Terra Sigillata

A paper in last month’s issue of Nature Reviews Drug Discovery reported that US drug approvals during 2007 were the lowest number since 1983. (17 new molecular entities and 2 biologicals; see this figure for 1996-2007 data.) The review cites increased regulatory action as a factor in this reduction, especially following high-profile post-marketing safety issues with blockbuster drugs like Vioxx or Avandia. But other commentators have noted other problems such as the science of drug discovery in pharma being overridden by managers or the reluctance to develop agents for diseases that afflict less-than-blockbuster-sized patient populations.

I mention this in light of an article earlier this week by Sabine Vollmer of the Raleigh News & Observer on the establishment of drug discovery centers at Duke University and the University of North Carolina at Chapel Hill, each of which are led by former pharmaceutical company scientist/managers. Vollmer notes that Emory and Vanderbilt University have established similar programs. I believe that Vanderbilt has even invested in its own GMP drug manufacturing facility and was probably one of the first to have such a concerted effort.

NIH maintains intramural drug discovery and development programs and its extramural funding programs to academic drug discovery centers has expanded in the last several years. Traditionally, pharmacy schools and departments of chemistry have been the academic nuclei around which drug discovery and development was often seeded. That’s where novel small molecules have traditionally come from academia and colleges of pharmacy often have the drug metabolism and preclinical/clinical pharmacokinetics expertise to get a drug to the point that might interest pharma in an outlicensing deal. As an example, the semisynthesis of the natural product antitumor drug, Taxol (paclitaxel), was licensed by Bristol-Myers Squibb from the laboratory of Robert Holton at Florida State University’s Dept of Chemistry. (An engaging and detailed story can be found at FSU’s Office of Research.)

But where will these new, concerted academic drug discovery programs fit in, especially if they are led by former Big Pharma scientists?

Pharmaceutical medicinal chemist and pioneering science blogger Derek Lowe at In the Pipeline discussed his own thoughts on the role of academia in drug discovery. Dr Lowe argues that while primary drug discovery requires huge, non-academic resources, university researchers can and should do what they do best to augment the process:

Another place where some academic thinking could come in very useful would be in attacking the important pharmaceutical processes that we don’t understand: things like pharmacokinetics, oral availability, human versus animal toxicology, and (lots of) better disease models. The inefficiencies in these areas caused by our lack of knowledge are costing everyone billions of dollars – any improvement at all would be good news. Of course, it’s not like the industry hasn’t taken a crack at them, too (after all, there are those billions of dollars out there to be rescued from the bonfire). But we really need every approach we can get, and some fresh thinking would be welcome.

One thought is that, as I began this post, that academic centers may have more interest in working on therapeutics for diseases being overlooked by pharma, primarily due to economic reasons. I also think that the presence of faculty with pharmaceutical industry experience might inject some reality into the thinking of basic scientists who think they have a great compound when one need only look at the structure to realize it will be glucuronidated to hell.

Universities, in thinking more and more as revenue generating corporations, are probably looking at these drug discovery centers as cash cows. Again, there needs to be another injection of reality: the expectation should be no more than these centers will be great places for research and in training of scientists who are better equipped to enter the pharmaceutical industry than your average molecular biologist. One might hope that university leadership might have a longer view toward the time from investment to payoff (especially in investigators must obtain NIH funding for their efforts after the initial university investment has been consumed), as contrasted with pharma lead discovery efforts that last no more than 9-12 months before moving on.

So, universities must also have the appetite for investment and recognize, as pharma has learned, there are a lot of failures before there is a big hit. Only time will tell if this “new” approach will improve on traditional academic drug discovery efforts.

Comments

  1. #1 Becca
    March 29, 2008

    “…a great compound when one need only look at the structure to realize it will be glucuronidated to hell.”
    a great compound, like, say, morphine?

  2. #2 Abel Pharmboy
    March 29, 2008

    A superb point, Becca, although I would submit that morphine glucuronidation is a truly unique animal. M6G not only has several hundred-fold greater μ affinity than morphine, but the dang thing can actually cross the blood-brain barrier. (We do care about the benzomorphans here – just look at the structure above next to John Jacob Abel!)

    I was thinking more along the lines of traditional glucuronidation-as-inactivation since the vast majority of drugs with phenolic hydroxyls require them for pharmacologic activity.

    But your point is well-taken: there are always exceptions. And this example does raise the question of whether morphine would’ve made it successfully through the drug development pipeline today.

  3. #3 PhysioProf
    March 29, 2008

    Another place where some academic thinking could come in very useful would be in attacking the important pharmaceutical processes that we don’t understand: things like pharmacokinetics, oral availability, human versus animal toxicology, and (lots of) better disease models.

    In other words, “basic fucking science”. This is also Alberts’s point in his Science editorial this week.

  4. #4 Dan Brown
    March 29, 2008

    I’m a grad student at Vandy and currently using the center to try and find new antibiotics. The Drug Discovery Center here has really been embraced by the University as a whole and is being used by people studying many different disease areas. As such, I think that it has great potential for the production of future therapeutic compounds. One reason, though, that it was able to be embraced so successfully was that we had a lot of people doing the basic research first.

  5. #5 trrll
    March 30, 2008

    I think that antibiotics are a great area where academic drug development can be complementary to industry efforts. The financial incentives for industry development of new antibiotics are not great, particularly in advance of epidemic resistance to existing antibiotics, and as Steven Projan likes to emphasize, antibiotic discovery is hard. An academic institute may be able to take a longer-term view.

  6. #6 Abel Pharmboy
    March 30, 2008

    The point by Dan and PP are well-taken: that none of this is possible without a strong basic science foundation. As one of my early mentors told me, advances in pharmacology come only from advances in our understanding of physiology and pathophysiology.

    A question to Dan: how do your committee members view your Ph.D. project regarding the balance between HTS and hypothesis-driven research? Is there any resistance to Ph.D. work being done in the Drug Discovery Center, especially by faculty not directly associated with the Center? (btw, thanks Dan for coming by to comment.)

  7. #7 Dan Brown
    March 31, 2008

    I’ll really find out what my committee thinks in a couple of weeks when I have my next review. I only started the discovery project last summer after I had finished a project on glutathione binding (some structural and functional enzymology) and my other project looking at the evolution of the resistance enzymes that I’m studying was hitting a wall. So far my adviser has been behind it. We need to get some funding for it to go further, though. Overall though, most PI here are pretty accommodating to students wanting to do a discovery project.

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