About this Author
College chemistry, 1983
The 2002 Model
After 10 years of blogging. . .
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: firstname.lastname@example.org
September 2, 2014
There is some good news from the clinic today. Novartis reported data on LCZ696, a combination therapy for congestive heart failure, and the results have really grabbed a lot of attention. (The trial had been stopped early back in March, so the news was expected to be good). This is a combo of the angiotensin II antagonist valsartan and a neprilysin (neutral endopeptidase) inhibitor, AHU-377.
Compared to enalapril, the standard ACE inhibitor therapy for CHF, the Novartis combo lowered the risk of cardiovascular death by 20% and the risk of hospitalization by 21%, while having at least as good a safety profile as the generic ACE drug. Those are powerful arguments for the company to make, both to physicians and to insurance payers, so the future of the therapy, barring any sudden misfortunes, looks assured. There's not a lot that you can do for people with congestive heart failure as it is, and this looks like a real advance.
As Matthew Herper mentions, though, this isn't the first time that a similar combination has been tried in CHF. A few years ago, Bristol-Myers Squibb had a major failure with a single drug that inhibited both the ACE and neprilysin enzyme pathways, Vanlev (omapatrilat). That compound had a persistent problem with angioedema, as detailed here, and that led to its eventual rejection by the FDA on risk/benefit grounds, after a great deal of expensive Phase III work. Back in 2002, in the early days of this blog, I predicted that no ACE/endopeptidase combination would ever see the light of day again, which shows you how much I know about it. But I wasn't alone, that's for sure. It's very interesting and surprising that LCZ696 has worked out as well as it has, and it's a very worthwhile question to wonder what the difference could have been. Balance between the two pathways? Having an receptor antagonist on the ACE end rather than an enzyme inhibitor? Whatever it was, it seems to have done the trick.
The only question I have about the new combo is how it would compare to an ACE/diuretic combination, which (from what I know) is also a standard course of therapy for CHF patients. On the other hand, you'd expect that a diuretic might also be added to LCZ696 treatment - it was shown that it could be combined with omapatrilat, since they're all different mechanisms.
And one other point - I always make this one in these kind of situations. I'm willing to bet that critics of the drug industry, who like to go on about "me-too" drugs and lazy industrial research efforts, would have had LCZ696 on the list of eye-rolling follow-up drugs (that is, if they'd been paying attention at all). I mean, the angiotensin pathway is thoroughly covered by existing drugs, and neprilysin/NEP has been targeted before, too (both by omapatrilat and by Pfizer's so-called "female Viagra", UK-414,495). But there's an awful lot we don't know about human medicine, folks.
+ TrackBacks (0) | Category: "Me Too" Drugs | Cardiovascular Disease | Clinical Trials
Exelixis is a company with a very interesting history, but that's in the sense of "much rather read about it than experience it", like the interesting parts in a history book. At one point they had a really outsized pipeline of kinase inhibitors, to the point where it could be hard to keep track of everything, but these projects have largely blown up over the last few years. Big collaboration deals have been wound down, compounds have been returned to them, and so on.
Most recently, the company has been developing cabozantinib for prostate cancer. Along the way (2011) they had a dispute with the FDA about clinical trial design - the company had a much speedier surrogate endpoint in mind, but the agency wasn't having it. At this point, there are enough options in that area to make overall survival the real endpoint that matters, and the FDA told them to go out and get that data instead of messing around with surrogates. So the company plowed ahead, and yesterday announced Phase III results. They weren't good. The compound showed some effects in progression-free survival (PFS), but seems to have no benefit in the longer-running overall survival (OS) measurement. And that one's the key.
There's no way to put a good spin on it, either. The same press release that announced the results also announced that the company was going to have to "initiate a significant workforce reduction" in order to make it through the two other ongoing cabozantinib trials (for renal cell carcinoma and advanced hepatocellular carcinoma). Exelixis has had some pretty brutal workforce reductions over the years already, so this would appear to be cutting down as far as things can be cut (from 330 employees down to 70). And those two remaining indications are tough ones, too - if the compound shows efficacy, it'll be very good news, but those are not the first battlefields you'd choose to fight on. The prostate results don't offer much room for optimism, but on the other hand, the compound has orphan drug status for medullary thyroid cancer, for which it has shown real benefit in a disease that otherwise has no real treatment at all.
So Exelixis will try to stay alive long enough to get through these last trials, and if nothing comes up there, I'd have to think that this will be it for them. You wouldn't have predicted this back in about 2002, but you can't predict anything important in this industry to start with.
