: are their filing dates just as hosed up here, or not? And even if they are, is there anyone motivated enough to challenge them?
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+ TrackBacks (0) | Category: Cancer | Patents and IP
May 4, 2004
Posted by Derek
Bad days for Genta and Allos, as the FDA first made their advisory committee minutes public on Friday, then turned down their drug applications yesterday. Both are nominally cancer therapeutics, and both were seen as tests of a supposedly more open attitude at the FDA, but they're very different situations.
Genta is, at first glance, a time warp of a company. They (and some others, like Isis) have been trying for years to get antisense DNA therapeutics to work. It hasn't been a very rewarding area, although most anyone who've been in the field for ten or fifteen years can recall when it was so hot you couldn't stand next to it. Delivering the DNA (or DNA analogs) has been hard, formulating them has been hard, and showing that they do anything has been very hard indeed. That was Genta's big problem this week. And that means that is was also, to a lesser extent, their partner Aventis's problem. I hope Sanofi wasn't counting on this one, but since I don't really understand why Sanofi went after Aventis at all, who can say?
The compound, Genasense, goes after the production of a protein called Bcl-2, about which more information than you want is here. A lack of Bcl-2 would make cells more vulnerable to programmed cell death (apoptosis - pronounced, if you're as much of a pain as I am, as "ay-po-tosis", not "ay-pop-tosis".) A major thing cancer cells manage to do is to bypass the you're-a-mutant-kill-yourself apoptosis signal and keep on growing, so this is a target of great interest.
But Bcl-2 works through interactions with other proteins, so it doesn't have any real small-molecule binding regions. That makes it a tough target for drug therapy (although that hasn't stopped people from trying.) Antisense or siRNA techniques could potentially stop production of the protein in the cell, though, and provide a completely new cancer therapy. Enter Genasense - and exit it, too, because it doesn't work well enough on its own to be a monotherapy, and didn't meet statistical significance as additional chemotherapy in a trial of over 700 patients.
Genta believes that a subset of the treatment group, the ones who received the compound the longest, showed enough of an effect to approve the compound, though, along with other data on things like mean tumor size. The FDA clearly didn't agree, pointing out the drug's significant toxicity, which decision should throw some cold water on the people who were hoping that things were going to be approved more easily now, with less rigorous efficacy data.
Allos got the cold shower too, but for a different sort of compound. Their RSR13 is a radiation sensitizer, working on the principle that much radiation damage in cells is done through oxidative free radicals. Unfortunately, many solid tumors are rather oxygen-deprived, due to poor circulation, so the Allos approach was to increase the rate of oxygen release from hemoglobin in general. Makes me wonder if they're going to start finding this stuff in the blood of bicycle racers.
Allos went after brain metastases in advanced breast cancer, a patient population that needs all the help it can get. Unfortunately, they didn't reach significance, either, but countered that, you guessed it, a subgroup showed a much larger effect. They might have a point, although it's always risky to ex-post-facto your clinical data. We had a discussion about this on this site a while back, and it was pointed out that for a sufficiently large set of sliced-and-diced subgroups, the real surprise would be if one of them didn't show an outlier effect.
Of the two drugs, though, I find the RSR13 story to have (at least as far as I can tell) a better chance of actually coming true after another round of clinical trials. Antisense worries me, at least in its present incarnation, and I'm not sure how many more forms it's going to get a chance to take. Both stocks were hammered on Friday and Monday, and (truth in trading time) I picked up several hundred shares of Allos today at $2.50 for the long term.
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+ TrackBacks (0) | Category: Business and Markets | Cancer
April 29, 2004
Posted by Derek
The real news on the cancer front is in the post below, but I have a few other things to take care of tonight, too. Yesterday's post on Imclone's stock price was not well-received over on the IMCL message boards on Yahoo, where I've picked up several of the usual responses. They include the standard-issue Dark Suspicions that I'm one of the Evil Stock Bashers trying to scare The Little Guys into parting with their beloved Imclone, presumably so my top-hatted overseers can scoop it up for a song.
Well, folks, the guy with the top hat who was scooping up Imclone when it was cheap is Carl Icahn, more power to him. I don't work for him, sad to say. He bought the majority of his stake, several million shares worth, below $20, and he's for damn sure not buying in at $70 a share - in fact, he's probably selling his shares to you.
On a slightly higher plane, one comment sums up several others that I've received:
"These guys are clueless. (Erbitux) works against a growth factor common in numerous cancers. What they do not comprehend is the fact that if it works against one, it works against many; and if it works late stage, it works early and middle stage too. They value Erbitux based only on its approval, as if it will never receive any other indication approvals. Like I said, clueless."
I'd like to point out to this fellow and the other Yahoots that, unfortunately for this argument, I do drug research for a living. Blogging most certainly does not pay my bills; Big Pharma does. And among the therapeutic areas I work in is cancer, giving me a reasonable familiarity with the field. I can state, then, with some assurance, that the commentator above is full of fertilizer.
Yes, the epidermal growth factor receptor is indeed common in many cancers. But its importance varies widely in different tumor lines, and widely among different strains of what superficially appear to be the same kind of tumor. The same goes for all the other cancer targets you can name. A more accurate restatement of the above person's doctrine would be: If it works against one, it might work against some others. Or it might not.
We're only beginning to figure out the details, and - this is important - they're not going to increase Erbitux's market share when we do. Read the next post below for more on this. Erbitux will pick up some off-label sales, sure, but it's not going to end up with a long list of approved indications that will push it into the stratosphere.
And why not? Well, don't let those shimmering waves of greed blind you to the facts: in their clinical trials, Imclone, BMS, and Merck-Darmstadt carefully picked the tumor types that would be expected to give the most robust response. That's how you get a drug approved, by going to the agencies with the best data you can get. Erbitux has already been tested in the areas where it's likely to gain the most market share and make the most profit.
And there are plenty more drugs breathing down its neck. Go on and hold that IMCL, guys, go ahead and mortgage the house to buy some more. Maybe you'll watch it go to $150; stupider things have happened. But I think that the odds are that you're going to wish you'd taken your profits in 2004.
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+ TrackBacks (0) | Category: Business and Markets | Cancer
April 28, 2004
Posted by Derek
It's been a wild time recently in the oncology field - well, not so much scientifically as financially. OSI took a huge leap the other day on good clinical news about Tarceva, the drug they're developing with Genentech. I'll gloss over the fact that I owned OSI stock at one point, and sold it in the 30s. Watching it go straight up to 90 in one day caused me a bit of a twinge, although I really don't think it has any business being that high. If I had still owned it, I'd have been knocking over things on my desk trying to get to the phone to sell my shares.
To further illustrate the fact that I should not be managing my own hedge fund, readers may recall that I was short Imclone stock earlier this year. I shorted at $40, and got out in March at $46, having been first ahead and then behind on the position. By the time I got out, the famous Erbitux had been approved, and it looked as if people were going to allow themselves to believe a lot of good things about its prospects.
