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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

« Inadvertent Day Off | Main | How Others See Us (And How We See Them) »

May 24, 2011

Maybe It Really Is That Hard?

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Posted by Derek

Here's an interesting note from the Wall Street Journal's Health Blog. I can't summarize it any better than they have:

"When former NIH head Elias Zerhouni ran the $30 billion federal research institute, he pushed for so-called translational research in which findings from basic lab research would be used to develop medicines and other applications that would help patients directly.

Now the head of R&D at French drug maker Sanofi, Zerhouni says that such “bench to bedside” research is more difficult than he thought."

And all across the industry, people are muttering "Do tell!" In fairness to Zerhouni, he was, in all likelihood, living in sort of a bubble at NIH. There probably weren't many people around him who'd ever actually done this sort of work, and unless you have, it's hard to picture just how tricky it is.

Zerhouuni is now pushing what he calls an "open innovation" model for Sanofi-Aventis. The details of this are a bit hazy, but it involves:

". . .looking for new research and ideas both internally and externally — for example, at universities and hospitals. In addition, the company is focusing on first understanding a disease and then figuring out what tools might be effective in treating it, rather than identifying a potential tool first and then looking for a disease area in which it could be helpful."

Well, I don't expect to see Sanofi's whole strategy laid out in the press, but that one doesn't even sound as impressive as it sounds. The "first understanding a disease" part sounds like what Novartis has been saying for some time now - and honestly, it really is one of the things that we need, but that understanding is painfully slow to dawn. Look at, oh, Alzheimer's, to pick one of those huge unmet medical needs that we'd really like to address in this business.

With a lot of these things, if you're going to first really understand them, you could have a couple of decades' wait on your hands, and that's if things go well. More likely, you'll end up doing what we've been doing: taking your best shot with what's known at the moment and hoping that you got something right. Which leads us to the success rates we have now.

On the other hand, maybe Zerhouni should just call up Marcia Angell or Donald Light, so that they can set him straight on the real costs of drug R&D. Why should we listen to a former head of the NIH who's now running a major industrial research department, when we can go to the folks who really know what they're talking about, right? And I'd also like to know what he thinks of Francis Collins' plan for a new NIH translational research institute, too, but we may not get to hear about that. . .

Comments (34) + TrackBacks (0) | Category: Academia (vs. Industry) | Drug Development | Drug Industry History


COMMENTS

1. johnnyboy on May 24, 2011 8:13 AM writes...

"With a lot of these things, if you're going to first really understand them, you could have a couple of decades' wait on your hands, and that's if things go well. More likely, you'll end up doing what we've been doing: taking your best shot with what's known at the moment"

Indeed. Besides, who in their right mind would actually work by "identifying a potential tool first and then looking for a disease area in which it could be helpful" ? Are there actually any discovery depts that would work this way ?

Seems to me Zerhouni is trying to frame what's already being done in as a "new paradigm". I suppose that's his job now, as an upper executive.

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2. imatter on May 24, 2011 8:37 AM writes...

Well, different paradigms have their appropriate place in research. I think university research should focus on basic research, and not force basic research labs to be more translational.

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3. SP on May 24, 2011 8:53 AM writes...

Technically a center, not an institute, although I've heard centers described as small institutes.

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4. William B Swift on May 24, 2011 9:01 AM writes...

To an extent it is the old saw: "Everything is easy to the person who doesn't have to do it themselves." But worse, too many government officials and journalists have never even worked in the fields they are regulating/administering/commenting on/criticising and have at best a vague idea of what they actually do.

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5. luysii on May 24, 2011 9:16 AM writes...

Well, of course it's hard. One reason is that we don't know all the players in cellular metabolism. For one example from this year see --

https://luysii.wordpress.com/2011/03/02/we-dont-know-all-the-players-which-is-why-finding-good-drugs-is-so-hard/

A second reason is that even when we think we know what our drug is doing we really don't. Gabapentin (Neurontin) looks very much like gamma amino butyric acid, the major inhibitory neurotransmitter in the brain which exactly why it was developed. However, it doesn't work that way -- it binds to a type L-type voltage gated calcium channel. This wasn't understood until years after it came out.