+ TrackBacks (0) | Category: Cancer | Clinical Trials
August 28, 2014
A reader has sent along the question: "Have any repurposed drugs actually been approved for their new indication?" And initially, I thought, confidently but rather blankly, "Well, certainly, there's. . . and. . .hmm", but then the biggest example hit me: thalidomide. It was, infamously, a sedative and remedy for morning sickness in its original tragic incarnation, but came back into use first for leprosy and then for multiple myeloma. The discovery of its efficacy in leprosy, specifically erythema nodosum laprosum, was a complete and total accident, it should be noted - the story is told in the book Dark Remedy. A physician gave a suffering leprosy patient the only sedative in the hospital's pharmacy that hadn't been tried, and it had a dramatic and unexpected effect on their condition.
That's an example of a total repurposing - a drug that had actually been approved and abandoned (and how) coming back to treat something else. At the other end of the spectrum, you have the normal sort of market expansion that many drugs undergo: kinase inhibitor Insolunib is approved for Cancer X, then later on for Cancer Y, then for Cancer Z. (As a side note, I would almost feel like working for free for a company that would actually propose "insolunib" as a generic name. My mortgage banker might not see things the same way, though). At any rate, that sort of thing doesn't really count as repurposing, in my book - you're using the same effect that the compound was developed for and finding closely related uses for it. When most people think of repurposing, they're thinking about cases where the drug's mechanism is the same, but turns out to be useful for something that no one realized, or those times where the drug has another mechanism that no one appreciated during its first approval.
Eflornithine, an ornithine decarboxylase inhibitor, is a good example - it was originally developed as a possible anticancer agent, but never came close to being submitted for approval. It turned out to be very effective for trypanosomiasis (sleeping sickness). Later, it was approved for slowing the growth of unwanted facial hair. This led, by the way, to an unfortunate and embarrassing period where the compound was available as a cream to improve appearance in several first-world countries, but not as a tablet to save lives in Africa. Aventis, as they were at the time, partnered with the WHO to produce the compound again and donated it to the agency and to Doctors Without Borders. (I should note that with a molecular weight of 182, that eflornithine just barely missed my no-larger-than-aspirin cutoff for the smallest drugs on the market).
Drugs that affect the immune system (cyclosporine, the interferons, anti-TNF antibodies etc.) are in their own category for repurposing, I'd say, They've had particularly broad therapeutic profiles, since that's such a nexus for infectious disease, cancer, inflammation and wound healing, and (naturally) autoimmune diseases of all sorts. Orencia (abatacept) is an example of this. It's approved for rheumatoid arthritis, but has been studied in several other conditions, and there's a report that it's extremely effective against a common kidney condition, focal segmental glomerulosclerosis. Drugs that affect the central or peripheral nervous system also have Swiss-army-knife aspects, since that's another powerful fuse box in a living system. The number of indications that a beta-blocker like propanolol has seen is enough evidence on its own!
C&E News did a drug repurposing story a couple of years ago, and included a table of examples. Some others can be found in this Nature Reviews Drug Discovery paper from 2004. I'm not aware of any new repurposing/repositioning approvals since then, but there's an awful lot of preclinical and clinical activity going on.
+ TrackBacks (0) | Category: Clinical Trials | Drug Development | Drug Industry History | Regulatory Affairs
August 20, 2014
Perseverance is a critical variable in drug discovery. Too little of it, and you are absolutely guaranteed to fail - no drug has ever made it to market without trying the patience of everyone involved. Too much of it, and you are very nearly guaranteed to waste all your money: most drug development projects don't work, and eventually reach a point where no amount of time or money could make them work, either. Many are the efforts where leaders have gritted their teeth, redoubled their efforts, and led everyone further into the abyss.
But sometimes these things come through, and that's what seems to have happened with Amicus and their drug migalastat for Fabry's. It's a protein chaperone, one the the emerging class of drugs that work by stabilizing particular protein conformations to help regain function. At the end of 2012, Amicus and their partner GSK announced clinical trial results that didn't meet significance, which prompted GlaxoSmithKline to return rights to the drug to Amicus.
Who kept on with it. And who announced today that the second Phase III study had come back positive, enough so that they plan to file for regulatory approval. (The belief is that the first Phase III enrolled an inappropriate mix of patients). Congratulations to the company, who may well have given many Fabry's patients their first opportunity for an oral therapy for their disease.
+ TrackBacks (0) | Category: Clinical Trials
August 15, 2014
There's a post by Peter Bach, of the Center for Health Policy and Outcomes, that's been getting a lot of attention the last few days. It's called "Unpronounceable Drugs, Incomprehensible Prices", and you know what it says.
