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: email@example.com
In the Pipeline:
Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline
September 2, 2014
I wanted to let readers know of a fun new book that's out this week. Randall Munroe, of webcomic XKCD fame, has written What If?: Serious Scientific Answers to Absurd Hypothetical Questions. There are a lot of truly odd ones in there, and he takes them on as best he can. I'm glad to say that I'm quoted in the chapter on "What would happen if you made a periodic table of cube-shaped bricks, where each brick was made of the corresponding element?" (That should give you an idea of the sorts of questions that come in to him; it makes my mail look fairly sane by comparison). And no, you wouldn't want to do that one - consider astatine and francium, for starters.
+ TrackBacks (0) | Category: Book Recommendations
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.
Update: here's a deep look at the IP and patent situation around the combo.
Update 2: and here's a detailed exchange about the way the trial was conducted and the drug's possible impact.
+ 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 29, 2014
I'm going to be taking an extra day of vacation before the kids start back to school, so I'm adding to the Labor Day weekend today. Blogging will resume on Tuesday, unless something gigantic happens before then. If I can come up with something appropriate, maybe I'll put up a recipe!
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August 28, 2014
Here's a short video history of the FDA, courtesy of BioCentury TV. The early days, especially Harvey Wiley and the "Poison Squad", are truly wild and alarming by today's standards. But then, the products that were on the market back then were pretty alarming, too. . .
+ TrackBacks (0) | Category: Drug Industry History | Regulatory Affairs
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 27, 2014
Here is the updated version of the "smallest drugs" collection that I did the other day. Here are the criteria I used: the molecular weight cutoff was set, arbitrarily, at aspirin's 180. I excluded the inhaled anaesthetics, only allowing things that are oils or solids in their form of use. As a small-molecule organic chemist, I only allowed organic compounds - lithium and so on are for another category. And the hardest one was "Must be in current use across several countries". That's another arbitrary cutoff, but it excludes pemoline (176), for example, which has basically been removed from the market. It also gets rid of a lot of historical things like aminorex. That's not to say that there aren't some old drugs on the remaining list, but they're still in there pitching (even sulfanilamide, interestingly). I'm sure I've still missed a few.
What can be learned from this exercise? Well, take a look at those structures. There sure are a lot of carboxylic acids and phenols, and a lot more sulfur than we're used to seeing. And pretty much everything is polar, very polar, which makes sense: if you're down in this fragment-sized space, you've got to be making some strong interactions with biological targets. These are fragments that are also drugs, so fragment-based drug discovery people may find this interesting as the bedrock layer of the whole field.
Some of these are pretty specialized and obscure - you're only going to see pralidoxime if you have the misfortune to be exposed to nerve gas, for example. But there are some huge, huge compounds on the list, too, gigantic sellers that have changed their whole therapeutic areas and are still in constant use. Metformin alone is a constant rebuke to a lot of our med-chem prejudices: who among us, had we never heard of it, would not have crossed it off our lists of screening hits? So give these small things a chance, and keep an open mind. They're real, and they can really be drugs.
+ TrackBacks (0) | Category: Chemical News | Drug Industry History
What scientific journals can you not be bothered to keep up with? I know, sometimes it's tempting to answer "all of them", but a well-informed chemist really should watch what comes out in the better ones. But how about the not-so-better ones? The "Life's too short" ones? Reading journals by RSS gives a person some perspective on signal-to-noise.
One problem is that Elsevier's RSS feeds are sort of perpetually hosed. Are they working now? I haven't checked in a while, because I finally gave up on them. And that means that I don't regularly look at Tetrahedron Letters or Bioorganic and Medicinal Chemistry Letters, even though (once in a while) something interesting turns up there. I look at ACS Medicinal Chemistry Letters more often, just because it has a working RSS feed (and I should note that I've rotated off their editorial board, by the way). Overall, though, I can't say that I miss either of those Elsevier journals, because you have to scroll through an awful lot of. . .stuff. . .to see something worth noting.