That they have. The stock hasn't pulled an OSIP, at least not yet, but there's been a lot of sustained buying. As of today, Imclone stock is around $70, and who knows how far it'll go? After all, the same mindset that takes it to that price from $40 is perfectly capable of going to $100 from here. No problem at all - hey, on a percentage basis, that's less of a haul than what's been accomplished so far. I'm glad that I decided not to stand in front of that particular train.
But what kind of track are the current buyers standing in the middle of? Guys, Erbitux is a drug that does some good for some people with some kinds of tumors. There's nothing wrong with that at all - in fact, it's a valid description of every form of cancer therapy on the market. But there are a lot of interesting therapies out there already, and there are a lot more coming. An antibody that costs thousands of dollars a month cannot possibly rule that world, not with that kind of efficacy. I wholeheartedly agree with Charly Travers over at the Motley Fool, who says:
"I really have to wonder who is buying this stock and just what the heck they are thinking. ImClone's Erbitux is approved as third-line therapy in patients with metastatic colorectal cancer that expresses the epidermal growth factor receptor. Taking into account this population size and assuming 30% market penetration and a drug cost of $10,000 per month, I arrive at a peak U.S. sales figure near $600 million. With a 39% royalty on those sales due to ImClone from partner Bristol-Myers Squibb (NYSE: BMY), ImClone's revenues would be near $225 million. Adding in a royalty on European sales from partner Merck (NYSE: MRK), my ballpark figures for peak ImClone revenues from worldwide sales of Erbitux are $275 million to $325 million."
Problem is, that means that Imclone is already priced at between 50% and 100% higher than it probably should be at its peak. When you buy a stock like this, aren't you buying it in the expectation of growth? Where on earth is that going to come from? Today's buyers can only hope for people who can't do math to come along and relieve them of their shares. More likely, the mathematically impaired are already in there buying right now, which will gradually limit the target audience for a profitable resale to either pretechnological tribesmen or the crews of recently arrived UFOs.
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+ TrackBacks (0) | Category: Business and Markets | Cancer
January 11, 2004
Posted by Derek
In my industry, you hear a lot of talk about drug targets and their relative chances of success. Targets fall into several broad classes, and when you take a close look, there are clearly some that are easier to hit than others. The G-protein coupled receptors (GPCRs) are one of those (antihistamines and beta-blockers are classic examples), and various hydrolytic enzymes are another (ACE inhibitors, HIV protease inhibitors, PDE inhibitors like Viagra, etc.)
But there are some other categories that are severely under-represented. "Interaction" targets is what I'd call a broad group of these. The ligands for the easier enzymes and GPCRs fit into defined binding pockets, which have evolved for small molecules, It's the old lock-and-key picture. But trying to affect the binding between two proteins, or of a protein with a stretch of DNA/RNA - now, that's something else again. There's no single binding pocket there, at least not on the scale of a drug-sized molecule. Instead of fitting different-shaped keys into existing locks, we're faced with trying to wedge something in between a door and its frame.
It's hard to get in there, and our molecules are often too small to have much effect. But the number of drug targets in this class is huge; we're going to have to come to terms with them eventually. . But for now, one of the best ways is to carefully study the various high-value targets and see if there are some that look more likely to work, given what we already know how to do. That's what a group at Roche has been up to recently, and they've reported their success in an online preprint in Science.
They're after a protein called MDM2, which acts as a brake on the activity of a more famous protein from the p53 tumor-suppression gene. In many cancers, it would be good to block this interaction and get the p53 system as back to being revved-up as possible. (Of course, in many other cancers, this gene has already been taken out of action by one mutation or another, which is probably a key step in their formation. Those won't be candidates for MDM2 blocking therapies.)
In 1996, a group at Sloan-Kettering published an X-ray crystal structure of the two proteins, which showed that there was a fairly clear pocket that seemed responsible for a lot of the binding. It looked like a possible candidate for a small molecule, but this is the first report of real success in targeting it (although others are hard at work.) The Roche group found some polyaryl imidazoline structures through high-throughput screening that seem to do the job. One of them is even orally active in a rodent tumor model, which is quite an accomplishment. And as proof of the mechanism, the compounds are inactive against those cancer cell lines that have already lost their p53 gene.
This is good news, since we can always use another route to cancer therapy. But I'm not sure how broadly applicable this is going to be. I'm sure that there will be talk of new interest in protein-protein drug targets, but this one is (unfortunately) an anomaly. That type of small, reasonably well-defined pocket that plays a role here doesn't show up that often, and it's not like people haven't been looking. News that these things can succeed will stimulate more work in the area, true. But that's where a lot of the effort was going already, because other protein-protein targets have seemed destined to fail.
My mental picture of those targets is of two oil tankers slowly coming together, brought closer as dozens of small grappling hooks whiz out and clang onto different parts of their decks. With a small molecule, we're trying to interfere with that by sticking a fishing boat in between them. Not easy, but we're going to have to figure it out eventually. Protein-protein interactions are a hot topic these days (go off and Google "proteomics", but stand well clear while you do it!) so we're bound to learn a lot more in the next few years.
For now, congratulations to Roche as they move forward toward the clinic. They'll be the first to find out what blocking MDM2 binding is going to do to animals - how well it'll treat those with cancer, and what side effects it might have on those without. I hope there's daylight in between those two groups!
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+ TrackBacks (0) | Category: Biological News | Cancer
December 30, 2002
Posted by Derek
After a (reasonably) refreshing holiday break, Lagniappe is back. Thanks to everyone who kept doggedly hitting this site during the last few days - I admire your persistance.
I notice from my site's counter that I get a small but steady flow of Google hits for various miracle cures. I said some nasty things about the Budwig flaxseed-oil diet a while back, for example, and I still get Googled for that one. For those visitors, here's a post that (with any luck) will show up for a long time to come.
To put it in one sentence, distrust simple cures for complex diseases. Cancer is a complex disease, so are arthritis, MS, Alzheimer's and diabetes. What's a simple disease? An infectious one: there's a proximate cause, and a path to cure it. Get rid of the bacteria, and your septicemia goes with them. Clear out the parasites, and no more malaria. (You'll note that we don't have a universal malaria cure yet, which should say something about how hard even the simpler diseases are.)
The really tough ones, though, are all things that originate from some misfiring of the body's own systems. It's true that there are single-gene diseases, which would be simple to treat if we only knew how to get gene therapy to work. Most of them are rarities, diagnostic zebras that many physicians will never see. The ones that every physician sees are multifactorial and very hard to deal with.
I've spent a lot of time on this site talking about autism recently, and there's a common factor. I believe that many diseases only look like single conditions, which turn into dozens of other diseases on closer inspection. There's no such disease as "cancer," for example. Cancer is the name we sloppily apply to the end result of dozens, hundreds of metabolic or genetic defects and breakdowns, all of which end up as vaguely similar cell-differentiation diseases. It wouldn't surprise me if Alzheimer's ends up as something that can be caused several different ways, all of which end up in the same alternate low-energy state for the brain's metabolic order. (I speculated on this back in the first month of this blog's existence.)