No, really, you do, even if you haven't seen it. Too high, unconscionable, market can't support, what they can get away with, every year, too high. Before I get to the uncomfortable parts of my own take on this, let me stipulate a couple of things up front: (1) I do think that the industry is inviting trouble for itself by the way it it raising prices. It is in drug companies' short term interest to do so, but long term I worry that it's going to bring on some sort of price-control regimen. (2) Some drug prices probably are too high (but see below for what that means). Big breakthroughs can, at least in theory, command high prices, but not everything deserves to be priced at the level it is.
I was about to say "see below" again, but this paragraph is below, so here goes. Let me quote a bit from Bach's article:
Cancer drug prices keep rising. The industry says this reflects the rising costs of drug development and the business risks they must take when testing new drugs. I think they charge what they think they can get away with, which goes up every year. . .Regardless of the estimate, the pricing of new drugs for cancer and now other common diseases has come unglued from the rationale the industry has long espoused. Instead, pricing is explained by a phenomenon of increasing boldness by the industry against a backdrop of regulators and insurers who have no legal authority to dictate or even propose alternative pricing models.
Bach's first assertion is correct: drug companies are charging what they think they can get away with. In that, they are joined by pretty much every other business in the entire country. I did a post once where I imagined car sales transplanted into the world of drug sales- you couldn't just walk in and buy a car, for example. No, you had to go to a car consultant first, licensed by the state, who would examine your situation and determine the sort of car you needed. Once they'd given you a car prescription, you could then go to a dealer.
Well, we don't have that, but what car companies do charge is, well, what they can get away with. The same as steel companies, soft drink companies, cardboard box companies, grocery stores, and people who are selling their houses. You charge what you think the market will bear. Even people selling basic necessities of life like food and shelter charge what they think the market will bear. It's true that health care does feel different from any of those (a point that I went into in that post linked in the last paragraph), and there's the root of many a problem.
And, some will say, a big difference is that none of these other sellers have patents on their side, the legal right to put the screws on. But remember the flip side of the patent system: the legal certainty that you will lose that pricing power on a set date. The pricing of new drugs is completely driven by their expected patent lifetimes, because almost all the money that the developing company is ever going to make off the drug is going to have to be made during that period.
And sometimes that period isn't very long. The patent clock starts ticking a long time before a drug ever gets on the market; there are often only five to ten years left when it's finally approved for sale. There are other factors, too. Everyone is talking about the price of Sovaldi for hepatitis C, but no as many people have thought about the fact that the drug is, in fact, so effective that it has blown two other recently approved Hep C treatments right out of the market, well before their patent lifetimes had even expired. There really is competition in the drug business, and that sector shows it in action.
Now, what there isn't so much of is competition on price, true. And that's what you do see in the other businesses I named above. There are grocery stores that occupy the "Wonderful Prestigious High Quality" part of the market, and others that occupy the "Low Low Prices Every Day" part. (And interestingly, if you Venn-diagram out what's on the shelves of those two, there's still some overlap, allowing you to watch people paying wildly different prices for blueberries that came off the same truck, not to mention even less perishable stuff like aluminum foil). You don't see this in the drug industry, partly because for patented drugs we're never selling the same blueberries. the same gasoline, or the same khaki trousers. Even the biggest "me-too" drugs still differ from each other to some degree.
And that brings up another point. Bach uses (as his example of pricing in the cancer field) two Alk compounds, Xalkori (crizotinib) from Pfizer and Zykadia (ceritinib) from Novartis. Xalkori was first, and Bach makes a lot of the fact that Zykadia is priced higher, even though he says that Pfizer ran bigger clinical trials, had to work out the associated diagnostic test with the FDA, and launch the new mechanism into the oncology market. Novartis, he says, got to piggy-back on all that, and yet their drug is priced higher. There can be no other reason for that pricing decision, Bach says, other than that they can.
Let's go into some details that Bach's article leaves out. Zykadia is indeed second to market. But the time gap between the two drugs means that Novartis was working on it before they knew that Xalkori worked in the clinic. Bach makes an error here made by many others who have not actually done drug discovery work: the time course of these things is longer than it looks. A screen had to be run against Alk, compounds had to be confirmed, a medicinal chemistry team had to optimize them and make lots of new structures, all of which except one fell by the side of the road. The compound had to go through animal tests for efficacy and safety, and it had to be scaled up and formulated. And so on, and so on. Novartis did not sit back, watch Xalkori succeed, and then decide "Hey, we should get us some of that action, too".
Now Zykadia is, as Bach says, a second-line therapy. But it's approved for patients who do not respond to, or have become intolerant to Xalkori. So this "me-too" drug is, in fact, different enough to work on patients for whom Xalkori has failed. In fact, most patients will start to show relapse inside of a year on Xalkori, so it would appear that most non-small-cell lung cancer patients with multiyear survival are probably going to end up taking both compounds. Cancers mutate quickly, and we need all the options we can get - and guess what, some of those options are going to be second to market, because they can't all be first.
