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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: Twitter: Dereklowe

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March 29, 2011

The NIH Goes For the Gusto

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Posted by Derek

Here's an interesting funding opportunity from NIH:

Recent advances in neuroscience offer unprecedented opportunities to discover new treatments for nervous system disorders. However, most promising compounds identified through basic research are not sufficiently drug-like for human testing. Before a new chemical entity can be tested in a clinical setting, it must undergo a process of chemical optimization to improve potency, selectivity, and drug-likeness, followed by pre-clinical safety testing to meet the standards set by the Food and Drug Administration (FDA) for clinical testing. These activities are largely the domain of the pharmaceutical industry and contract research organizations, and the necessary expertise and resources are not commonly available to academic researchers.

To enable drug development by the neuroscience community, the NIH Blueprint for Neuroscience Research is establishing a ‘virtual pharma’ network of contract service providers and consultants with extensive industry experience. This Funding Opportunity Announcement (FOA) is soliciting applications for U01 cooperative agreement awards from investigators with small molecule compounds that could be developed into clinical candidates within this network. This program intends to develop drugs from medicinal chemistry optimization through Phase I clinical testing and facilitate industry partnerships for their subsequent development. By initiating development of up to 20 new small-molecule compounds over two years (seven projects were launched in 2011), we anticipate that approximately four compounds will enter Phase 1 clinical trials within this program.

My first thought is that I'd like to e-mail that first paragraph to Marcia Angell and to all the people who keep telling me that NIH discovers most of the drugs on the market. (And as crazy as that sounds, I still keep running into people who are convinced that that's one of those established facts that Everyone Knows). My second thought is that this is worth doing, especially for targeting small or unusual diseases. There could well be interesting chemical matter or assay ideas floating around out there, looking for the proper environment to have something made of them.

My third thought, though, is that this could well end up being a real education for some of the participants. Four Phase I compounds out of twenty development candidates - it's hard to say if that's optimistic or not, because the criteria for something to be considered a development candidate can be slippery. And that goes for the drug industry too, I hasten to add. Different organizations have different ideas about what kinds of compounds are worth taking to the clinic, and those criteria vary by disease area, too. (Sad to say, they can also vary by time of the year and the degree to which bonuses are tied to hitting number-of-clinical-candidate goals, and anyone who's been around the business a while will have seen that happen, to their regret).

It'll be interesting to see how many people apply for this; the criteria look pretty steep to me:

Applicants must have available small-molecule compounds with strong evidence of disease-related activity and the potential for optimization through iterative medicinal chemistry. Applicants must also be able to conduct bioactivity and efficacy testing to assess compounds synthesized in the development process and provide all pre-clinical validation for the desired disease indication. . .This initiative is not intended to support development of new bioactivity assays, thus the applicant must have in hand well-characterized assays and models.

Hey, there are small companies out there that don't come up to that standard. To clarify, though, the document does say that "Evaluation of the approach should focus primarily on the rationale and strengths/weaknesses of proposed bioactivity studies and compound "druggability," since all other drug development work (e.g., medicinal chemistry, PK/tox, phase I clinical testing) will be designed and implemented by NIH-provided consultants and contractors after award", which must come as something of a relief.

What's interesting to me, though, is that the earlier version of this RFA (from lsat year) had the following language:

The ultimate goals of this Neurotherapeutics Grand Challenge are to produce at least one novel and effective drug for a nervous system disorder that is currently poorly treated and to catalyze industry interest in novel disease targets by demonstrating early-stage success.

That's missing this time around, which is a good thing. If they're really hoping for a drug to come out of four Phase I candidates in poorly-treated CNS disorders, then I'd advise them to keep that thought well hidden. The overall attrition rate in the clinic in CNS is somewhere around (and maybe north of) 90%, and if you're going to go after the tough end of that field it's going to be even steeper.

Comments (7) + TrackBacks (0) | Category: Academia (vs. Industry) | Drug Development | The Central Nervous System


1. Vladimir Putin on March 29, 2011 9:30 AM writes...

What is interesting here is that it seems as though they don't even know what they don't know. I want my taxes back.

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2. Virgil on March 29, 2011 9:33 AM writes...

It's a pity this is neuro focused. THere are a bunch of other diseases that could benefit from such an approach. Maybe they just went with the most difficult one first? If it can be made to work despite the best efforts of the blood-brain-barrier, then there might be hope for it working in less problematic organs.

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3. SP on March 29, 2011 10:29 AM writes...

Keep in mind it's not 4 our of 20, it's 4 out of how ever many applications they get, out of which they'll only try to advance the best 20.

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4. pete on March 29, 2011 10:35 AM writes...

On the plus side, they should be able to recruit some pretty savvy folks given what appears to be the current, cyclic wane of Neuroscience w/in Pharma.

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5. luysii on March 29, 2011 12:28 PM writes...

Wasn't the Decade of the Brain (1990 - 2000) supposed to have solved all this? Just like management, science funding has fads as well. Pardon the cynicism.

Hard problems deserve hard work by our best minds. I'm not surprised that not much has turned up so far. The major advance for muscular dystrophy when I was running one of their clinics in the 70s and 80s was lighter braces (it really was a major advance as it kept weak kids out of wheelchairs longer).

Keep at it,guys . The patients and their families are still out there, still suffering.

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6. johnnboy on March 29, 2011 1:44 PM writes...

So if I understand correctly, the NIH is asking small companies (or top-notch large academic labs, judging from their application criteria) to apply to this program, upon which the NIH will basically fund the preclinical and phase I work for 20 compounds. Is that it ?
One hopes that the NIH has a developed a clear idea of what CROs charge for all the preclinical tox work, as well as for phase I studies. I didn't think they had so much free money floating around over there.

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7. Rick on March 29, 2011 5:06 PM writes...

If this is done right, of which I'm skeptical, I think this could actually be a pretty cool thing. There's a lot of valuable information that comes from failure in drug discovery, but I suspect most of it never sees the light of day because it is kept hidden behind corporate walls of IP, trade secrets and paranoia. If the failures of this program (and there will be scads of them!) are shared and studied openly, the program will have been worth it, even if they go 0-for-20. If on the other hand they try to behave like pharma and place getting that one drug at all costs above learning something about how small molecules interact with the biochemistry and physiology of the nervous system, it will fall far short of its potential, even if they to get their one drug out of it.

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