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
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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.
Comments (46)
+ TrackBacks (0) | Category: Business and Markets | Cancer
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.
Comments (19)
+ 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.
Comments (12)
+ TrackBacks (0) | Category: Cancer
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.
Comments (19)
+ 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”.
Comments (8)
+ 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.
Comments (5)
+ 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.
Comments (37)
+ TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History
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. . .
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+ 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. . ..
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+ 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. . .
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+ 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.
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+ 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?
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+ 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. . .
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+ 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. . .
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+ 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. . .
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+ 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 |