The same goes, I'm afraid, for Chemical Communications, and that makes me wonder if it's possible to keep up with the Letters/Communications style journals usefully at all. There are just so many papers pouring through them, and since Chem Comm takes them in from every sort of chemistry there is, vast numbers of them are of little interest to any particular reader. Their mini-review articles are perhaps an attempt to counteract this problem, and the journal also seems to have a slant towards "hot" topics. It's still in my RSS feed, but I look at the numbers of papers that pile up in it, and wonder if I should just delete and get it over with.
Organic Letters, on the other hand, I seem to be able to stay on top of, perhaps because it's focused down to at least organic chemistry (as opposed to Chem Comm). And I find a higher percentage of papers worth looking at than I do in Tet Lett (do others feel the same way?) And as for the other short-communications organic chemistry journals, I don't have them in the feed. Synthesis, Syn Comm, Synlett - writing this prompts me to go in and add them, but we'll see over the next couple of months if I regret it.
What it comes down to is that there's room for only a certain number of titles that can be followed as the papers publish. (The rest of them turn up in literature searches, responses to directed queries). And there are only a certain number of titles that are worth following in real time. So to get back to the question at the start of the post, which well-known journals do you find to be not worth the trouble?
+ TrackBacks (0) | Category: The Scientific Literature
August 26, 2014
There have been several analyses that have suggested that phenotypic drug discovery was unusually effective in delivering "first in class" drugs. Now comes a reworking of that question, and these authors (Jörg Eder, Richard Sedrani, and Christian Wiesmann of Novartis) find plenty of room to question that conclusion.
What they've done is to deliberately focus on the first-in-class drug approvals from 1999 to 2013, and take a detailed look at their origins. There have been 113 such drugs, and they find that 78 of them (45 small molecules and 33 biologics) come from target-based approaches, and 35 from "systems-based" approaches. They further divide the latter into "chemocentric" discovery, based around known pharmacophores, and so on, versus pure from-the-ground-up phenotypic screening, and the 33 systems compounds then split out 25 to 8.
As you might expect, a lot of these conclusions depend on what you classify as "phenotypic". The earlier paper stopped at the target-based/not target-based distinction, but this one is more strict: phenotypic screening is the evaluation of a large number of compounds (likely a random assortment) against a biological system, where you look for a desired phenotype without knowing what the target might be. And that's why this paper comes up with the term "chemocentric drug discovery", to encompass isolation of natural products, modification of known active structures, and so on.
Such conclusions also depend on knowing what approach was used in the original screening, and as everyone who's written about these things admits, this isn't always public information. The many readers of this site who've seen a drug project go from start to finish will appreciate how hard it is to find an accurate retelling of any given effort. Stuff gets left out, forgotten, is un- (or over-)appreciated, swept under the rug, etc. (And besides, an absolutely faithful retelling, with every single wrong turn left in, would be pretty difficult to sit through, wouldn't it?) At any rate, by the time a drug reaches FDA approval, many of the people who were present at the project's birth have probably scattered to other organizations entirely, have retired or been retired against their will, and so on.
But against all these obstacles, the authors seem to have done as thorough a job as anyone could possibly do. So looking further at their numbers, here are some more detailed breakdowns. Of those 45 first-in-class small molecules, 21 were from screening (18 of those high-throughput screening, 1 fragment-based, 1 in silico, and one low-throughput/directed screening). 18 came from chemocentric approaches, and 6 from modeling off of a known compound.
Of the 33 systems-based drugs, those 8 that were "pure phenotypic" feature one antibody (alemtuzumab) which was raised without knowledge of its target, and seven small molecules: sirolimus, fingolimod, eribulin, daptomycin, artemether–lumefantrine, bedaquiline and trametinib. The first three of those are natural products, or derived from natural products. Outside of fingolimod, all of them are anti-infectives or antiproliferatives, which I'd bet reflects the comparative ease of running pure phenotypic assays with those readouts.