Another point to note is that while Zykadia was indeed approved on the basis of a smaller clinical trial set, that's because it received "breakthrough" designation from the FDA for accelerated review and approval. Startlingly, it actually got approved after Phase I trials alone. (Not bad for what Bach characterizes as a simple copycat drug, by the way). Novartis has run the compound in more clinical trials than that, and they continue to do so. It's not like they slipped in with a mere 163 patients and then trotted off to the FDA while brushing the dust off their hands. To find this out, by the way, you'll want to use "LDK378", the internal Novartis designation for the drug, and I'm passing this information on to Bach for free. Clinicaltrials.gov shows 13 trials in the US when you do that, and there are others outside the country as well.
Bach's article, as mentioned, plays down any differences between these two drugs, saying that "they have not been directly compared". But that's not accurate. Let me quote from that link in the paragraph just above:
As described by Shaw and colleagues in the New England Journal of Medicine, ceritinib has striking activity in ALK-rearranged NSCLC, both in treatment-naïve patients and in those who experienced tumor progression on crizotinib. . .The drug has clear pharmacological advantages over crizotinib. Its surprising level of activity in crizotinib-resistant tumors may be explained by its greater potency and its particular ability to inhibit ALK with gatekeeper mutations that confer resistance to crizotinib.
The two drugs have had a very important comparison: people who are going to die on Xalkori are going to survive longer if they switch to Zykadia. "Me-too" drug, my ass.
But rather than end on that note, tempting as that is, let me circle back to pricing once again. The price for these cancer drugs is not borne by individual patients emptying their piggy banks. It is borne by insurance, both private and government. And drug companies do indeed price their drugs at what the think the insurance plans will pay for them. This is not a secret, and should not be a surprise, and I continue to be baffled by people who react to this with horror and disbelief. Prices appear when you find out what the payers will pay. If Pfizer, Novartis, or Gilead priced their drugs at fifty million dollars a dose, no insurance company would reimburse. But the insurance companies are paying the current prices, and if they believe that they will be put out of business by doing so, they need to stop doing that. And they could.
They will, too, if we in the industry keep pushing them towards doing it. That's our big problem in drug development: our productivity has been too low, and we're making up for it by charging more money. But that can't go on forever. There are walls closing in on us from both sides, and we're going to have to scramble out from between them at some point. Pricing power can only take you so far.
+ TrackBacks (0) | Category: Cancer | Clinical Trials | Drug Prices | Regulatory Affairs | Why Everyone Loves Us
August 11, 2014
Via the Economist's "Free Exchange" blog comes this provocative paper (PDF) from the University of Chicago, Harvard, and MIT. Its authors are looking at the effect of patents on the oncology drug market, and they conclude that the current system is probably hurting patients (and the broader economy).
That's a big statement to make, so the first thing to do is dig into the paper and see how it was arrived at. The authors are looking at effective patent terms: how long an invention really has an exclusive market term. That's a big issue in drug development, of course, since the regulatory pathway to approval can be so long that only a few years are left on the patent by the time a drug can be sold.
. . .Since society cares about an invention’s total useful life, but private firms care only about monopoly life, a distortion emerges not just in the level of R&D (as arises in standard models), but also in the composition of R&D: society might value invention A more highly than invention B, but private industry may choose to develop B but not A. Note that, other things equal, commercialization lag lowers both monopoly life and total useful life: both society and private firms prefer inventions to reach the market quickly. But, under a fixed patent term, commercialization lag reduces monopoly life more rapidly than total useful life, hence the distortion away from inventions with both a long total useful life and a long commercialization lag.
The problem with oncology, the paper claims, is that drug firms therefore have an incentive to work on compounds whose clinical trials are shorter, because they have a better chance of a longer effective patent lifetime). Slow-moving cancers, which might be more treatable, are relatively neglected, because there is less likelihood of return from them given the patent timelines.
Cancer drug development tends to be specific to a cancer type (e.g. prostate) and stage of disease (e.g. metastatic). . .providing a natural framework for estimating how expected commercialization lags (as proxied by survival time) and R&D investments vary across different groups of patients. Aggregating survival information from patient-level cancer registry data, we document stark variation in survival times across patients of different cancer types and stages of disease. In order to measure R&D investments on cancer treatments relevant to each cancer type and stage of disease, we use newly-constructed data from a clinical trial registry that has cataloged cancer clinical trials since the 1970s. The key feature of this data which makes it amenable to our analysis is that for each clinical trial, the registry lists each of the specific patient groups eligible to enroll in the trial - thus allowing a match between our measures of expected commercialization lag (as measured by survival time) and R&D activity (as measured by clinical trial investments) across cancer types and stages of disease.
