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
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. . .
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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.
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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.
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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, with an increased chemical space, the time might be right to further broaden the target space and open up new avenues. This could well be achieved by investing in phenotypic screening using the compound libraries that have been established in the context of target-based approaches. We therefore consider phenotypic screening not as a neoclassical approach that reverts to a supposedly more successful systems-based method of the past, but instead as a logical evolution of the current target-based activities in drug discovery. Moreover, phenotypic screening is not just dependent on the use of many tools that have been established for target-based approaches; it also requires further technological advancements.
That seems to me to be right on target: we probably are in a period just like the mid-to-late 1980s. In that case, though, a promising new technology was taking over because it seemed to offer so much more. Today, it's more driven by disillusionment with the current methods - but that means, even more, that we have to dig in and come up with some new ones and make them work.
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August 25, 2014
Mentioning such a small compound as pirfenidone prompts me to put up the graphic shown below: these are the smallest commonly used drugs that I can think of. (OK, there's cocaine as a nasal anaesthetic - no, really - but that's where I draw the line at "commonly used". Nominations for ones that I've missed are welcome, and I'll update the list as needed. Note: four more have been added since the initial post, with more to come. This sort of thing really makes a chemist think, though - some of these compounds are very good indeed at what they do, and have been wildly successful. We need to keep an open mind about small molecules, that's for sure, no matter how small they are.
Update: see this follow-up post for the latest version of the graphic.
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August 22, 2014
Science has an article by journalist Ken Garber on palbociclib, the Pfizer CDK4 compound that came up here the other day when we were discussing their oncology portfolio. You can read up on the details of how the compound was put in the fridge for several years, only to finally emerge as one of the company's better prospects. The roots of the project go back to about 1995 at Parke-Davis:
Because the many CDK family members are almost identical, “creating a truly selective CDK4 inhibitor was very difficult,” says former Parke-Davis biochemist Dave Fry, who co-chaired the project with chemist Peter Toogood. “A lot of pharmaceutical companies failed at it, and just accepted broad-spectrum CDK inhibitors as their lead compounds.” But after 6 years of work, the pair finally succeeded with the help of some clever screens that could quickly weed out nonspecific “dirty” compounds.
Their synthesis in 2001 of palbociclib, known internally as PD-0332991, was timely. By then, many dirty CDK inhibitors from other companies were already in clinical trials, but they worked poorly, if at all. Because they hit multiple CDK targets, these compounds caused too much collateral damage to normal cells. . .Eventually, most efforts to fight cancer by targeting the cell cycle ground to a halt. “Everything sort of got hung up, and I think people lost enthusiasm,” Slamon says.
PD-0332991 fell off the radar screen. Pfizer, which had acquired Warner-Lambert/Parke-Davis in 2000 mainly for the cholesterol drug Lipitor, did not consider the compound especially promising, Fry says, and moved it forward haltingly at best. “We had one of the most novel compounds ever produced,” Fry says, with a mixture of pride and frustration. “The only compound in its class.”
A major merger helped bury the PD-0332991 program. In 2003, Pfizer acquired Swedish-American drug giant Pharmacia, which flooded Pfizer's pipeline with multiple cancer drugs, all competing for limited clinical development resources. Organizational disarray followed, says cancer biologist Dick Leopold, who led cancer drug discovery at the Ann Arbor labs from 1989 to 2003. “Certainly there were some politics going on,” he says. “Also just some logistics with new management and reprioritization again and again.” In 2003, Pfizer shut down cancer research in Ann Arbor, which left PD-0332991 without scientists and managers who could demand it be given a chance, Toogood says. “All compounds in this business need an advocate.”
So there's no doubt that all the mergers and re-orgs at Pfizer slowed this compound down, and no doubt a long list of others, too. The problems didn't end there. The story goes on to show how the compound went into Phase I in 2004, but only got into Phase II in 2009. The problem is, well before that time it was clear that there were tumor types that should be more sensitive to CDK4 inhibition. See this paper from 2006, for example (and there were some before this as well).
It appears that Pfizer wasn't going to develop the compound at all (thus that long delay after Phase I). They made it available as a research tool to Selina Chen-Kiang at Weill Cornell, who saw promising results with mantle cell lymphoma, then Dennis Slamon and RIchard Finn at UCLA profiled the compound in breast cancer lines and took it into a small trial there, with even more impressive results. And at this point, Pfizer woke up.
Before indulging in a round of Pfizer-bashing, though, It's worth remembering that stories broadly similar to this are all too common. If you think that the course of true love never did run smooth, you should see the course of drug development. Warner-Lambert (for example) famously tried to kill Lipitor more than once during its path to the market, and it's a rare blockbuster indeed that hasn't passed through at least one near-death-experience along the way. It stands to reason: since the great majority of all drug projects die, the few that make it through are the ones that nearly died.
There are also uncounted stories of drugs that nearly lived. Everyone who's been around the industry for a while has, or has heard, tales of Project X for Target Y, which was going along fine and looked like a winner until Company Z dropped for Stupid Reason. . .uh, Aleph. (Ran out of letters there). And if only they'd realized this, that, and the other thing, that compound would have made it to market, but no, they didn't know what they had and walked away from it, etc. Some of these stories are probably correct: you know that there have to have been good projects dropped for the wrong reasons and never picked up again. But they can't all be right. Given the usual developmental success rates, most of these things would have eventually wiped out for some reason. There's an old saying among writers that the definition of a novel is a substantial length of narrative fiction that has something wrong with it. In the same way, every drug that's on the market has something wrong with it (usually several things), and all it takes is a bit more going wrong to keep it from succeeding at all.