And autism, too, could well be the name we're giving to several different diseases, distinguished by their time course, onset, and severity, caused by all sorts of intricate interplay - the wrong chord played on the instrument at just the wrong time.
You can, at times, find single factors that lead into these diseases - a compound called benzidine leads to bladder cancer, for example, although not in every person exposed, and at unpredictable exposures over unpredictable times. But that doesn't mean that everyone who has bladder cancer has been exposed to benzidine - not many people ever are these days. And stomach cancer, for example, has nothing to do with benzidine at all. Even the simple cases aren't too simple.
Remember the power line scare? How those electromagnetic fields from high-tension lines were messing up everyone's lives? You could see stories about how power-line exposure had been linked to brain cancer, to kidney cancer, to skin cancer. The problem was, one study would show a barely-there tenuous link to brain cancer - but not to anything else. Another would show the same wispy possible connection to kidney cancer - but not to anything else. And so on - after looking over all the data, the best conclusion was that this was all statistical noise. Beware statistical noise - that's another long-running theme around here.
Epidemiology hasn't been a simple field since the days of yellow fever, if it even was then. And medicine hasn't been a simple one since the first days that ever counted. As time goes on, we're clearing out more and more of the easy stuff. The really hard stuff is what's left, and it's going to be resistant to simple fixes.
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+ TrackBacks (0) | Category: Alzheimer's Disease | Cancer | Toxicology
November 4, 2002
Posted by Derek
There seems to be something odd going on with Iressa, AstraZeneca's great oncology hope. In Japan (the only place where it's on the market,) there's been an unusually high incidence of interstitial pneumonia among its patients. The FDA has scheduled a December meeting, almost certainly to talk about this situation and how it affects the US approval process.
It's not obvious, on the face of it, how a kinase inhibitor would lead to increased risk of pneumonia (and increased severity once you get it, apparently.) My first thought was that this had to be some non-mechanism based tox effect, something to do with the compound but not its mode of action. But on further thinking (and further speculating with colleagues down the hall,) I'm not so sure. Since Iressa is involved in inhibiting the signaling of epidermal growth factor, it's conceivable that it could alter the surface characteristics of pulmonary tissue. Perhaps a tissue change makes the bacteria adhere better, or hinders the immune response?
This is, as I mentioned, sheer speculation. I hope it's wrong. But if it's on the right track, then that's further bad news for what (a few months ago) looked like a potentially huge drug. And it would also be a major concern to all the other drug companies involved in epidermal growth factor receptor signaling (and there are plenty.) You can bet that everyone generating clinical data in the area is frantically digging through their records, looking for pneumonia.
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October 27, 2002
Posted by Derek
I mentioned that Amgen had a rough time with their leptin program, but there are people who benefit tremendously from the protein. There are some people (very few, actually) who are similar to the ob/ob mouse, in that they have a mutation in their leptin protein gene. They tend to have a lot of metabolic troubles, starting with morbid obesity and a terrible blood lipid profile. Administration of the human protein works wonders for them.
So leptin, therapeutically, is an orphan drug. And the identification of patients who can benefit from it is a harbinger of the era of "personalized medicine" that everyone says is coming. They're probably right, because we're actually learning to pick up on more and more cues like this, and finding them is an area of frantic research (and frantic funding.) The push is on to identify things in both directions: positive (who will benefit from Drug X?) and negative (who will show nasty side effects from Drug X?)
That second category could have saved a lot of drugs that have disappeared from advanced clinical trials, or even some that have disappeared from the market. It's quite possible that we'll see some of these brought back from cold storage in some fashion, when we find ways to get around their bad low-incidence problems. This sort of thing (toxicogenomics) is what many drug industry researchers think of when they think of the promise of genomics - who could blame them?
But it's that first category, pharmacogenomics, that'll make life interesting. Look, for example, at some of the cancer therapies in the clinic now. Even though things like Iressa and Erbitux seem to work dramatically in some patients, they completely fail in others. There's no way to tell which group a new patient will end up in - if you could sort them out, you'd only give it to the dramatic-recovery crowd, and tell the others not to waste their time (or their money.)
Or their money. . .there's the rub. What happens when we get to this point, when we can predict who will respond to our new drugs and who won't? The customers sure will be happy - but there won't be nearly as many of them. Face it, when a new therapy for a grave disease (cancer, AIDS, diabetes, etc.) hits the market now, everyone's going to try it out. Even as it fails in a certain percent of users, everyone's going to. . .well. . .buy it. And that's figured into industry calculations. When you think about the potential market for your new drug, you aim for the biggest number of possible patients/customers.
What if you cut that market in half? Or more? What if the only people who buy your drug are the ones that it's certain to work for? You've now got a smaller market. A well-served one, that's for sure, but smaller all the same. But developing your drug didn't cost any less than it did when you developed it for the whole crowd, hit or miss, and it just might have cost even more. So how are you going to do it, selling it to a smaller group?
Well, as far as I can see, the price will go up. It'll have to. No one will care for this one bit, but that's what's going to have to happen. That'll be the surcharge for making sure that the drug does what it's supposed to. And those of us in research will have to get used to the idea that we're going to have to develop even more new drugs as we do now, to make sure that we cover all the patient groups in what used to be larger, less differentiated markets. Given the struggles we're having to develop things as they stand, that's going to be a lively undertaking indeed.
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+ TrackBacks (0) | Category: Business and Markets | Cancer
October 17, 2002
Posted by Derek
I'm late to this particular party - see Charles Murtaugh and Medpundit for the low-down on a particularly irritating LA Times column. (It requires registration to read, which is fairly irritating all by itself.)
In a nutshell, the writer attempts to blame environmental factors for many cases of breast cancer, specifically chemicals produced by the very companies that are working on treatments. This comes very close to one of the things that will set off even the most mild-mannered pharmaceutical researcher: the conspiracy theory that says that They're Making Us Sick Just So They Can Sell Us Their Drugs. (That one's right next to They've Really Got A Cure, But They're Just Waiting Until More People Are Sick.)
Well, I'm not exactly the most mild-mannered pharmaceutical researcher, myself. And this stuff makes want to throw a one-liter filter flask at the person who espouses it. If the author wants to indulge in stupid breast cancer etiology, why not go for the deodorant theory? That one's even more mindless.
I understand the human tendency to look for a proximate cause for everything, and to search for patterns even in random noise. It's even more tempting to think that the answer's been right under our nose (or under our arms!) the whole time. "Aha! We should have known!"
But this is offensively foolish stuff. I don't have the time to dismantle it thoroughly enough tonight, but perhaps I'll give it another kick in the shins next week. We'll talk about real epidemiology instead of inflammatory guano.
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+ TrackBacks (0) | Category: Cancer | Press Coverage
October 8, 2002
Posted by Derek
he genetic news of the day, subject of good-sized headlines in the Wall St. Journal and elsewhere, is an upcoming paper in PNAS on a candidate cancer gene called DBC2. Some of these abbreviations are pretty recondite, but not this one - it stands for "Deleted in Breast Cancer," which is pretty tame by the standards of genomic nomenclature.
These researchers (at Cold Spring Harbor) have looked at a lot of different cell lines, and they've spent years tracking everything down. This gene seems to be altered in a number of breast and lung cancers, and (equally importantly) doesn't seem to be changed in normal tissue samples. There's a reasonable chance that DBC mutations are indeed a causative factor in some of these cancers, and the evidence is good enough to put a lot more people working on it (which is no doubt happening as we speak.) Still, this would be a good time for everyone to recite the Pharmacogenomics Pledge. All together now, especially you folks at New Scientist:
Correlation Does Not Imply Causation
I singled out the New Scientist article because of lines like this one, from their article:
"Hamaguchi thinks treatments based on switching on the gene, dubbed DBC2, could be available in three or four years."
If he really said that, then I hate to be the bearer of bad news: he's almost certainly wrong. Even if they found such a treatment this afternoon, it would take more time than that to make it available. Development, testing, full-scale clinical trials, regulatory scrutiny - it really adds up.
And that's after the hard part, finding the treatment. The problem is, switching on an individual gene isn't something that we're really good at - we tend to switch a few hundred others on (and switch a few hundred others off) when we try that via drug therapy. (And keep in mind that this gene is defective in many cancer cell lines, so presumably switching it on won't do much good in those cases.) This sounds like a possible candidate for gene therapy, but how to apply that to solid tumors is a non-trivial question.
If it were a question of switching the gene off, there would be some hope from either an antisense DNA approach (not that it's easy to get that to work - no drug has made it yet, despite years of effort,) or through a very interesting new technique called RNA interference. That needs to be the subject of another posting entirely, but it's potentially promising - for turning things off, that is.
As the press articles generally make clear, no one knows what the actual function of DBC2 is. It's from somewhere in the wilderness of chromosome 8, and it seems to be from a family of proteins about which almost nothing is known. It doesn't look like a typical cell-surface receptor, nor like the usual classes of enzymes. I'll go out on a limb and guess it's some sort of transcription factor, but that's a pretty broad category.
The real accomplishment of this work is finding the gene, not finding ways to use it. Good new drug targets are getting harder to find, as is becoming painfully clear these days, and a whole new potential class of them is a welcome development. Figuring out what they might be is bound to lead to some useful information. Let's hope it leads to a drug, too - but it's going to be more than four years before that happens, I'm sad to say.
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September 24, 2002
Posted by Derek
Here we are again. Back in February (see the Feb. 27th post), the FDA asked for more data for Imclone's cancer therapy, Erbitux, saying the existing studies were not sufficient to approve the drug. The Wall Street Journal's editorial page threw a memorable fit about what they saw as the FDA's intransigence (to which piece I responded on June 18th.)
Now comes AstraZeneca to the FDA, similarly looking for fast-track approval of their similarly targeted (see the August 20th post) small molecule therapy, Iressa. The FDA's advisory panel met today, and ended up appoving the drug. The reviewer comments in the briefing documents suggested on Monday, though, that AZN was in for a hard time - and because of similarly unconvincing data.
And once again, the Journal weighed in today with a table-pounding editorial. Allow me to comment on their worldview:
Earlier this year, Astra-Zeneca reported very encouraging results from a couple of small trials totaling about 400 patients. The drug shrank tumors in 10 to 19% of lung cancer patients who had not responded to chemotherapy, and improved symptoms in about 40%. Most importantly, it appeared to add to the length and quality of life.
Sounds impressive when you put it that way! Let's look at the trial that AstraZeneca is using as their showpiece: 216 patients with non-small cell lung cancer who had failed standard chemotherapy. Unfortunately, the FDA contends that only 139 of those patients had truly not responded to earlier treatments. (The presence of these patients muddies the statistical evidence quite a bit, and it's just this sort of thing that helped to get Imclone's application in trouble.)
How many of these 139 responded to Iressa? Ten percent. Is a 10% response rate good enough to provide real-world clinical benefits? Is it enough reason to approve a drug on an accelerated schedule? Both those questions are very much open to argument, and even if the answer to the first one is "yes," reasonable people can believe that the answer to the second one is "no"
How about those improved symptoms? We have AstraZeneca's word that 40% showed some improvement in coughing and shortness of breath. But these results are not compared to any sort of control group, making them very hard to interpret - actually, it flat out makes it hard to determine that they're not an illusion. Other medications were also administered during the trial, and the study design makes it difficult (perhaps impossible) to say if those were responsible.
Most importantly, it appeared to add to the length and quality of life. Studies of Iressa in other cancers, such as head-and-neck, and yielding similar results.
That last statement is, unfortunately, true. The overall response rate in the head and neck trial (reported in May at the ASCO meeting) was 11%. As for quality of life, measuring that is hard enough under any circumstances, and measuring it without a control group is, I believe, basically impossible.
How about the other studies? The ones that this impassioned editorial doesn't mention? The two lung cancer studies that dosed Iressa plus standard chemotherapies - you know, the studies that actually had control groups? Iressa didn't have a 10% response rate in those. It had a zero per cent response rate - it didn't add to the effects of either one of the standard agents at all. The FDA found itself in the position of being asked to approve a drug that has completely failed to work in two studies, and shown marginal effects in two more.
. . .it is actually a repudiation of the speedier approval process the FDA has come to accept in drugs for terminal disease. . .that means approval base don smaller, so-called Phase 2 trials, along with compassionate use data to help establish safety. . .compassionate use programs can make a nit-picking bureaucrat's life difficult, by getting good drugs into the hands of many doctors and patients, who thereafter become a constituency urging formal FDA approval.
Nice use of the adjective. Compassionate use can also make a drug company's life difficult, as an avalanche of requests comes pouring in. It can make a scientist's life difficult, because the data obtained are usually of poor quality - heterogeneous and not well controlled.
But let's get emotional, since the Journal does: compassionate use can also make things damned difficult for terminally ill patients and their families. Remember, patients know they're getting an experimental drug, their last chance for survival. The FDA heard from some of those patients today, and I'm glad that they're still here to testify. And let's talk about those "good drugs": remember, in the lung cancer trials, 90% of the patients who took Iressa as monotherapy did not respond. And 100% of the patients who took it in combination therapy saw no added benefit. We didn't hear from these patients today. Many of them aren't around to talk about how hopeful they were that this new drug might save their lives.
The point here isn't to quibble with the FDA's suggestion yesterday that the data could be better. Studies can always be larger.
Yep. That helps. And drugs could always show some convincing efficacy; that would help, too. That's one good definition of the data being better.
The point is that this isn't a good reason, and certainly not an ethical one, for delaying approval. Particularly in cases of terminal disease, any safe drug with even a hint of effectiveness should be brought to market as quickly as possible.
An uncontrolled trial of powdered milk could end up showing "a hint of effectiveness," guys. Iressa's better than that, of course, but where do we draw the line? If we don't insist on solid statistics from well-run trials, we might as well just throw open the floodgates. The FDA is trying to get companies focused on proving that their therapies actually do something, while (because of the state of the industry) many companies are focused on trying to get their drugs on the market by the quickest route possible, cutting the clinical trials as thin as they can. Imclone's a much more spectacular example of that, but AstraZeneca should still count itself lucky to have gotten Iressa through.