They show that there is much more clinical focus on the severe short-time-course cancers than on the slow-moving localized types, and they ascribe this to distortion caused by patent terms. But as far as I can tell, the authors don't consider some other factors, and as someone who's done drug discovery work in oncology, I'd like to bring these out as well.
There's no doubt that patent lifetimes are a factor, since these allow a company to recoup its development costs - and the costs of all the other failed projects. It's worth remembering that the overall clinical failure rate is still roughly 90%, so there are a lot of costs to be made up whenever sometime actually does work. But imagine that patent terms were suddenly doubled to forty years instead of twenty. This might bring in more investment into slower-moving long-term cancer projects, but I don't think it would be as simple as this paper's model suggests. Overall, a drug company would prefer not to tie up its time, effort, and capital for longer than necessary in the uncertain business of a clinical trial. Even with the prospect of a longer patent term reward at the end of the process, the disincentive for multiyear trials would still be there, because there are so many shorter alternatives in oncology. (That's as opposed to Alzheimer's, where it's long trials or nothing, at least until we understand a lot more about the disease). It's not like the slower-moving cancers are any easier to understand, find targets for, or progress into the clinic: they're all hard.
This is even more the case when you consider that the oncology field has a good number of small companies in it. The barriers to oncology drug development are lower than in some other areas - it's easier to identify patients, and there's a lot of unmet medical need. And those relatively short clinical trial times are another incentive: to do another thought experiment, if you suddenly required all drug companies working on oncology to work only on the slower-moving cancers, there would be far fewer drugs in development, since most of the smaller companies would drop out. They don't have the funds to keep going that long. So while short clinical trials may be a distortion in one direction, they have distorted the market in another, arguably beneficial direction as well, by bringing more companies and more ideas into the field.
I say "beneficial", because some of the drug mechanisms that are being tried on the faster-moving cancers would also be of use on the slower, more localized ones. The genomic, metabolic, and proteomic information learned by studying the faster-moving varieties (and the techniques used to do so) are immediately applicable to the slower-moving ones as well. It's not a zero-sum game.
There's also that unmet-medical-need factor to consider. It's easier for a company, especially a small one, to raise money and justify its spending to investors when it's working against form of cancer with a low survival rate and a relatively fast progression. The belief is that the regulatory barriers to approval are lower for such drugs, and that uptake by physicians would be faster if the drug gets approved. Side effects are also going to be more tolerated for more severe conditions, too, and oncology drugs, as is well known, tend to have some pretty significant ones.
The authors, after considering several alternatives, present evidence that when regulatory agencies allow surrogate endpoints as a factor for drug approval that investment in the longer-term cancers improves. They suggest that research into validated markers of this sort could have the best returns overall, compared to other possibilities (such as just lengthening patent terms, not that that's going to happen in the real world, anyway). And I agree with them there - but I also note that drug companies themselves have been seeking such surrogate endpoints on their own, for the same reasons. (These things speed up all trials, not just the longer ones). Large incentives for good clinical trial markers already exist, but such markers are pretty damned hard to come by, unfortunately.
But as for the main subject of this paper and its explanatory power, I'm not quite convinced. As far as I can see from going through the manuscript, none of the other factors mentioned above have been considered - everything is tied to the effective patent lifetime. And while that's probably real, and a partial surrogate for some of these issues, I have trouble buying it as the only thing that's going on. Now, this may be what economists do: find a correlation that is open to a mathematical treatment and run with it. But I don't see how you can make statements this sweeping without going into more of what (from my perspective) I see as the real world of drug discovery and development.
+ TrackBacks (0) | Category: Cancer | Clinical Trials | Patents and IP
July 28, 2014
Targacept's attempt to salvage something by testing TC-5214 for overactive bladder has failed. John Carroll at FierceBiotech counts eight straight failed clinical trials from this company: a record? I don't see anyone beating that very easily, that's for sure. Nicotinic receptors have proven to be a very, very difficult field to work in, and I'm not sure that Targacept has anything left in their tank.
+ TrackBacks (0) | Category: Business and Markets | Clinical Trials
July 23, 2014
Yet another entry in the "Why do people keep investing in biopharma?" files. Take a look at the case of Puma Biotechnology. Their stock was as high as $140/share earlier in the year, and it gradually deflated to the high 50s/low 60s as time went on. But yesterday, after hours, they reported unexpectedly good Phase III results for neratinib in breast cancer, and as I write, they're at $228 or so, up about $167 per share.
