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About this Author
DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png 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: derekb.lowe@gmail.com Twitter: Dereklowe

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August 28, 2014

Drug Repurposing

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Posted by Derek

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.

Comments (33) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Drug Industry History | Regulatory Affairs

August 26, 2014

A New Look at Phenotypic Screening

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Posted by Derek

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.

Comments (7) + TrackBacks (0) | Category: Drug Assays | Drug Development | Drug Industry History

August 22, 2014

The Palbociclib Saga: Or Why We Need a Lot of Drug Companies

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Posted by Derek

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.)

Comments (13) + TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History

August 21, 2014

Why Not Bromine?

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Posted by Derek

So here's a question for the medicinal chemists: how come we don't like bromoaromatics so much? I know I don't, but I have trouble putting my finger on just why. I know that there's a ligand efficiency argument to be made against them - all that weight, for one atom - but there are times when a bromine seems to be just the thing. There certainly are such structures in marketed drugs. Some of the bad feelings around them might linger from the sense that it's sort of unnatural element, as opposed to chlorine, which in the form of chloride is everywhere in living systems.

But bromide? Well, for what it's worth, there's a report that bromine may in fact be an essential element after all. That's not enough to win any arguments about putting it into your molecules - selenium's essential, too, and you don't see people cranking out the organoselenides. But here's a thought experiment: suppose you have two drug candidate structures, one with a chlorine on an aryl ring and the other with a bromine on the same position. If they have basically identical PK, selectivity, preliminary tox, and so on, which one do you choose to go on with? And why?

If you chose the chloro derivative (and I think that most medicinal chemists instinctively would, for just the same hard-to-articulate reasons we're talking about), then what split in favor of the bromo compound would be enough to make you favor it? How much more activity, PK coverage, etc. do you need to make you willing to take a chance on it instead?

Comments (36) + TrackBacks (0) | Category: Drug Development | Odd Elements in Drugs | Pharmacokinetics | Toxicology

August 20, 2014

Did Pfizer Cut Back Some of Its Best Compounds?

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Posted by Derek

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.

Comments (20) + TrackBacks (0) | Category: Business and Markets | Cancer | Drug Development | Drug Industry History

August 19, 2014

Don't Optimize Your Plasma Protein Binding

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Posted by Derek

Here's a very good review article in J. Med. Chem. on the topic of protein binding. For those outside the field, that's the phenomenon of drug compounds getting into the bloodstream and then sticking to one or more blood proteins. Human serum albumin (HSA) is a big player here - it's a very abundant blood protein that's practically honeycombed with binding sites - but there are several others. The authors (from Genentech) take on the disagreements about whether low plasma protein binding is a good property for drug development (and conversely, whether high protein binding is a warning flag). The short answer, according to the paper: neither one.

To further examine the trend of PPB for recently approved drugs, we compiled the available PPB data for drugs approved by the U.S. FDA from 2003 to 2013. Although the distribution pattern of PPB is similar to those of the previously marketed drugs, the recently approved drugs generally show even higher PPB than the previously marketed drugs (Figure 1). The PPB of 45% newly approved drugs is >95%, and the PPB of 24% is >99%. These data demonstrate that compounds with PPB > 99% can still be valuable drugs. Retrospectively, if we had posed an arbitrary cutoff value for the PPB in the drug discovery stage, we could have missed many valuable medicines in the past decade. We suggest that PPB is neither a good nor a bad property for a drug and should not be optimized in drug design.

That topic has come up around here a few times, as could be expected - it's a standard med-chem argument. And this isn't even the first time that a paper has come out warning people that trying to optimize on "free fraction" is a bad idea: see this 2010 one from Nature Reviews Drug Discovery.

But it's clearly worth repeating - there are a lot of people who get quite worked about about this number - in some cases, because they have funny-looking PK and are trying to explain it, or in some cases, just because it's a number and numbers are good, right?

Comments (14) + TrackBacks (0) | Category: Drug Assays | Drug Development | Pharmacokinetics

July 25, 2014

The Antibiotic Gap: It's All of the Above

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Posted by Derek

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:

Antibiotics face a daunting proposition. They are not only becoming more difficult to develop, but they are also not obviously profitable. Unlike, say, cancer drugs, which can be spectacularly expensive and may need to be taken for life, antibiotics do not command top dollar from hospitals. What’s more, they tend to be prescribed for only short periods of time.

Importantly, any new breakthrough antibiotic is likely to be jealously guarded by doctors and health officials for as long as possible, and used only as a drug of last resort to prevent bacteria from developing resistance. By the time it became a mass-market drug, companies fear, it could be already off patent and subject to competition from generics that would drive its price down.

Antibiotics are not the only drugs getting the cold shoulder, however. Research on treatments to combat H.I.V./AIDS is also drying up, according to the research at Yale, mostly because the cost and time required for development are increasing. Research into new cardiovascular therapies has mostly stuck to less risky “me too” drugs.