Reading the editorials that the Journal has pumped out over the last few months, you get the mental picture of mustache-twirling FDA baddies snickering as cancer patients expire all around them. It's a caricature of the truth. It feels odd for me to stick up for a regulatory agency, but I'll stick up for this one. Speaking as a researcher in the industry, I can say that the FDA drives us all nuts, but we need them. We need people to poke holes in the studies, to question the data, to give us a hard time. It's called science. It's how we've made it as far as we have.
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August 28, 2002
Posted by Derek
Man, with headlines like that, I can't think of why I'm not pulling in thousands of hits a day. Anyway, I wanted to follow up on yesterday's posting by emphasizing that aneuploidy hasn't been ignored for all these years. It's just that the chicken-and-egg question about its role in cancer is heating up.
For example, the "micronucleus test" is often done alongside the Ames test. It's a direct measurement for this sort of chromosome breakage and malformation. The "micronucleus test" can be done with various cell lines, but one popular method is to administer the compounds to rodents and check their red blood cells (erythrocytes.) This looks at the effects on the precursor bone marrow stem cells, and depends on the odd fact that erythrocytes have their nucleus removed while they're developing.
If severe genomic damage occurs, odds and ends of chromosomes often end up lumped together in a separate "micronucleus" floating around detached from the main one. The micronucleus doesn't get pushed out of the erythrocyte, though, and it ends up standing out dramatically in a finished red blood cell. You can do such tests on other cells in culture as well, but those variations haven't been as well validated as the in vivo one.
If there are human cells with a tendency towards induced aneuploidy (as Duesberg and others claim) then there are some new possibilities for a useful screening test. One hitch might be that cultured cell lines often forget their origins after a while and act differently - not being exposed to all the various extracellular signals they're used to probably explains a lot of this. It's worth a look, though, particularly if aneuploidy does turn out to be an early event in carcinogenesis.
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August 27, 2002
Posted by Derek
My recent posts about the Ames test (see July 29 and July 30) went into some detail about its use for estimating the mutagenicity of a compound. And mutagenicity is of course a bad thing, because increased DNA damage is generally held to be a factor in carcinogenesis.
But just how that works is the subject of some major disagreement. To wit: How many mutations does it take? How quickly do cells mutate under normal conditions, anyway, and do different types mutate at different rates? How much are those rate differences influenced by the environment? Are all cancers caused this way?
These question all bear on a current hot topic: do cells become cancerous due to some specific small mutations, or because of wide-ranging genomic instability (aneuploidy)? The latter hypothesis is having its inning recently, as witness some major articles in the July 26 issue of Science. This genomic instability is, by all accounts, a real junkpile of broken and reglued chromosomes. It really makes you respect what you can to the basic machinery of a cell and have it still function. Aneuploidy is found in a wide range of cancer cells - but is it a cause of cancer, or is it an effect?
The specific-mutation hypothesis has had a deservedly long run. Many candidate genes have been discovered, and they've been the subject of massive research efforts. At this point, there's little doubt that they're important, although their importance varies greatly between tumor types. Typically, these genes code for proteins that are important for cell growth - either positive factors or negative ones. Mutations that switch positive growth factors permanently on can lead to a cancer, as can those that wipe out the braking functions of a negative growth factor.
An example of the former is the ras oncogene, important in bladder tumors, among others: a single DNA base switch leads to an amino acid substitution (valine for glycine) in the expressed protein. That sends this protein into a permanent "on" state in its cellular signaling cascade, with out-of-control growth the result. And a good example of a negative-control mutations is p53, a protein whose normal function is in one of the cell-cycle checkpoints. It's part of the error-checking machinery. If p53 is functioning correctly, cells with many types of DNA damage are prevented from going on through cell division. Several mutations have been shown to impair p53 function, though, and these are found in a wide variety of aggressive tumor lines.
And it's not just single point mutations like these, either. Fusion proteins (front part from one gene, back part from another, for example) can lead to the same problems, as can mutations that don't change a protein's structure, but change the amount of it that's expressed in the cell. It usually takes more than one of any of these mutations to really set off a tumor.
Where things start to get messy, is when you try to figure out where those changes are coming from, and if they're always associated with cancer. The aneuploidy advocates believe that some cell types are prone to genomic instability, giving them a much greater chance of racking up enough mutations to become cancerous. Even that's subject to dispute. Does that mean instability toward point mutations, or toward large-scale chromosome breakage and shuffling? There's evidence pointing both ways.
While many chemical carcinogens are known to produce mutations, others don't seem to cause any. (Those are presumably the ones that an Ames test would miss, a prospect that keeps toxicologists up at night.) Peter Duesberg's group at Berkeley claims that such compounds do cause aneuploidy, though, and that this state is one of the early events in tumor development. And yes, that's the same Duesberg whose HIV theories keep the adjective "controversial" glued to his name. There's a group at Johns Hopkins whose work supports this sequence of events, too - and work from Harvard that argues against it. It's going to be a while before anyone gets this all sorted out.
I think it's likely that answer is going to turn out to be a mix. Gross chromosomal disturbance would certainly seem likely to cause either cell death or conversion to a cancerous state. Making this a one-size-fits-all precondition, though, seems like overreaching. But that goes for the small-mutation crowd, too. They have some good examples on their side, but there are plenty of cancers that don't fit into the established categories very well. It seems quite plausible that some cell types are more susceptible to chromosomal abnormalities than others. At the very least, some would be expected to be more susceptible to smaller mutational changes. At some point between these two, the explanations start to converge.
As a medicinal chemist, what I'm interested in are new drug targets. That's where aneuploidy is still a bit young, as a well-investigated hypothesis, to offer me anything to work on. Are there particular enzymes that could be targeted to reduce genomic instability, active-site switches to throw on or block? No one knows yet. I'll watch the debates with interest, but the parties involved should call folks like me when those questions are closer to being answered.
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August 20, 2002
Posted by Derek
AstraZeneca's revelation yesterday was quite disturbing. Their experimental cancer therapy (Iressa) doesn't seem to offer any added benefits when given in chemotherapy combinations, at least in non-small cell lung cancer. That's a type of tumor that the approach really should have worked in, and one that the compound had shown some efficacy in as a monotherapy. The data were particularly unexpected, given that preclinical models had shown that the compound should have added to the effects of standard chemotherapy agents (taxol, cisplatin, etc.) So much for the model systems.
This news sure didn't do AstraZeneca any good, but it really torpedoed the stock of competitor OSI, whose similar compound (Tarceva, developed with Genentech) is a much greater percent of that company's future. Two others in the field, Abgenix and everyone's favorite, Imclone, also declined.
The reporting on this story in the general press has been pretty poor (but with the Wall St. Journal doing a much better job than the New York Times, for example.) The problem is that it's a fairly complex biological issue, and some of the key issues are still unresolved.