So where I fault Pfizer in all this is in the way that this compound got lost in all the re-org shuffle. If it had developed more normally, its activity would have been discovered years earlier. Now, it's not like there are dozens of drugs that haven't made it to market because Pfizer dropped the ball on them - but given the statistics, I'll bet that there are several (two or three? five?) that could have made it through by now, if everyone hadn't been so preoccupied with merging, buying, moving, rearranging, and figuring out if they were getting laid off or not.
The good thing is that other companies stepped into the field on the basis of those earlier publications, and found CDK4/6 inhibitors of their own (notably Novartis and Lilly). This is why I think that huge mergers hurt the intellectual health of the drug industry. Take it to the reducio ad not all that absurdum of One Big Drug Company. If we had that, and only that, then whole projects and areas of research would inevitably get shelved, and there would be no one left to pick them up at all. (I'll also note, in passing, that should all of the CDK inhibitors make it to market, that there will be yahoos who decry the whole thing as nothing but a bunch of fast-follower me-too drugs, waste of time and money, profits before people, and so on. Watch for it.)
+ TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History
August 20, 2014
John LaMattina has a look at Pfizer's oncology portfolio, and what their relentless budget-cutting has been doing to it. The company is taking some criticism for having outlicensed two compounds (tremelimumab to AstraZeneca and neratinib to Puma) which seem to be performing very well after Pfizer ditched them. Here's LaMattina (a former Pfizer R&D head, for those who don't know):
Unfortunately, over 15 years of mergers and severe budget cuts, Pfizer has not been able to prosecute all of the compounds in its portfolio. Instead, it has had to make choices on which experimental medicines to keep and which to set aside. However, as I have stated before, these choices are filled with uncertainties as oftentimes the data in hand are far from complete. But in oncology, Pfizer seems to be especially snake-bit in the decisions it has made.
That goes for their internal compounds, too. As LaMattina goes one to say, palbociclib is supposed to be one of their better compounds, but it was shelved for several years due to more budget-cutting and the belief that the effort would be better spent elsewhere. It would be easy for an outside observer to whack away at the company and wonder how incompetent they could be to walk away from all these winners, but that really isn't fair. It's very hard in oncology to tell what's going to work out and what isn't - impossible, in fact, after compounds have progressed to a certain stage. The only way to be sure is to take these things on into the clinic and see, unfortunately (and there you have one of the reasons things are so expensive around here).
Pfizer brought up more interesting compounds than it later was able to develop. It's a good question to wonder what they could have done with these if they hadn't been pursuing their well-known merger strategy over these years, but we'll never know the answer to that one. The company got too big and spent too much money, and then tried to cure that by getting even bigger. Every one of those mergers was a big disruption, and you sometimes wonder how anyone kept their focus on developing anything. Some of its drug-development choices were disastrous and completely their fault (the Exubera inhaled-insulin fiasco, for example), but their decisions in their oncology portfolio, while retrospectively awful, were probably quite defensible at the time. But if they hadn't been occupied with all those upheavals over the last ten to fifteen years, they might have had a better chance on focusing on at least a few more of their own compounds.
Their last big merger was with Wyeth. If you take Pfizer's R&D budget and Wyeth's and add them, you don't get Pfizer's R&D post-merger. Not even close. Pfizer's R&D is smaller now than their budget was alone before the deal. Pyrrhus would have recognized the problem.
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July 30, 2014
It's not the most cheerful topic in the world, but NPR recently had an item on the decommissioned pharma research sites of New Jersey (of which there are many). Some of these are quite large, and correspondingly hard to unload onto anyone else. (This is, of course, a problem that is not unique to New Jersey, with plenty of ex-pharma sites around the US and the UK in particular falling into this category).
I got to see this in an earlier and less severe form when I worked at Schering-Plough: the company's old Bloomfield site proved difficult to deal with in the early 1990s once everyone had moved out of it. No other company (large or small) wanted it, and I was told that an attempt to more or less donate it to Rutgers University had fallen through as well. In the end, the buildings were demolished and the land was sold, with a Home Depot (and its parking lot) taking up a good part of the space.
That's always one option. Another is what happened to my next stop in pharma, the Bayer campus at West Haven. Yale picked that one up for what we heard was a good price, and turned it into the Yale West Research Campus. So that at least keeps the place doing research, which has to beat turning it into a hardware store. Breaking things up into an incubator for smaller companies is a good plan, too, when it can be done.
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July 25, 2014
Here's a business-section column at the New York Times on the problem of antibiotic drug discovery. To those of us following the industry, the problems of antibiotic drug discovery are big pieces of furniture that we've lived with all our lives; we hardly even notice if we bump into them again. You'd think that readers of the Times or other such outlets would have come across the topic a few times before, too, but there must always be a group for which it's new, no matter how many books and newspaper articles and magazine covers and TV segments are done on it. It's certainly important enough - there's no doubt that we really are going to be in big trouble if we don't keep up the arms race against the bacteria.
This piece takes the tack of "If drug discovery is actually doing OK, where are the new antibiotics?" Here's a key section: