Drug discovery in academia and NIH, a new type of U01

First off, WOW!!, this has easily been the busiest day ever on juniorprof. Many, many, thanks to Abelpharmboy, Zuska, Melissa McEwan and Almost Diamonds for linking here and sharing your support for the campaign and also to DM for all the support over on twitter for the #painresearchmatters campaign. I am humbled by all of your support and encouragement. Keep the tweets pouring in on twitter with the hashtag #painresearchmatters!

Now, onto our regularly scheduled program: Drug discovery in academia. To some of you this may seem like a strange thing to post about since the common perception is that there is no drug discovery (at least no REAL drug discovery) in academia. I have to admit, I tend to agree that drug discovery in academia is limited and oftentimes lacks the type of rigor that is really needed to develop a drug. For an extensive series of posts on industry vs. academic drug discovery head on over to Derek Lowe’s place. He has all his posts on the topic nicely categorized and they are a very interesting read. One of my all time favorites is this one where he points out that while the compound may be useful as an in vitro tool, it is likely less than useful as a scaffold for further drug development for very obvious reasons. This brings us to the bane of drug discovery: absorption, distribution, metabolism and excretion (ADME). This is something that industry does very well. After all, if you want to make a drug that enters the brain it damn sure better cross the blood brain barrier. ADME in academia, well, let’s just say, not so much. The reasons for this are likely pretty simple: its an important area of drug development but not the most exciting, by any stretch of the imagination (sorry you ADME specialists), and it often requires all sorts of rather expensive testing in model organisms that aren’t used often in academic labs. Its also highly compound-specific and this makes grant writing very hard (or so I hear).

On the other hand, there are very good reasons to do more drug discovery in academia. First, most of the disease models employed for drug development are created in academic labs. Ditto on the development of drug targets for diseases. Its also true that many, if not most, of the endogenous activators of receptors and enzymes have been discovered through the efforts of NIH-funded research. These endogenous ligands are usually the platforms on which additional drug scaffolds are made and academic pharmacologists are pretty darn good at generating structure activity relationships (SAR) for drug-receptor interactions. So what’s the hold-up? In my view its the nature of the academic beast. The medicinal chemists and in vivo and in vitro pharmacologists that are needed to bring a drug discovery effort to fruition just don’t have the opportunities to come together in an academic setting like they do in pharma industry. Pharma industry is built for this sort of thing. NIH grants are not. All of this adds up to major impediments to drug discovery in academia while the potential benefit is huge. Drugs developed through academic efforts have the potential to be much cheaper, target diseases were there is little, if any, potential profit margin (orphan drug programs aside) and would be a huge boon for NIH. Imagine how much easier justifying big increases in NIH funding would be if NIH funded labs were doing work that was leading directly (in the most literal sense of the word) to new therapies. I think this would be huge.

NIH has run a number of drug discovery efforts over the years. There are intramural and extramural programs for either discovery or compound banking. There are traditional U-mechanism grants and there are program projects aimed specifically at developing drugs. However, to my knowledge, there has never been an NIH mechanism that unifies academic capacity for biological target and screening development with industrial chemistry capabilities wherein the chemistry is done a contract basis. At least not until now. Very recently the Neurotherapeutics Grand Challenge was released within the NIH Blueprint for Neuroscience Research. The idea is simple, you, the academic, bring a disease of interest, a lead compound and screening capability to the table and, if you are funded, NIH will find a suitable chemistry contractor to do the chemical library generation with ADME, and all the other things that us academics don’t specialize in, in mind.

Personally, I think this is a brilliant idea. We’ve been dabbling in some drug discovery quite a bit lately and while we have some good leads and screening capability in hand, it becomes very obvious, very quickly, that going from a lead compound to a drug-like molecule is a huge stumbling block. First, it costs a ton of money to start generating the compounds you need to generate SAR that takes ADME into account. Second, even the best medicinal chemists simply cannot dedicate all of their academic time to doing this sort of thing, it drains their labs of resources that are needed to produce on projects that bring in funding. Finally, screening compounds is time consuming and is also expensive. We all know that fishing expeditions aren’t the best way to get your lab funded and if ever there was a fishing expedition this is one of them.

Most of these problems are covered by the program. Chemistry is contracted in consultation with the academic med chem partner. Screening is done in the academic lab and paid for by the program (it is the express experimental aim of the program). Phase I clinical trials (if you get that far) are also taken care of by NIH and decisions to move forward with efficacy trials are done in consultation with NIH and a clinical partner that the applicants need to identify. While the moving to humans part of the project is all a long way off from the nitty-gritty of the drug discovery it is nice to see that this is part of the program and that decisions-to-come will be considered early on.

There are some negatives to the program. The most obvious is that funding for year one is no guarantee of continued funding. There is a board that will review progress and if your lead compound proves to be a dead end for a drug-like molecule, chances are that funding will be cut sooner rather than later. I would imagine that they are envisioning about 50% attrition after one or two years. We all know that this is not an ideal way to run our labs but if you want to play the game, this is how its gonna work for now. Funding levels are also a bit low. NIH wants to fund 10 projects this year at 1.75 million. That means about 175K/year and its going to be tough to budget for full screening capacity for that amount of money. Then again, alot of the costs go to contract work and that is not included in the academic budget so I imagine it can be doable for most. The final disadvantage is that there appear to some intellectual property hurdles that need to be cleared. This is likely to be institution or state specific but I’m not an expert in these areas so I’m not certain.

All in all, I think that this is a novel and exciting idea with some real chance for success. Moreover, I am hopeful that some stories of accomplishment in programs like these can generate more opportunities for full-fledged drug discovery efforts within the structure of academia. I’ll have more to come on the logistic of drug discovery in the coming days.

UPDATE: I got the budget wrong on this… they are looking for $125K/year budgets. That’s a big difference!

10 responses to “Drug discovery in academia and NIH, a new type of U01

  1. I think, in many ways, drug discovery process is in the midst of changing dramatically, to bring more collaboration between companies-especially mid-size pharma/biotechs-and academics-on the individual and institutional level. It will be interesting to see where this goes.

    In academia, Vanderbilt has really built up what I think is quite a unique program to drive drug discovery, which has garnered some fairly substantial industrial and non-profit funding support. One feautre of the program is the development of core facilities, which essentially serve as internal contractors to assist with synthesis, screening, and purportedly PK/PD. One PI there, recruited from a successful career in pharma, commented that he expected to carry the process from target discovery to early clinical trials. It will be interesting to see how this plays out in the long term.

  2. M Alburquerque

    Exciting initiative and nice commentary. The”negatives” of the program are understandable given the finite nature of resources and the need to effectively prioritize priorities. But I am sure that there are excellent, adventurous scientist academics willing to give it a try ASAP.

  3. Biochembelle, thanks for pointing out the program at Vandy. A similar program has been started between Pfizer and Washington University (St. Louis): http://pipeline.corante.com/archives/2010/05/19/another_set_of_eyes.php

    Agreed that drug discovery and the way Big Pharma runs their discovery operations is changing. With the massive cuts that have taken place among their basic biology and chemistry programs over the past three years I think that they are forced to do more and more either with startups or through collaborative efforts with academia.

  4. I agree that this is the future of drug research.

    However I don’t see this giving rise to your Utopian vision of cheap drugs for all. Although you are in good company; I recently saw David Baltimore give a talk on will there ever be a cure for cancer and this was his punchline: “personalized” medicine, consisting of massively complex combination regimens selected from a battery of thousands of targeted compounds. To make these drug regimens financially viable, they need to be developed academically, blah, blah, blah.

    Anyhow the reason I disagree is that whether a drug is developed in academia or not, it has to get through serious phases of clinical trials if it’s going to make it into medical practice. Regulatory, legal, manufacturing, marketing issues etc. Takes billions $/drug. I don’t see how anyone shelling out this kind of cash is going to pass on IP rights and pass along the savings to the insurance companies. But maybe I don’t know the American system.

    Anyhow I think that academic products will be the same as industry products. The important differences will be that “academic” biomedical researchers will be tapping into massive cash flows of a magnitude previously only available to industry, and academic institutions will increasingly become factories driven to creating tangible products, most likely at the expense of “basic” knowledge-focused research.

    But at the end of the day the drugs coming out will continue to fetch the highest prices the market can support, just like they do now.

  5. Good points all Bayman, however, I find it hard to see how drugs that result completely from NIH programs could ever cost as much as many BigPharma products, the overhead and marketing costs will simply not be there and the incentive to grab the highest price the market will bear is also not present. Having said that, the FDA clearance costs are simply massive and until there is a concerted effort to reform those regulations (or at least their costs) such drugs will never be “cheap”. Either way, you will never take my utopian dream away from me :-)

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  7. I would like to subscribe.

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  10. Carol Berthelots

    A ce sujet, en matière d’académicien, ll semblerait que le célèbre libraire M. Collard, qui dirige la librairie Griffe Noire, se présente pour devenir à l’Academie Française .. Je trouve que ça donnerait un second élan à la noble institution, foi de Saint Maurien. Qu’en pensez-vous ?

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