Even worse is the following example: https://luysii.wordpress.com/2011/02/02/medicinal-chemists-do-you-know-where-your-drug-is-and-what-it-is-doing/

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6. David Bradley on May 24, 2011 9:20 AM writes...

Probably explains why of the 10 million new chemical entities added to the CAS registry in the last 18 months or so (bringing total to 60 million) we still have so few blockbusters.

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7. luigi on May 24, 2011 9:51 AM writes...

The WSJ blog was also linked to additional comments by Roy Vagelos that in essence questioned why the NIH was moving away from basic research and why the NCAT concept was viable. Roy actually used the term "destructive"
Having been approached by the NIH to submit my CV to be considered as a consultant for their drug discovery efforts and having talked to the folks there - the only conclusion I can come to is that the NIH doing drug discovery is a pipedream - Bethesda represents a cocoon in which naive assumptions - like Zerhouni's mistaken view of how easy translational research would be if only pharma would see the NIH viewpoint - are reinforced by the blind leading the blind. Collins. like Zerhouni before him, wastes taxpayer money on grandiose schemes and wild assertions that lack any proven scientific basis. As GWAS populates the literature with papers where the list of authors is close to exceeding the content of the paper, how does Collins explain the association of PINK1, a candidate gene for Parkinson's disease with heart failure (PNAS Early Edition, May 23, 2011). Do mitochondria have more than one disease association? Does physiology trump genetics? Who would have thought.... other than the gene jocks running the NIH?

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8. Josh on May 24, 2011 11:13 AM writes...

@luigi- brilliant. you really nailed it.

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9. CR on May 24, 2011 12:19 PM writes...

@johnnyboy:

"Indeed. Besides, who in their right mind would actually work by "identifying a potential tool first and then looking for a disease area in which it could be helpful" ? Are there actually any discovery depts that would work this way ? "

You mean, the way it used to be done in pharma research, back when they were actually successful?

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10. johnnboy on May 24, 2011 12:39 PM writes...

@CR: here's a list of the 10 most profitable drugs in history:
Lipitor, Plavix, Nexium, Seretide/advair, Zocor, Norvasc, Prevacid, Zyprexa, Risperdal, Effexor.

How many of these were developed without having a clear goal or disease target in mind ?

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11. Oldchemist on May 24, 2011 12:56 PM writes...

Just FYI, Derek, since last week the company has dropped the "Aventis" part of the name and is now known just as Sanofi.

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12. Hap on May 24, 2011 1:28 PM writes...

It might be fair to ask, though, how many of the drugs you cited actually hit their designed targets - Lipitor, for example, is surely doing something besides hitting HMG CoA reductase, because that's what Zocor hits, too, but they don't obviously behave the same way. I think the same could be said for the CNS drugs on your list (Zyprexa and Effexor) and for a lot of the ones made before - they hit their targets, presumably, but I didn't think it was anywhere near certain that they work because they hit those targets.

Diseases are too big a haystack to just aim randomly and expect to hit something, but they're also kind of big to run through a strainer to find the needles. I figured we made educated guesses, found things that worked, and incorporated them into the models we built. The holistic model is probably a better way to understand everything, but finding how everything fits together (correlations between phenomena) seems like a job to keep statisticians in milk and cookies, and scientists in the market for pain drugs, but not much else.

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13. Anonymous on May 24, 2011 2:01 PM writes...

Seems like it worked better when we gave all those tax breaks to big pharma and eased up regulations.

We just seem to shovel tax money into pseudo academic work.

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14. Anonymous on May 24, 2011 4:02 PM writes...

So why did Sanofi hire someone to head its R&D who just admitted that he didn't have a clue?

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15. Anonymous on May 24, 2011 5:10 PM writes...

Johnnyboy@10: except lipitor, zocor, and effexor, the other drugs on your list would be unlikely to be discovered in today's environment. Most prototype CNS drugs were found in clinic with no target in mind. The follow-ons were more "rational", but they are follow-ons.

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16. milkshake on May 24, 2011 5:33 PM writes...

yep, when you are sitting at the apex of a giant organisation that spends billions on research, it is very easy to fool yourself into thinking that you know what you are doing.

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17. Anonymous BMS Researcher on May 24, 2011 8:40 PM writes...

SP on May 24, 2011 8:53 AM wrote...

> Technically a center, not an institute,
> although I've heard centers described as small
> institutes.

Academic institutions are full of outfits called "Center for this" and "Center for that" because "Center" is such an elastic term. A "Center" can be anything from a large building to a few offices with a Director, an administrative associate, and a few postdocs. In my academic days I worked in a Center at an Ivy League University that was in between these extrema of size -- we occupied most of one floor on an 8 story building. This building was across the street from the hospital, with an underground tunnel connection; I really appreciated that tunnel when going to the hospital cafeteria for lunch during the worst of New England winter.

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18. barry on May 24, 2011 11:50 PM writes...

re: Hap #12:
You don't have to invoke off-target effects to explain the difference in efficacy between Lipitor and Zocor. Differences in tissue distribution are enough to explain this one (although that was only elucidated long after they were on the market).

Permalink to Comment

19. imaging guy on May 25, 2011 5:58 AM writes...

Dear Barry #18,
Thanks for the information. Do you know any papers where biodistribution of these two drugs were discussed?

Permalink to Comment

20. Industry Guy on May 25, 2011 7:49 AM writes...

@#14 anonymous
Thanks for the laugh this morning.....

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21. Rick on May 25, 2011 8:01 AM writes...

Anonymous #15,
I would add that it's not just "Most prototype CNS drugs were found in clinic with no target in mind." Most prototype drugs in the large majority of therapeutic areas were discovered with no therapeutic target in mind. Having the drug in hand enabled more effective target hypotheses and enabled discovery of follow-on drugs in some cases, but knowing the target was not essential to finding first-in-class drugs in most cases. I'm NOT saying that target-based drug discovery is useless, but exclusively steering the industry in that direction is useless and harmful. The dogma "no target, no research funding" has hindered drug discovery by cutting of a proven avenue of exploratory research, but today no one knows how to do drug discovery research without a genetically "validated" target. It's hardwired into every presentation about "the drug discovery process", including the FDA and NIH web sites. Pity.

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22. CR on May 25, 2011 11:05 AM writes...

@14, Anonymous:
"So why did Sanofi hire someone to head its R&D who just admitted that he didn't have a clue?"

You obviously have not work for Sanofi. This is par for the course. Frank (Drugless) Douglas, Cluzel, etc.

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23. Anonymous on May 25, 2011 1:26 PM writes...

@17:

I've worked in a few Centers myself. I think it's just academic marketing to get funding.

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24. srp on May 25, 2011 10:12 PM writes...

#21 Rick:

Doesn't that scare you? I mean, people keep asking what's happened to R&D productivity and here's a giant elephant in the room. Now the FDA apparently demands a targeting story, too, institutionalizing the folly.

Until the science types start saying the emperor has no clothes here, this bottleneck is going to restrict progress.

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25. mike on May 26, 2011 7:29 AM writes...

Sometimes you need the tools to affect an enzyme or process before you can understand what it does. Ask any biologist how easy it would be to study a process and find out what disease states it might affect if he only had a very selective, dose-responsive agonist and a very selective, dose-responsive antagonist to a protein that might be of interest! After all, it was the discovery of PDE-5 inhibitors that led to the development of a treatment for erectile dysfunction, not a detailed knowledge of the underlying biology...

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26. Jacob From NIH on May 26, 2011 7:31 AM writes...

The amount of uninformed comments here are shocking.

People are mouthing off as though they themselves have a drug on the market where they made a significant intellectual contribution.

Let's face it, most of those commenting on this piece here don't have a drug on the market. Let's keep that in perspective.

In my previous career, I had the opportunity to listen in on my pitches to VCs by prospective biotech founders. If those pitches were made public and you all heard them, you would laugh at the "pipe dreams" sold. But that's what it takes to get funded. That's how many biotechs got started.

Vertex (ahem) was also selling a pipe dream early on with rational drug design. But good for all of us that it got funded because it now is a fantastic pharmaceutical company in my opinion.

And once upon a time, fragment based drug discovery was pitched as a pipe dream and many laughed. But that worked out okay.

People like Collins and Zerhouni are making a pitch. So let's not be naive and think they don't know the reality is a bit more tempered. Because it's in the public domain unlike biotech startup pitches, we all get to see it in plain sight.

I would rather be a dreamer, take a risk and try than be a whiner and succumb to mediocrity. Last I checked, whiners don't move the world forward. Instead, they sit in a corner and point fingers at others.

Most importantly, whiners don't own a mirror.

Regarding this new center... from everything I read, there is no new money being allocated. It's just a reorganization of existing funding so that there is a cultural change that takes place. The amount of money devoted to actual pre-clinical drug discovery at the NIH is less than a drop in the bucket from the overall NIH budget. Most of the 'translational' money is the CTSA's, and that money goes out to institutions throughout the US.

So a majority of the money from NCATS will not stay at the NIH. It will make its way out to others. .

I have seen biotechs and pharmas burn orders of magnitude more, costing share holders (equivalent of tax payers) lots of money. And judging from the numbers, I would say it's a random walk that's getting drugs out the door with many of them being me-toos rather than first in class.

The NIH is not dropping basic research. The % of funding going to basic research still remains the same and it takes up a huge majority of the NIH budget. All of that is in the public domain.

I don't have anything to do with this new center, and I don't know much about drug discovery.

But I know enough to know very few medicinal chemists have real success (marketed drug) under their belt, and the ones that are successful tend to be a bit wiser in their commenting on others' research.

Keep up the good work here, Derek. I enjoy your blog.

Permalink to Comment

27. Hap on May 26, 2011 9:33 AM writes...

#18: I though Lipitor had antilipidemic effects that Zocor didn't have.

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28. Rick on May 26, 2011 3:37 PM writes...

SRP #24,
It scares the crap out of me. It used to scare me so bad that it was unhealthy for me and my family. I was able to fight the gorilla for a while and change things locally and even had some success doing so (drug in the clinic with a completely novel mechanism of action that couldn't have been found through mechanism-based screening). In the end, my family and I suffered, I lost my career and the gorilla rages on. There's an unstoppable stupidity here that may just have to play itself out. But it's still in its growth phase (see Derek's post on Pfizer's new med chem strategy) and I suspect it's going to be more than a decade before it's finished.

Permalink to Comment

29. srp on May 26, 2011 5:33 PM writes...

Rick:

Thanks for cheering me up.

Without knowing the details, let me say I respect someone who put some skin in the game on a point of scientific principle.

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30. Jose on May 26, 2011 10:03 PM writes...

Jacob writes: "Let's face it, most of those commenting on this piece here don't have a drug on the market. Let's keep that in perspective."

So you're implying that the professional opinion of 99.5% of all med chemists is wholly irrelevant? And moreover, that intelligence/skill is the main driver for getting a drug on the market??? Suuuurrreee, I see. Who exactly is delusional?

Permalink to Comment

31. Marc Lemay on May 27, 2011 12:23 AM writes...

jonnhyboy: well, not the same field, but with Apple as an obvious example of ass-backwards successful technology discovery, I imagine that "first find the solution, then find a problem" might work for drugs too. (this idea is from Carmine Gallo)

Permalink to Comment

32. Rick on May 27, 2011 9:30 AM writes...

Mark, #31 and johnnyboy, #1,
Finding a tool first then finding a use for it, or not, has been a major feature of drug discovery research for decades. A great case in point is microbial "-omics". Billions were spent sequencing and analyzing the bejesus out of bacterial genomes, "validating" targets, then conducting mechanism-baed screens against those targets (e.g. hundreds of millions in one deal alone from Bayer to Millenium), yet how many antimicrobial drugs emerged? Zero. How many drugs are in clinical trials today as a result? Zero.

Having said that, I strongly believe that the problem lies not in the search for or deployment of tools per se, which is a good thing, but in the mania and myopia that often characterize the search and deployment. Without justification, many tools became the ONLY way to search for drugs, i.e. if you didn't use them, you didn't get funding from VCs, Wall Street or internal management.

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33. luigi on May 27, 2011 12:43 PM writes...

#22 - Frank Drugless - now a member of the embarassing Rockstars of Science according to a Geoffrey Beane ad in Vanity Fair. What Frank knows about science wouldn't fill half of the reverse side of a business card - what he knows about politics would fill a couple of books!! How's the biotech scene in Akron Frank?

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34. Medical Supply on June 9, 2011 11:19 PM writes...

I am totally agree with Rick i have facing problem i want to idea from someone for my skin..
Thanks for sharing..

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