Here are the authors on the discrepancies between their paper and the earlier one:
At first glance, the results of our analysis appear to significantly deviate from the numbers previously published for first-in-class drugs, which reported that of the 75 first-in-class drugs discovered between 1999 and 2008, 28 (37%) were discovered through phenotypic screening, 17 (23%) through target-based approaches, 25 (33%) were biologics and five (7%) came from other approaches. This discrepancy occurs for two reasons. First, we consider biologics to be target-based drugs, as there is little philosophical distinction in the hypothesis driven approach to drug discovery for small-molecule drugs versus biologics. Second, the past 5 years of our analysis time frame have seen a significant increase in the approval of first-in-class drugs, most of which were discovered in a target-based fashion.
Fair enough, and it may well be that many of us have been too optimistic about the evidence for the straight phenotypic approach. But the figure we don't have (and aren't going to get) is the overall success rate for both techniques. The number of target-based and phenotypic-based screening efforts that have been quietly abandoned - that's what we'd need to have to know which one has the better delivery percentage. If 78/113 drugs, 69% of the first-in-class approvals from the last 25 years, have come from target-based approaches how does that compare with the total number of first-in-class drug projects? My own suspicion is that target-based drug discovery has accounted for more than 70% of the industry's efforts over that span, which would mean that systems-based approaches have been relatively over-performing. But there's no way to know this for sure, and I may just be coming up with something that I want to hear.
That might especially be true when you consider that there are many therapeutic areas where phenotypic screening basically impossible (Alzheimer's, anyone?) But there's a flip side to that argument: it means that there's no special phenotypic sauce that you can spread around, either. The fact that so many of those pure-phenotypic drugs are in areas with such clear cellular readouts is suggestive. Even if phenotypic screeningwere to have some statistical advantage, you can't just go around telling people to be "more phenotypic" and expect increased success, especially outside anti-infectives or antiproliferatives.
The authors have another interesting point to make. As part of their analysis of these 113 first-in-class drugs, they've tried to see what the timeline is from the first efforts in the area to an approved drug. That's not easy, and there are some arbitrary decisions to be made. One example they give is anti-angiogenesis. The first report of tumors being able to stimulate blood vessel growth was in 1945. The presence of soluble tumor-derived growth factors was confirmed in 1968. VEGF, the outstanding example of these, was purified in 1983, and was cloned in 1989. So when did the starting pistol fire for drug discovery in this area? The authors choose 1983, which seems reasonable, but it's a judgment call.
So with all that in mind, they find that the average lead time (from discovery to drug) for a target-based project is 20 years, and for a systems-based drug it's been 25 years. They suggest that since target-based drug discovery has only been around since the late 1980s or so, that its impact is only recently beginning to show up in the figures, and that it's in much better shape than some would suppose.
The data also suggest that target-based drug discovery might have helped reduce the median time for drug discovery and development. Closer examination of the differences in median times between systems-based approaches and target-based approaches revealed that the 5-year median difference in overall approval time is largely due to statistically significant differences in the period from patent publication to FDA approval, where target-based approaches (taking 8 years) took only half the time as systems-based approaches (taking 16 years). . .
The pharmaceutical industry has often been criticized for not being sufficiently innovative. We think that our analysis indicates otherwise and perhaps even suggests that the best is yet to come as, owing to the length of time between project initiation and launch, new technologies such as high-throughput screening and the sequencing of the human genome may only be starting to have a major impact on drug approvals. . .
Now that's an optimistic point of view, I have to say. The genome certainly still has plenty of time to deliver, but you probably won't find too many other people saying in 2014 that HTS is only now starting to have an impact on drug approvals. My own take on this is that they're covering too wide a band of technologies with such statements, lumping together things that have come in at different times during this period and which would be expected to have differently-timed impacts on the rate of drug discovery. On the other hand, I would like this glass-half-full view to be correct, since it implies that things should be steadily improving in the business, and we could use it.
But the authors take pains to show, in the last part of their paper, that they're not putting down phenotypic drug discovery. In fact, they're calling for it to be strengthened as its own discipline, and not (as they put it) just as a falling back to the older "chemocentric" methods of the 1980s and before:
Perhaps we are in a phase today similar to the one in the mid-1980s, when systems-based chemocentric drug discovery was largely replaced by target-based approaches. This allowed the field to greatly expand beyond the relatively limited number of scaffolds that had been studied for decades and to gain access to many more pharmacologically active compound classes, providing a boost to innovation. Now, wi