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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: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

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June 9, 2011

Academic Drug Discovery: A Survey

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Posted by Derek

Nature Reviews Drug Discovery has an interesting survey of academic drug discovery (summary at SciBx here). The authors were motivated, they say, by the large number of opinions and impressions about this topic, with a corresponding lack of actual data - I think they've done everyone a service.

What they found was 78 centers of academic drug discovery (in one form or another) in the US. Cancer and infectious diseases are the most widely worked-on, but tropical and orphan diseases make a strong showing (and I'm glad to see this; they should). Another interesting stat: "49% of targets being investigated are based on unique discoveries that had little validation in the literature".

But when we say "drug discovery", we should really be saying "very early stage drug discovery", with little or no actual development to follow it up. The technologies that these centers report having are almost entirely in the early part of the pipeline - screening, in vitro assay, target ID. Capacity for hit-to-lead chemistry is claimed by 72% of the centers that responded (70% response rate), which, the authors say, shows that ". . .the integration of chemistry into (academic drug discovery) centers has progressed considerably". On the other hand, only half report the ability to do in vivo assays, and less than half can do any metabolism and/or pharmacokinetics. For those who don't do this sort of thing for a living, it's worth pointing out that these functions (all of which are valuable) still only take you to the stage where you can say that you're really getting started.

So what stage are these academic projects, for the most part? Assay development and screening, for the most part - even those places with PK and the like don't have much at all in that stage yet, which, the authors say, reflects the fact that most of these centers haven't been operating for very long. (32 of the 56 centers that provided a founding date gave one between 2003 and 2008). And I particularly enjoyed this paragraph:

"Questions regarding comparisons between academic and industrial drug discovery evoked intense and informative responses. Academia was perceived to be much stronger than industry in disease biology expertise and innovation, and was considered to be better aligned with societal goals. . . By contrast, industry was perceived to be much stronger in assay development and screening, and particularly in medicinal chemistry."

I would really enjoy seeing some of the more intense responses! But a very large divide between academia and industry is apparent when the respondees were asked about their centers' priorities. Number 3 was generating intellectual property, but number one? Publications. Half of the centers say that only a quarter of their staff (or less) have industrial experience, but my impression is that these numbers are shifting rapidly - for one thing, a lot of good, experienced people from industry are becoming much more available than they ever thought they'd be.

It's also important to realize that most of this work is being done on a very modest scale. When asked about funding and expenditures, you see a long-tail distribution. A handful of centers report total expenditures in the low tens of millions, but 57% of the responding centers report $2 million or less. I'm not sure if that's per year, or total since the centers were founded, to be honest, but either way, it's not much money at all by the standards of drug research, even the early-stage stuff. Looked at another way, though, if much comes out of these efforts at all, they'll have been cost-effective for sure.

But at that point, they're facing the same problems that the rest of us do. The SciBx piece quotes Bruce Booth, whose blog I link to here regularly. And he's right on target:

“At the end of the day, it's not typically the initial chemical matter that plagues a startup spinning out of academia. Instead it's the validity of the initial biologic hypothesis and whether the biology is relevant to disease"

Comments (17) + TrackBacks (0) | Category: Academia (vs. Industry)


COMMENTS

1. Jonathan on June 9, 2011 9:47 AM writes...

Not sure if you've seen it but there's also this NEJM paper from February: The Role of Public-Sector Research in the Discovery of Drugs and Vaccines

http://www.nejm.org/doi/full/10.1056/NEJMsa1008268

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2. Jonathan on June 9, 2011 9:51 AM writes...

Oh, I think the Booth quote is perfect, but I don't think anyone is exempt from the charge of having lost sight of the underlying biology of disease when it comes to drug discovery and development these days. The problem is that it's very easy to be reductionist, and conversely it's more than a little hard to actually get a proper idea of what's actually going on.

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3. chris on June 9, 2011 10:28 AM writes...

A similar picture in the UK, but with the closure of a couple of major Pharma sites there is a significantly increased number of people in universities with industrial experience, and also an increased number on the review committees of the funding bodies.

I remember a quote (but not from whom) "Target validation is critical, almost everything else the chemists can fix".

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4. Stephen_Frye on June 9, 2011 11:05 AM writes...

Thanks for picking up our paper Derek. I do hope people find it useful - especially funders in thinking about how to make these efforts sustainable/impactful. For clarification - the funding we asked about was % of annual operating expenses. Also, our question about capabilities (What capabilities are resident in your center?) did not rule out collaborations/outsourcing for later stage DD activities. My assumption is that, like mine, many centers rely on their biological collaborators for in vivo models and outsource their dmpk - it is tough to sustain a dedicated group - though I know we lose some insights that having this expertise adjacent would bring. Having spent 20 years in 'big pharma' it has been fun patching together a DD approach that can work in academia. There are trade-offs, but the freedom from myopic committees and the access to academic biology expertise (i.e. - biologists who are NOT rated by how flexible thay can be....)is refreshing. Realistically, we are more focused on target validation with high-quality leads/probes than actually getting to the clinical candidate all that often. We have to be opportunistic about the latter - sometimes the funding and the science (chemistry and biology quickly gels around a drug-like series) will be aligned to permit this, often not. And to be honest (hope no one takes offense), a lot of lead optimization is not a great scientific training ground - it is threading the needle to weed-out herg, p450s, fix solubility etc..... The next time you get impactful science results after you have a high-quality lead, is in the clinic. For us to have an impact, industrial medchem (hope it still exists) will finish the process. I think this can be a win-win for medicinal chemists on both sides of the academia/industry interface.

Designing a survey is tough and this one is full of my own biases/interests - I'd be very thankful if your readers would contribute questions we should have asked (which was actually the last question in the survey - What question did we fail to ask that you think is important and why?). We may endeavor to do this again in 5 years.

I enjoy your blog - thanks for the effort!

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5. bacillus on June 9, 2011 11:18 AM writes...

Speaking as one, I think that most academic scientists have no clue how much it costs to move beyond the lab bench with a candidate NME. My own group has spent >$20M of taxpayer money on a very good vaccine candidate, but we are still at least 3 years away from Phase I clinical trials

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6. anchor on June 9, 2011 11:30 AM writes...

Derek: Unless I am misinformed , to the best of my recollection there have been only two block busters at this point in time. These are reverse transcriptase inhibitor for HIV trasmission(one component of TRUVADA from Gilead) initially developed by Georgia tech ( Liotta group)and a psychotic drug Lyrica (by Richard Silverman group). I have seen lot of academia based drug molecules and I betcha, none of them would see a day beyond P-1 trial. I see lot of rushing in to discover drug in academia, but their notions are too naive or misplaced. I do not have sufficient information on biologics to give any meaningful input but welcome some information on this.

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7. Anonymous on June 9, 2011 11:39 AM writes...

Well, there ya' go. It's always the biologist's fault. SAR? What SAR?

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8. MoMo on June 9, 2011 11:45 AM writes...

Anchor- Liotta is out of Emory and he is as good at Medchem as any of you in Industry-Land. And our own successes have a drug in PIII and one in PI so don't discount the academics and their ability to generate drugs. Sure many academics are naive and make hydrophobic membrane killers and will hold their breaths until they get the money they think they deserve, but at least they are trying.

But if industry just questioned themselves more and recognized when their drugs were actually inferior or toxic, perhaps better candidates would emerge and more drugs would make it to market.

But many in industry have a paralysis of perspective and are too timid to speak up. I have seen it time and time again.

Give us more industry money and all will be OK, I promise! You have my word.

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9. Anonymous on June 9, 2011 12:50 PM writes...

MoMo: "But if industry just questioned themselves more and recognized when their drugs were actually inferior or toxic, perhaps better candidates would emerge and more drugs would make it to market."

Um, you've never worked on a project in industry have you?
I thought we were fairly obssessed with efficacy and toxicity. It borders on the pathogical.

Sooo, that can't be the reason more drugs aren't making it through the pipeline. I'm going to go with 1.) there's no such thing as a perfect drug and 2.) the FDA keeps raising the bar to achieve the perfect drug, which is unattainable. We do the best we can. We work on multiple series, we rescaffold, we do ADMET early and often. There's always going to be some person our there who metabolizes the suckers differently or has some other unforeseen reaction.

Well, anyway, you'll see. It's not as cut and dried as you make it out to be.

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10. anchor on June 9, 2011 1:28 PM writes...

momo: I am not sure you are reading me correctly. I have seen lot of hype...and What they sell as drug ( to innocent administrators who are ever ready to pitch it to the industry) ..in my experience is not "druggable". They may be a good lead to bring the program to a maturity. It is as simple as that. When the RTI(for HIV) was developed, Prof. Dennis Liotta was in Georgia Tech and am talking about a story that is at least 10 years old. Anyway, both he and GT made their buck with very little investments and I would do the same...if i hit a jackpot in academia!

Permalink to Comment

11. MoMo on June 9, 2011 1:38 PM writes...

Drug discovery is situational specific. And I have experienced and seen the best and worst in both worlds so to Anonymous and Anchor, I dont disagree with your statements.

But industry is plagued by idea killers, co-opters and patent stompers, and those who think they will become King Midas by generating a block-buster. While academics dream of becoming rich while their tech transfer departments become greedy and ridiculous at the same time.

There is no real answer to these discovery phenotypes. One should just try to avoid such toxic situations and people, if they can.

But you arent taught abnormal psychology in Grad school, but it wouldn't be a bad idea.

Permalink to Comment

12. Cellbio on June 9, 2011 1:52 PM writes...

Don't think the final quote you say is right on the mark is even close to being on the mark in a meaningful way. All start-ups in biotech/pharma and all efforts in bigcos are plagued by the failure of biological hypotheses to translate meaningfully into clinical benefit. Not all start-ups are based on chemical matter, so simplistically, the statement appears true. However, the nature of chemical matter, and what knowledge is derived from its effect on systems when used in poorly constructed experiments (mega dosing, formulation issues, no PK etc), and what is not know about what needs to be done before it can be considered reasonable starting material for an investment is precisely where small molecule start-ups fail, IMO. I am surprised you think otherwise Derek. I must be missing something.

Permalink to Comment

13. ProteinChemist on June 9, 2011 2:23 PM writes...

@12: I think that it is a simplistic statement, but only in the sense that a complete statement would take several volumes in a large journal. For a start-up to achieve success there needs to be a fine balance between biological validity (and etc.), chemical stability (and etc.), and functional/realistic management. With that said, though, an idea not firmly based on a relevant and realistic biological model is destined for failure without a major change. After all, the real goal of a start-up in this industry is clinical success, and that is based on human biology.

Permalink to Comment

14. Cellbio on June 9, 2011 3:07 PM writes...

ProteinChemist,
I hope most start-ups do have the real goal of clinical success, even if the trial is run by an acquirer, but I think too often the goal is the deal, with not a lot of work done that would point to knowable show stoppers.

not sure what you mean by " an idea not firmly based on a relevant and realistic biological model is destined for failure without a major change.", but I would offer that human biology, and our succes in the clinic, is clearly not too impressed with our models, and most people I know are struggling to find the relevant bd realistic models, so far without success. I don't suggest we go totally random in our drug trials, as we do need rationale, but I believe that rationale should come from properly executed pharmacology more than mouse genetics, human genetics or experiments that only examine desired outcome with in experiments with poorly controlled exposure levels with no observation of broader biological impact. OK, so maybe it does come close to a volume of a journal, or in place of that, a team of experienced people.

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15. petros on June 10, 2011 8:01 AM writes...

anchor

Temozolomide (Temodar) originated in Malcolm Stevens group in Birmingham, UK and has reached blockbuster status

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16. NuclearOption on June 13, 2011 3:38 AM writes...

Derek and colleagues, thank you.  I wind down many nights enjoying this column and comments.  Thank you also, Dr. Frye, for trying something new and standing up so publicly in it's defense. 

I spent the weekend taking care of cancer patients. It is fair to say that the responsibility to develop impactful medicines for this disease is shared between academic, governmental and industrial researchers. And it's fair to say that the productivity has been underwhelming.  

In the trenches we observe layoffs in discovery chemistry within pharma, pressure from Wall Street to be profitable in short horizons, and pressure on early stage biotechs to have clinical programs. This is not an ideal economic climate for creativity in drug discovery, well-evidenced by the many historic targets still without even proof-of-concept drugs and the five Abelson kinase inhibitors, the six near derivatives of nitrogen mustard, the three thalidomides, well you get the picture. 

I have a few thoughts and welcome any feedback.

Truthfully, I am a little deflated that you perceive publications at odds with progress in drug discovery, particularly at this early stage.  Immediate access to early  research (often providing pharmacological target validation) can catalyze competitive efforts throughout pharma, which is of course good for public health. And approached carefully, I am not convinced publication isn't a great thing for a business to establish leadership in an area (locally here in Boston see Agios in cancer metabolism and Epizyme in cancer epigenetics).

Also,  I am not convinced the investment in academic drug discovery is modest, even by industrial standards. Existing within the massive physical and intellectual research infrastructure of a University, specialized centers frequently directed by ex-pharma scientists could have tremendous reach on short dollars. Keep in mind most salaries are covered by other funds, and you don't have to wait for an MTA or pay overhead to collaborate. Given all the postings about overseas outsourcing and joblessness among chemists, I might have expected a little enthusiasm for an emerging stateside market!

 Most importantly, I struggle to see the relevance of the distinction between "early" drug discovery and "very early" drug discovery. The drugs we lack access to for cancer patients are not held up in hit-to-lead by an intractable solubility problem. I sense they are equally if not more likely to emerge from a foraging, nimble, time and profit insensitive discovery effort deeply rooted in disease biology. And I suppose our patients have no preference if this unit rests in academia or industry, as in the end both groups will integrate around clinical development. Please then start at the very beginning, and embrace the challenge to do something original and ground-breaking.  We are desperate for this.

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17. Moxie Mann on June 14, 2011 4:18 PM writes...

Derek - Thank you for all your efforts in maintaining this fascinating blog.

For what it's worth, here's a short story of one ex-pharma med chemist who went academic. I was the prototypic pharma med chem person (PhD by synthesizing natural products; then to pharma from bench chemist to co-project leader to program co-leader, etc.). After well over two decades, my job disappeared along with hundreds of others (some consider us the poster child of the current RIF activity). So off I went to a tenure-track position at a well-known research university to pursue my lifelong dream of being an academic. I wanted to do med chem research with the goal identical to what I did at pharma (the usual - identify an orally available small molecule to treat a disease with unmet therapeutic need).
If what I have done (university-patented library of compounds licensed to a pharma company sponsoring multiple P2 clinical trials) as an academic is to be considered successful, then I would advise the pharma med chemist who aspires to succeed in academia as follows:
1. Chose a target/disease that the NIH is interested in funding but is not popular in pharma (won't hurt to "work the crowd" in Bethesda or at meetings).
2. Work hard to find a competent academic biology collaborator (he/she can later adopt a pharma mentality with your help). I have found academic biologists very friendly to molecule makers. You don't need to be part of a large drug discovery effort - we consist of one PI (med chem), one co-PI (head biologist), 2-5 chemists at any given time (mix of undergrads, graduate students and PDs) and 1-2 biology experimentalists.
3. Work your @#$*& off knowing that with persistence and good ideas, the NIH will come through.
4. Keep your pharma skills sharp (e.g., what's druggable and what's not; patent application before publishing, etc.)
5. Be your own advocate when seeking a pharma partner (unless your university has vast experience at this).
6. Remember Louis Pasteur's quote "Chance favors the prepared mind" (i.e., keep your fingers and toes crossed).
Being an academic is a superb life - students energize you daily in both the classroom and lab; no @#%%# goals/objectives review every December 31. Also, there are no stock options to agonize over at tax time (ha,ha)

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