It's another HER2/EGFR tyrosine kinase inhibitor (like Tykerb/lapatinib in the small molecule space, although neratinib is an irreversible inhibitor) and would be targeted at patients who are now taking Herceptin. Neratinib itself has not had a smooth path to this stage, though. Puma licensed the compound out from Pfizer, and took on the responsibility for all of the development. Pfizer ditched the compound a few years ago in a review of their oncology portfolio. I note that the two companies have reworked their licensing agreement on this news as well. Puma's entire business model is taking up oncology candidates that other companies have shed, and it certainly seems to have come through for them this time.
So chalk one up for irreversible kinase inhibitors, and (of course) for Puma. And for the patients who will be taking the drug, naturally, and lastly, for Puma's shareholders, who are having an excellent day indeed.
+ TrackBacks (0) | Category: Business and Markets | Cancer | Clinical Trials
July 14, 2014
Targacept has been working on some very hard therapeutic areas over the years, and coming up dry - dramatically so. They may have just done it again.
They've been testing TC-1734 in Alzheimer's over the last year or so, a partial agonist at nicotinergic receptors. That was a long-shot mechanism to start with, although to be sure, every Alzheimer's drug is a long-shot mechanism. This would be a stopgap compound even if it worked, like the existing acetylcholinesterase compound Donepezil.
And the company has apparently released the results of the clinical trial on its web site, inadvertently, you'd have to assume. The news first came out from BioRunUp on Twitter, and the text of the announcement was the the compound had failed to show superiority to Donepezil. The company has made no official announcement (as I write, anyway), and the press release itself appears to have been taken down a little while ago. But here's a screen shot, if you're interested. The stock (TRGT) has already reacted to the news, as you'd imagine it would, suddenly dropping like a brick starting at just before 2:30 PM EST. Not a good way to get the news out, that's for sure. . .
+ TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials
July 10, 2014
I've written several times about the NIH's NCATS program, their foray into "translational medicine". Now comes this press release that the first compound from this effort has been picked up for development by a biopharma company.
The company is AesRx (recently acquired by Baxter), and the compound is AES-103. This came from the rare-disease part of the initiative, and the compound is targeting sickle cell anemia - from what I've seen, it appears to have come out of a phenotypic screening effort to identify anti-sickling agents. It appears to work by stabilizing the mutant hemoglobin into a form where it can't polymerize, which is the molecular-level problem underlying the sickle-cell phenotype. For those who don't know the history behind it, Linus Pauling and co-workers were among the first to establish that a mutation in the hemoglobin protein was the key factor. Pauling coined the term "molecular disease" to describe it, and should be considered one of the founding fathers of molecular biology for that accomplishment, among others.
So what's AES-103? Well, you'll probably be surprised: it's hydroxymethyl furfural, which I would not have put high on my list of things to screen. That page says that the NIH screened "over 700 compounds" for this effort, which I hope is a typo, because that's an insanely small number. I would have thought that detecting the inhibition of sickling would be something that could be automated. If you were only screening 700 compounds, would this be one of them?
For those outside the business, I base that opinion on several things. Furans in general do not have a happy history in drug development. They're too electron-rich to play well in vivo, for the most part. This one does have an electron-withdrawing aldehyde on it, but aldehydes have their own problems. They're fairly reactive, and they tend to have poor pharmacokinetics. Aldehydes are, for example, well-known as protease inhibitors in vitro, but most attempts to develop them as drugs have ended in failure. And the only thing that's left on the molecule, that hydroxymethyl, is problematic, too. Having a group like that next to an aromatic ring has also traditionally been an invitation to trouble - they tend to get oxidized pretty quickly. So overall, no, I wouldn't have bet on this compound. There must be a story about why it was tested, and I'd certainly like to know what it is.
But for all I know, those very properties are what are making it work. It may well be reacting with some residue on hemoglobin and stabilizing its structure in that way. The compound went into Phase I in 2011, and into Phase II last year, so it does have real clinical data backing it up at this point, and real clinical data can shut me right up. The main worry I'd have at this point is idiosyncratic tox in Phase III, which is always a worry, and more so, I'd think, with a compound that looks like this. We'll see how it goes.
+ TrackBacks (0) | Category: Clinical Trials | Drug Development
July 9, 2014
Yesterday's post on yet another possible Alzheimer's blood test illustrates, yet again, that understanding statistics is not a strength of most headline writers (or most headline readers). I'm no statistician myself, but I have a healthy mistrust of numbers, since I deal with the little rotters all day long in one form or another. Working in science will do that to you: every result, ideally, is greeted with the hearty welcoming phrase of "Hmm. I wonder if that's real?"
A constant source for the medical headline folks is the constant flow of observational studies. Eating broccoli is associated with this. Chocolate is associated with that. Standing on your head is associated with something else. When you see these sorts of stories in the news, you can bet, quite safely, that you're not looking at the result of a controlled trial - one cohort eating broccoli while hanging upside down from their ankles, another group eating it while being whipped around on a carousel, while the control group gets broccoli-shaped rice puffs or eats the real stuff while being duct-taped to the wall. No, it's hard to get funding for that sort of thing, and it's not so easy to round up subjects who will stay the course, either. Those news stories are generated from people who've combed through large piles of data, from other studies, looking for correlations.
And those correlations are, as far as anyone can tell, usually spurious. Have a look at the 2011 paper by Young and Karr to that effect (here's a PDF). If you go back and look at the instances where observational effects in nutritional studies have been tested by randomized, controlled trials, the track record is not good. In fact, it's so horrendous that the authors state baldly that "There is now enough evidence to say what many have long thought: that any claim coming from an observational study is most likely to be wrong."
They draw the analogy between scientific publications and manufacturing lines, in terms of quality control. If you just inspect the final product rolling off the line for defects, you're doing it the expensive way. You're far better off breaking the whole flow into processes and considering each of those in turn, isolating problems early and fixing them, so you don't make so many defective products in the first place. In the same way, Young and Karr have this to say about the observational study papers:
Consider the production of an observational study: Workers – that is, researchers – do data collection, data cleaning, statistical analysis, interpretation, writing a report/paper. It is a craft with essentially no managerial control at each step of the process. In contrast, management dictates control at multiple steps in the manufacture of computer chips, to name only one process control example. But journal editors and referees inspect only the final product of the observational study production process and they release a lot of bad product. The consumer is left to sort it all out. No amount of educating the consumer will fix the process. No amount of teaching – or of blaming – the worker will materially change the group behaviour.
They propose a process control for any proposed observational study that looks like this:
Step 0: Data are made publicly available. Anyone can go in and check it if they like.
Step 1: The people doing the data collection should be totally separate from the ones doing the analysis.
Step 2: All the data should be split, right at the start, into a modeling group and a group used for testing the hypothesis that the modeling suggests.
Step 3: A plan is drawn up for the statistical treatment of the data, but using only the modeling data set, and without the response that's being predicted.
Step 4: This plan is written down, agreed on, and not modified as the data start to come in. That way lies madness.
Step 5: The analysis is done according to the protocol, and a paper is written up if there's one to be written. Note that we still haven't seen the other data set.
Step 6: The journal reviews the paper as is, based on the modeling data set, and they agree to do this without knowing what will happen when the second data set get looked at.
Step 7: The second data set gets analyzed according to the same protocol, and the results of this are attached to the paper in its published form.
Now that's a hard-core way of doing it, to be sure, but wouldn't we all be better off if something like this were the norm? How many people would have the nerve, do you think, to put their hypothesis up on the chopping block in public like this? But shouldn't we all?
+ TrackBacks (0) | Category: Clinical Trials | Press Coverage
June 26, 2014
I wrote a couple of years ago about Andrew Lo of MIT, and his idea for securitization of drug discovery. For those of you who aren't financial engineers, that means raising funds by issuing securities (bonds and the like), and that's something that (as far as I know) has never been used to fund any specific drug development project.
Now Pharmalot has an update in an interview with Lo (who's recently published a paper on the idea in Science Translational Medicine). In particular, he's talking about issuing "Alzheimer's bonds", to pick a disease with no real therapies, a huge need for something, and gigantic cost barriers to finding something. Lo's concerned that the risks are too high for any one company to take on (and Eli Lilly might agree with him eventually), and wants to have some sort of public/private partnership floating the bonds.
We would create a fund that issues bonds. But if the private sector isn’t incentivized on its own, maybe the public sector can be incentivized to participate along with some members of the private sector. I will explain. But let’s look at the costs for a moment. The direct cost of treating the disease – never mind home care and lost wages – to Medicare and Medicaid for 2014 is estimated at $150 billion. We did a calculation and asked ourselves what kind of rate of return can we expect? We came up with $38.4 billion over 13 years. . .
. . .Originally, I thought it could come from the private sector. We’d create a fund – a mega fund of private investors, such as hedge funds, pension, various institutional investors. The question we asked ourselves is will they get a decent rate of return over a 13-year period? The answer, which is based on a best guess, given the risks of development and 64 projects, and we believed the answer was ‘no.’ It wouldn’t be like cancer or orphan diseases. It’s just not going to work. I come from that world. I talked to funds, philanthropists, medical experts. We did a reality check to see if we were off base. And it sounded like it would be difficult to create a fund to develop real drugs and still give investors a reasonable rate of return – 15% to 20%.
He's now going around to organizations like the Alzheimer's Association to see if there's some interest in giving this a try. I think that it's going to be a hard sell, but I'd actually like to see it happen. The difficulty is that there's no way to do this just a little bit to see if it works: you have to do it on a large scale to have any hope of success at all, and it's a big leap. In fact, the situation reminds one of. . .the situation with any given Alzheimer's drug idea. The clinical course of the disease, as we understand it now, does not give you any options other than a big, long, expensive path through the clinic (which is why it's the perfect example of an area where all the risk is concentrated on the expensive late stages). Lo is in the position of trying to address the go-big-or-go-home problem of Alzheimer's research with a remedy that requires investors to go big or go home.
The hope is that you could learn enough along the way to change the risk equation in media res. There's an old science fiction story by A. E. van Vogt, "Far Centaurus", which featured (among other things - van Vogt stories generally had several kitchen sinks included) a multidecade suspended-animation expedition to Alpha Centauri. The crew arrive there to find the planets already covered with human-populated cities, settled by the faster-than-light spaceships that were invented in the interim. We don't need FTL to fix Alzheimer's (fortunately), but there could be advances that would speed up the later parts of Lo's fund. But will this particular expedition ever launch?
+ TrackBacks (0) | Category: Alzheimer's Disease | Business and Markets | Clinical Trials | Drug Development
June 24, 2014
In case you hadn't seen it, I wanted to highlight this post by Michael Gilman over at LifeSciVC. He's talking about risk in biotech, and tying it to the processes of generating, refining, and testing hypotheses. "The hypothesis", he says, "is one of the greatest intellectual creations of our species", and he's giving it its due.
I agree with him that time spent rethinking your hypothesis is often time well spent, whether for a single bench experiment or (most especially for) a big clinical trial. You need to be sure that you're asking the right question, that you're setting it up to be answered (one way or another), and that you're going to be able to get the maximum amount of useful information when that answer comes in, be it a Yes or a No. Sometimes this setup is obvious, but by the time you get to clinical trial design, it can be very tricky indeed.
For drug discovery, Gilman say, there are generally three kinds of hypothesis:
Biological hypothesis. What buttons do we believe this molecule pushes in target cells and what happens when these buttons are pushed? What biological pathways respond?
Clinical hypothesis. When these pathways are impacted, why do we believe it will move the needle on parameters that matter to patients and physicians? How will this intervention normalize physiology or reverse pathology?
Commercial hypothesis. If the first two hypotheses are correct, why do we believe anyone will care? Why will patients, physicians, and payers want this drug? How do we expect it to stand out from the crowd?
Many are the programs that have come to grief because of some sort of mismatch between these three. Clinical trials have been run uselessly because the original drug candidate was poorly characterized. Ostensibly successful trials have come to nothing because they were set up to answer the wrong questions. And ostensibly successful drug candidates have died in the marketplace because nobody wanted them. These are very expensive mistakes, and some extra time spent staring out the window while thinking about how to avoid them could have come in handy.
Gilman goes on to make a number of other good points about managing risk - for example, any experiment that shoulders a 100% share of the risk needs to be done as cheaply as possible. I would add, as a corollary, ". . .and not one bit cheaper", because that's another way that you can mess things up. At all times, you have to have a realistic idea of where you are in the process and what you're taking on. If you can find a way to do the crucial experiment without risking too much time or money, that's excellent news. On the other end of the scale, if there's no other way to do it than to put a big part of the company down on the table, then you'd better be sure that getting the answer is going to be worth that much effort. If it is, then be sure to spend the money to do it right - you're not going to get a second shot that easily.
The article also shows how you want to manage such risks across a broader portfolio. You'd like, if possible, to have plenty of programs that are front-loaded with their major risks, the sorts of things that you're not necessarily going to have to hopping around the room with crossed fingers while you're waiting for the Phase III data. It's impossible to take all the risk out of a Phase III, true - but if you can get some of the big questions out of the way earlier, without having to go that far, so much the better. A portfolio made up of several gigantic multiyear money furnaces - say, Alzheimer's or rheumatoid arthritis - will be something else entirely.
+ TrackBacks (0) | Category: Clinical Trials | Drug Development
No time for a morning blog post - I'm too busy exhaling sighs of relief around here. I'll see everyone later on in the day (on some other topic entirely). What a business this is!
+ TrackBacks (0) | Category: Clinical Trials
June 23, 2014
Here's one of those "Drug Discovery of. . .the. . .Future-ure-ure-ure" articles in the popular press. (I need a reverb chamber to make that work property). At The Atlantic, they're talking with "medical futurists" and coming up with this:
The idea is to combine big data and computer simulations—the kind an engineer might use to make a virtual prototype of a new kind of airplane—to figure out not just what's wrong with you but to predict which course of treatment is best for you. That's the focus of Dassault Systèmes, a French software company that's using broad datasets to create cell-level simulations for al