This mixes several different issues, unfortunately, and if a reader doesn't follow the drug industry (or medical research in general), then they may well not realize this. (And that's the most likely sort of reader for this article - people who do follow such things have heard all of this before). The reason that cardiovascular drug research seems to have waned is that we already have a pretty good arsenal of drugs for the most common cardiovascular conditions. There are a huge number of options for managing high blood pressure, for example, and they're mostly generic drugs by now. The same goes for lowering LDL: it's going to be hard to beat the statins, especially generic Lipitor. But there is a new class coming along targeting PCSK9 that is going to try to do just that. This is a very hot area of drug development (as the author of the Times column could have found without much effort), although the only reason it's so big is that PCSK9 is the only pathway known that could actually be more effective at lowering LDL than the statins. (How well it does that in the long term, and what the accompanying safety profile might be, are the subject of ongoing billion-dollar efforts). The point is, the barriers to entry in cardiovascular are, by now, rather high: a lot of good drugs are known that address a lot of the common problems. If you want to go after a new drug in the space, you need a new mechanism, like PCSK9 (and those are thin on the ground), or you need to find something that works against some of the unmet needs that people have already tried to fix and failed (such as stroke, a notorious swamp of drug development which has swallowed many large expeditions without a trace).

To be honest, HIV is a smaller-scale version of the same thing. The existing suite of therapies is large and diverse, and keeps the disease in check in huge numbers of patients. All sorts of other mechanisms have been tried as well, and found wanting in the development stage. If you want to find a new drug for HIV, you have a very high entry barrier again, because pretty most of the reasonable ways to attack the problem have already been tried. The focus now is on trying to "flush out" latent HIV from cells, which might actually lead to a cure. But no one knows yet if that's feasible, how well it will work when it's tried, or what the best way to do it might be. There were headlines on this just the other day.

The barriers to entry in the antibiotic field area similarly high, and that's what this article seems to have missed completely. All the known reasonable routes of antibiotic action have been thoroughly worked over by now. As mentioned here the other day, if you just start screening your million-compound libraries against bacteria to see what kills them, you will find a vast pile of stuff that will kill your own cells, too, which is not what you want, and once you've cleared those out, you will find a still-pretty-vast pile of compounds that work through mechanisms that we already have antibiotics targeting. Needles in haystacks have nothing on this.

In fact, a lot of not-so-reasonable routes have been worked over, too. I keep sending people to this article, which is now seven years old and talks about research efforts even older than that. It's the story of GlaxoSmithKline's exhaustive antibiotics research efforts, and it also tells you how many drugs they got out of it all in the end: zip. Not a thing. From what I can see, the folks who worked on this over the last fifteen or twenty years at AstraZeneca could easily write the same sort of article - they've published all kinds of things against a wide variety of bacterial targets, and I don't think any of it has led to an actual drug.

This brings up another thing mentioned in the Times column. Here's the quote:

This is particularly striking at a time when the pharmaceutical industry is unusually optimistic about the future of medical innovation. Dr. Mikael Dolsten, who oversees worldwide research and development at Pfizer, points out that if progress in the 15 years until 2010 or so looked sluggish, it was just because it takes time to figure out how to turn breakthroughs like the map of the human genome into new drugs.

Ah, but bacterial genomes were sequenced before the human one was (and they're more simple, at that). Keep in mind also that proof-of-concept for new targets can be easier to obtain in bacteria (if you manage to find any chemical matter, that is). I well recall talking with a bunch of people in 1997 who were poring over the sequence data for a human pathogen, fresh off the presses, and their optimism about all the targets that they were going to find in there, and the great new approaches they were going to be able to take. They tried it. None of it worked. Over and over, none of it worked. People had a head start in this area, genomically speaking, with an easier development path than many other therapeutic areas, and still nothing worked.

So while many large drug companies have exited antibiotic research over the years, not all of them did. But the ones that stayed have poured effort and money, over and over, down a large drain. Nothing has come out of the work. There are a number of smaller companies in the space as well, for whom even a small success would mean a lot, but they haven't been having an easy time of it, either.

Now, one thing the Times article gets right is that the financial incentives for new antibiotics are a different thing entirely than the rest of the drug discovery world. Getting one of these new approaches in LDL or HIV to work would at least be highly profitable - the PCSK9 competitors certainly are working on that basis. Alzheimer's is another good example of an area that has yielded no useful drugs whatsoever despite ferocious amounts of effort, but people keep at it because the first company to find a real Alzheimer's drug will be very well rewarded indeed. (The Times article says that this hasn't been researched enough, either, which makes me wonder what areas have been). But any great new antibiotic would be shelved for emergencies, and rightly so.

But that by itself is not enough to explain the shortage of those great new antibiotics. It's everything at once: the traditional approaches are played out and the genomic-revolution stuff has been tried, so the unpromising economics makes the search for yet another approach that much harder.

Note: be sure to see the comments for perspectives from others who've also done antibiotic research, including some who disagree. I don't think we'll find anyone who says it's easy, though, but you never know.

Comments (56) + TrackBacks (0) | Category: Business and Markets | Drug Development | Drug Industry History | Infectious Diseases

July 24, 2014

Phenotypic Assays in Cancer Drug Discovery

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Posted by Derek

The topic of phenotypic screening has come up around here many times, as indeed it comes up very often in drug discovery. Give your compounds to cells or to animals and look for the effect you want: what could be simpler? Well, a lot of things could, as anyone who's actually done this sort of screening will be glad to tell you, but done right, it's a very powerful technique.

It's also true that a huge amount of industrial effort is going into cancer drug discovery, so you'd think that there would be a natural overlap between these: see if your compounds kill or slow cancer cells, or tumors in an anim