All of these companies are nominally targeting EGFR, the epidermal growth factor receptor. But they're doing it in different ways, and there's more than one type of EGFR, too. The two that are most well-understood are HER1 (technically the only one that's really called EGFR) and HER2 (there's a HER3 and a HER4, too.) When activated, these stimulate cell growth and proliferation. The activating molecules can be just floating around, but in some cases the tumor cells are thought to make their own activating ligands, a particularly vicious mechanism. An added complication is that the active form of the receptor is actually a dimer of two HER types, and they seem to be able to mix-and-match. This fact is surely significant, but the details are still obscure.
HER2 is known to be overexpressed in many breast cancers, and overexpression of either it or HER1 seems to make a tumor more difficult to treat. How much the overexpression levels correlate with activity isn't well understood, either - the "tone" of the system seems to vary in different sorts of cancers.
One way that drug companies have gone after these targets is through antibodies. The antibodies bind, presumably, to a big swath of the surface of the receptor, blocking it from being activated. There's a possible bonus here, since this sort of antibody technique also seems to be toxic to the cells. There's a commercial HER2 antibody from Genentech, Herceptin, which seems to have decent activity (alone or in combination) in HER2-rich tumors. Imclone's Erbitux is an antibody to HER1, and Abgenix is the other antibody player.
The other way to attack these receptors is through small molecules. No one's ever found anything reasonable that'll do the job of an antibody (that is, physically blocking the receptor.) There is a target downstream, though. The receptor phosphorylates itself to activate, and this kinase activity is suitable for a small molecule inhibitor. That's Iressa, OSI's Tarceva, and some others from GSK, Novartis, Pfizer, and others.
These drugs vary in their potency against HER1 and HER2. Iressa and Tarceva are pretty similar - more HER1 than HER2. (thus the swoon in OSI's stock, which I'd say was justified, given the data.) GSK's GW-2016 is very potent against both, and Pfizer's CI-1033 is not only potent, but binds irreversibly. That's normally not a mechanism you'd want to see, but in oncology all the gloves are off.
As far as comparing the antibody therapies with the small molecules, though - well, the Wall St. Journal today suggested that Imclone could be in major trouble. I think that that's getting ahead of the science. The kinase inhibitors and the antibodies have differences in mechanism, HER selectivity aside. This certainly wasn't good news for Imclone, but it wasn't the red alert that it was for OSI and Genentech.
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June 18, 2002
Posted by Derek
Having unloaded on the Weekly Standardlast week, I now find myself taking aim at the Wall Street Journal. Pretty soon, I'm going to be in the pundit equivalent of Albania (as was,) having ditched my every natural ally.
But it has to be done. The Journal has an editorial today on the Imclone situation - an long impassioned one that starts from false premises and draws incorrect conclusions from them. Let's excerpt the thing:
After starting off by expressing sympathy for cancer patients (and no sympathy for Sam Waksal or Martha Stewart, all perfectly defensible positions,) the editorial calls for "focusing on the FDA's role in this fiasco. . .while Imclone has not produced a study of the size and type the FDA appears to want, the larger truth is that Erbitux continues to show promising results iin small trials."
Note the "appears." Actually, it "appears" that the FDA made its requirements for clinical trials very clear, and it was Imclone that obfuscated. The dispute, which came to light during the recent congressional hearings, centers on the Phase II trial, a combination therapy of Imclone's Erbitux and the current chemotherapy agent irinotecan for colorectal cancer. Originally, as of August 1999, patients were going to get the combination of the two drugs only if their disease had still progressed after two cycles of irinotecan alone. Imclone amended this in October to allow combination therapy after any irinotecan treatment at all, and it appears that the FDA didn't completely catch on. And as it turned out, this plan muddied eventually the data thoroughly enough to make it hard to see if Imclone's drug did anything at all. But it sure did speed things up, which seems to have been what really mattered.
Harlan Waksal of Imclone maintained that they didn't mislead anyone. Minutes of a key meeting in August of 2000, though, showed that the FDA was still under the impression that the original rules applied, and no one from Imclone bothered to correct them. Even when Imclone got "Fast Track" approval in January of 2001, the FDA letter shows their decision was based on the original clinical protocol. No one from Imclone said a word.
And the "larger truth" is that small trials don't mean much. You want meaning, you run a large trial, and you run it the right way, with a design that's capable of distinguishing your drug's effects from random clinical noise. Imclone set everything up to run the fastest, cheapest trial they thought they could possibly get away with, putting the approval of their drug at risk by doing so.
Back to the editorial: "Apparently, the FDA would like Erbitux to show "single-agent activity," even though there is good reason to believe it may work better in combination with traditional chemotherapy drugs." Well, these good reasons turn out to be largely propaganda. Imclone's colorectal cancer trial, as detailed above, relied on giving Erbitux as a combination therapy. When they asked for fast-track approval status, the FDA did indeed get recommendations to turn them down, since the drug had never been tried as a stand-alone therapy. Imclone made great protestations that their drug was not effective by itself, that it had synergistic effects with irinotecan, and that it would be downright unethical to run a trial as a monotherapy. The FDA bought it, and gave them fast-track.
But the data that Imclone backed all this up with wasn't from colorectal cancer patients - it was from renal cancer, which is a very different disease. In January 2001, the FDA (feeling that they'd been had) told Imclone that they needed a monotherapy trial, which they ran. You wouldn't know that from the Journal's editorial, would you? But they ran it in the quickest, shoddiest way possible, with a total of only 57 patients. Six of them responded to Erbitux as a single therapy, but the small number of data points made the results a statistical hairball. Maybe it worked, maybe it didn't.
Sam Waksal told Bristol-Meyers Squibb that this was good news, and that the FDA was pleased with it - but the agency has no record of ever having seen the data at that point, and "pleased" wasn't the right word when it finally showed up. Remember, this study could have shown that Erbitux worked by itself, which would have surprised people after Imclone's earlier statements, but would have been strong data for approval nonetheless. Or it could have confirmed their contention that the drug wouldn't work solo. It did neither, undermining both arguments.
"Too often," the Journal says as the editorial goes into the home stretch, "the FDA simply isn't clear about what a drug like Erbitux has to do to prove itself effective. . ." On the contrary, at least in this case. The record shows that the FDA was quite clear about what it wanted, and informed Imclone in a timely manner. The record also shows that Imclone misled the FDA, their partners at Bristol-Meyers Squibb, and their stockholders at almost every opportunity.
I understand the Journal's reflexive small-government postion, and I sympathize with it most of the time. But this isn't the big regulatory agency beating up on a poor company that only wants to help sick cancer patients. This is a company with their eye on their own stock options, playing games with the data to try to get their drug through as quickly as possible. They took stupid, unacceptable risks by doing so. To use the Journal's formulation, they played these games with the health and hopes of the terminally ill. I've no sympathy for Imclone at all. No one should.
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May 23, 2002
Posted by Derek
I see that some of my comments have spread to investors in Entremed, so let me take a few paragraphs to mention some points. I should write these up in a combination FAQ / disclaimer to deal with these situations.
First off, as it says on the top of the page, I don't speak for my employer. To avoid confusion on that point, I'm not even mentioning them by name, nor will I comment about specific situations that are directly relevant to their business. There are so many things to write about that I don't have to touch on anything sensitive.
So, the fact that I'm talking about Entremed means that, well. . .they aren't directly relevant. They're just another small company with a cancer drug candidate, trying to get it through trials. As you'll notice, I've also written about others in the same category, like Imclone and Sugen. If I held off commenting on companies like these, I might as well not write about anyone.
As for the personal end of things, I own no Entremed stock, nor am I short, nor do I have any option position in them. My policy is that I'll disclose any such holdings I may have in any company I write about. Frankly, anyone who uses this site as an investment tool had better hold onto their hat. The perspective I bring is that of an experienced (and sceptical) scientist, which I believe would be a good weltanschauungfor any pharma/biotech investor to have. But I'm not revealing inside information about anyone or anything, positive or negative.
Finally, there have been some comments about cancer patients and what Entremed's compounds could or could not do for them. That's an argumentum ad misericordiamby proxy, and it's worth just as much as the regular kind. To counteract another Latin tag (De mortius nil nisi bonum,)Voltaire once said that one owes respect to the living; to the dead one owes only the truth.
I believe that that applies to the gravely ill as well. Science deals with the facts, the dirty lowdown, and that's the most valuable currency there is when you're trying to find a treatment for a dread disease. Tumor cells won't listen to analyst reports, or message board posts. They respond only to facts. Right now, it's my considered opinion that those facts say that Entremed's compounds are likely to be inferior to other treatments in development.
The other side of that cold, hard coin is that I can be proven definitively, thoroughly wrong. That's another thing we're good at in science. In this case, I wouldn't mind a bit: I would be very happy indeed if these peptides turn out to be good enough to save lives. But as I see it now, I don't think it's the best place to put your money, or your hopes.
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May 22, 2002
Posted by Derek
I've received some mail pointing out that James Watson denied the "cure cancer in two years" quote which appeared in the 1998 Times article. I was aware of those denials, but (since you have to make a judgment call on these things,) I believe that he probably did say it.
Why? First of all, because it's hard for me to believe that Gina Kolata, the Times reporter, would invent such a doozy of a quote. It's one of the main things that people remember about the article, four years later. It would take nerves of steel (and some other metallic parts) to fabricate that one. Second, Watson has a history of, well, outspokenness. No one I heard at the time had much trouble believing that Watson would have said it. Or that he'd deny it. The incident occurred at a dinner party; I don't know if other witnesses came forward.
I'm also sticking to my interpretation of the Times story as well. Angiogenesis wasn't a new concept when the piece came out. Folkman certainly had been one of the main movers behind it for many years, and his story was well worth telling, but the article centered just as much on the peptides he was working on. Note the link above, which was written at the time of the initial furor. Its whole focus is on the two peptide drugs, and whether they were miracle cures or not. Here's another 1998 story from Time with the same take.
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Posted by Derek
Mickey Kaus, in his link to yesterday's post, mentioned that the company I work for seems down on peptides as drugs, and asked his readers to keep that in mind when they read my opinion on endostatin. All I can say is, it isn't just me (or my company.) You won't find much of anyone trying to develop a small protein as a drug. They're just too tempting for a variety of enzymes to tear up; this is a problem that's been known for decades.
Larger proteins, oddly, can have a bit more potential, although not for oral dosing. Depending on how they're folded, they can have a decent half-life in circulation, if you can get them that far (or, failing that, the effects they set off can be reasonably long-lasting.) Insulin and interferon are two examples that come to mind, both of which have to be injected, but work well.
There's been a huge amount of work devoted to making proteins stable enough to be given orally. Usually, the sorts of changes you have to make are also big enough to wipe out the activity you wanted, too. But there are some techniques that can work - attaching a long polyethylene glycol chain is a good one, known to the cognoscenti as "PEGylation." Glaxo SmithKline just signed a deal with a small company that is doing just this sort of thing to insulin. Many schemes have been hatched for encapsulating the proteins in some sort of vehicle that'll sneak them past the gut enzymes, with decidedly mixed success.
And there are ways to get around the digestion problem completely. It turns out that large proteins cross the nasal mucosa into the bloodstream surprisingly well (no, in case you're wondering, cocaine isn't in this category - it's a small molecule.) Several companies are working on this, with an inhaled form of insulin in advanced clinical trials (it's had its problems.)
For small proteins, there are all sorts of ways to modify the peptide bonds to make them less attractive to enzymes (putting in the wrong-handed amino acid, unusual methyl groups, other bonds instead of the usual amino acid amide connection, and so on.) It's a hard living, because many of these changes also get rid of the original protein's activity, and they don't always increase the levels in circulation, either. If you're going to go the peptidomimetic route (many have,) then you need some commitment, because it could take a while.
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May 21, 2002
Posted by Derek
Over at the new home of Kausfiles, Mickey Kaus wondered on Monday about all the news coming out of the ASCO (American Society for Clinical Oncology) meeting. Does it show that the hype in the famous 1998 NY Times front-page story on Judah Folkman and his cancer therapy was actually justified? Does the world owe Gina Kolata (the reporter) an apology?
You won't catch me offering too many opinions on welfare reform over here, so I can't resist weighing in when Mickey Kaus has some on drug discovery. Some background: the ASCO meeting is one of the most Wall Street-ocentric of the medical meetings. It's a forum for late-stage cancer trial results to be presented, and investors watch everything for signs. The headlines from the meeting tend to be out of proportion to the actual news.
Witness the NY Times the other day, saying that Imclone's Erbitux drug "fails" against a placebo. Nothing of the kind! (I seem to have imported some Kausfiles exclamation points.) I'm intensely sceptical of anything Imclone has to say, but these results (as the Times story pointed out about 3/4 of the way through) just failed to show Erbitux working well. Absence of evidence isn't evidence of absence. This was a small study, and the placebo group fared much better than expected, which blew the statistical significance of the Erbitux results. It happens, and that's why you try to run big studies when you can: a larger sample has less chance of showing this sort of jumpiness.
It's true, though, that there's a lot of anti-angiogenic drug news at the meeting this year. But there was a lot last year, and the year before. Angiogenesis has been the hot topic for many years now. Judah Folkman deserves the credit for pushing this idea, and for sticking with it for a long time without much company. But that was well before the Kolata article; by the time it came out, every major drug company (and plenty of minor ones) was on the case, and had been for years. There are a lot of different angiogenesis mechanisms, and a lot of room to work in.
That's why, when I read that article, I smiled to myself at the breathless tone it took about Folkman's peptide drug candidate (a tone that wasn't Folkman's fault.) Because peptides, like his Endostatin, generally make lousy drugs. For one thing, you can almost never give them orally; they have to be injected, like insulin. (The biggest reason is that your gut treats the peptides from a pharmacy exactly like it treats the ones from a hamburger: it digests them, rapidly tearing them down to amino acids.)
And angiogenesis inhibitors, like many of the other new cancer therapies, are probably going to be every-day drugs, which are no fun to inject. It's doubtful that they'll make the cancer disappear completely, and in some cases they'll do well just make it stop growing. If you stop taking the drug, the tumor will probably pick right up where it left off. I can't imagine anyone wanting to find out. (Combinations of the newer drugs with the older cytotoxic ones might deliver the knockout punch, but again, who wants to find out that it didn't? Those will be difficult trials. . .)
Orally active small molecules are the way to go - and I don't say that just because I get paid to discover them. They're cheaper to make, easier to purify, and you can take them with the beverage of your choice. Entremed, the company that licensed Endostatin, is still trying to turn it into a drug (burning through heaps of Bristol-Meyers Squibb money for a few years along the way.) Meanwhile, small molecules targeting angiogenesis are already closer to being approved. I honestly don't see what a difficult, unstable peptide is going to have that these compounds don't.
The person associated with the Kolata article who really deserved to be whacked over the head is James Watson. He grabbed the spotlight with his ill-considered statement that "Judah is going to cure cancer in two years." Well, it's been four years now, and it's not happening. Judah Folkman's concept is already going a long way toward curing cancer, but his compound isn't. And that's the real problem with Kolata's article: angiogenesis wasn't news, and endostatin wasn't news. Drug development is the news, but it's slow, expensive, and doesn't make a snappy above-the-fold very often.
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February 27, 2002
Posted by Derek
As you've no doubt heard, Imclone issued a press release this morning about their FDA meeting. It seems that if they can come up with more clinical data from Merck KGaA's European trials, along with clarifying some of their own numbers, then the FDA has agreed to look at a resubmission. Bristol Meyers-Squibb has been notable for their complete silence so far, which doesn't make them look very enthusiastic.
And as you've no doubt calculated, my short sale of Imclone's stock yesterday did not turn out to be very lucrative. Nor will it be, most likely. But I'm keeping the position for now, looking to escape fairly soon without too much financial damage. This FDA news, while not the worst that could have happened for the drug's development, isn't all that good, either.
The European data won't be available until the end of the year, even if all goes well. That trial is still in the enrollment phase, and it looks like Germany's Merck is being very careful about which patients go in (caution made even more important by the FDA's reaction to Imclone's data.)
That brings the drug to market a year late - again, if everything works like it's supposed to. That's bad news for the cancer patient population, because the patients who would benefit most immediately from the drug may not be around in another year to take it. And it's bad news for Imclone and BMS, too, because competing therapies aimed at the same molecular target (the epidermal growth factor receptor) are coming along. Some of these aren't antibodies, like Imclone's candidate - they're small drug molecules. If those work, they'll be easier and cheaper to produce in quantity. If they don't set off too many side effects, they could be real competition.
Who to blame for all this? The Wall St. Journal weighs in with another Imclone editorial (no free link,) as they did back on Feb. 13th. I'd been kicking around the idea of commenting that one out paragraph by paragraph, and now I'm already behind.
They came down hard on the FDA both times, suggesting that the government changed the requirements in mid-stream, and that the efficacy standards are too stringent. As odd as it feels for a pharma researcher, I have to come to the FDA's defense here. It was Imclone's (and, let's not forget, BMS's) responsibility to make sure that the clinical data were ready for approval. Arguing about what the FDA should be is beside the point: every drug company knows what the FDA is.
And every large drug company knows what sorts of submissions have a more solid chance of being approved. Imclone chose to do the shortest, smallest trial they possibly could get away with, and it backfired on them. One reason for that trial design was to be able treat cancer patients more quickly - that's a huge motivating factor for everyone in the field, and I don't want to minimize it. But another reason for Imclone's hurry is the hoofbeats that they can hear coming up behind them. They need this drug to be first to market. Bristol-Meyers Squibb, for their part, is already on the hook for two billion dollars for only 40% of the drug's profits. And every delay decreases their chances of ever earning that money back.
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February 26, 2002
Posted by Derek
Well, today is Imclone day at the FDA (see Jan 31 and Feb. 6 postings.) All parties will be meeting to decide what the path forward is: reworking the existing data, supplementing it with whatever else the companies can dredge up, or new clinical trials.
Analysts have raised the possibility of using some clinical data from Merck KgaA (German Merck, not the US company.) They're the licensees in Europe. But most of their data is for head and neck cancer, which won't cut it for Imclone's colon cancer application. Merck has apparently done a couple of small trials in colorectal patients, but most of their data for that indication's European filing was supposed to come from Imclone. There might not be enough new data to salvage things, considering how negative the FDA was the first time around.
If Imclone gets to reapply without new data, I'd chalk that up to the work of experienced regulatory-affairs people from BMS. I assume they've brought in everyone they can find. Of course, that brings up the question of where those folks were for the first filing, doesn't it?
I wouldn't be surprised if it turns out to be new trials, which is of course what the companies want to avoid. If that happens, look for more now-we're-really-mad statements from BMS, and another round of nasty press releases.
The pity of all this is that Erbitux very likely works. That puts pressure on for approval. You already see comments about the mean ol' FDA hasseling this small company with their wonder drug, but that's missing the point. If you want to get mad at someone, get mad at Imclone for doing the absolute minimum they thought they could get away with. And get mad at BMS: I still think they should have caught this before it went to the FDA at all.
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February 6, 2002
Posted by Derek
The Bristol-Meyers Squibb / Imclone story has taken a real bad-movie turn. (See my postings on this last week if you're not up on this one so far.) BMS has served up an ultimatum that I don't recall every seeing before: Ditch your CEO, or we walk.
Actually, it's even livlier than that: Ditch the CEO, ditch his brother (the chief operating officer,) give us control of your dealings with the FDA. . .oh yeah, and give us a bigger share of the profits from the drug. Or we walk.
It's an interesting threat, and I can't wait to see Imclone's response. Who will back down? You can argue that Imclone has to, since BMS is their best hope to get the drug to market - and at this point, the deal is still better than anything they're likely to get from anyone else. Their stock will sink even lower if BMS actually does walk, putting them in a weak negotiating position.
But you can argue that BMS has to back down, too. They've already sunk 1.2 billion into this, and to walk away after that (with no drug and some rather depreciated stock) would make the shareholders furious. (It's not like they're in a good mood already, although the tough talk must have cheered everone up.) And if they leave, their cancer pipeline is status quo ante- that is, still in the shape that made them think they needed to spend billions to improve it fast.
Much as I think that Imclone deserves what's happening to them, it doesn't take away from the fact that BMS didn't investigate this the way someone spending a billion dollars should have. There must be some pretty embarrassing PowerPoint presentations left on people's hard drives, talking about what a great job everyone's doing on the clinical and regulatory end. Eventually, BMS is going to have to figure out how this mess could have happened. It won't be easy, since everyone who even got close to the deal is probably hiding behind their nearest tree.
My prediction is that Imclone, with great protesting, will end up agreeing to almost all the terms. They might salvage some of the milestone payments that BMS wants to get rid of, or be able to talk them down a bit on their profit-percentage demands. But getting Erbitux through is probably their only hope for survival, and BMS is probably their only hope for getting it through.
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