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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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September 12, 2007

Drugs From Where?

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Posted by Derek

The mention of tropical diseases here the other day turns out to be timely, since the latest Nature has several articles on various ways for industry and academia to partner on attacking these. Some adjustments are needed every time you try this sort of thing, naturally. I particularly enjoyed this article. Here’s a sample:

“. . .translational research requires skills and a culture that universities typically lack, says Victoria Hale, chief executive of the non-profit drug company the Institute for OneWorld Health in San Francisco, California, which is developing drugs for visceral leishmaniasis, malaria and Chagas' disease. Academic institutions are often naive about what it takes to develop a drug, she says, and much basic research is therefore unusable. That's because few universities are willing to support the medicinal chemistry research needed to verify from the outset that a compound will not be a dead end in terms of drug development.

Academics will currently publish, say, a chemical scaffold, which they bill as a potential new target for parasites. "But had a medicinal chemist looked at it, he might immediately see that it will never work as a drug, because it has an inappropriate solubility or toxicological profile," says Els Torreele, a product manager at the DNDi. "Having a chemical structure that kills your parasite is only one of many aspects of what makes a drug a drug”.

Ted Bianco, director of technology transfer at the Wellcome Trust in London, agrees. "It's fine if a researcher is just using a compound as a ligand to probe a biological process," he says, "but don't kid yourself it's a drug unless you ask whether it has druggable properties." What's needed, says Hale, is a 'target product profile', which sets out the appropriate drug chemistry properties. "Getting a drug through regulatory processes is not just about how good your science is and how great your trials are; it is much more complex," says Hale. "And academics don't have the experience — they need to hire people from the drug industry."

This would make particularly interesting reading for the NIH-funding-discovers-all-the-new-drugs crowd. That idea seems pretty indestructible, although you’d think it would at least be dented by talking to the people who actually try to develop drugs (like me, or many readers of this blog), or to the people who are actually partnering with academia (see above).

I first came across this whole debate a few years ago, not having even realized that it was a debate at all. Even now, when I tell co-workers in the industry that there are people who believe that pretty much all drugs come right out of from publicly funded research, the usual result is an incredulous stare and a burst of laughter. That’s often followed by a question like “So what is it that I’m doing all day, then?”

Unfortunately, there really are occasional examples of companies scooping things up and making a killing on them – an example will follow in a coming blog post. And on the flip side, I have a recent example coming up of an academic compound which may well do exciting things in a dish, but has as much chance of becoming a drug as I do of becoming an Olympic pole-vault champion. And it’s not that I’m not reasonably aerodynamic – it’s just that there’s more to the pole vault than that, and there’s more to making a drug than working in vitro.

Comments (25) + TrackBacks (0) | Category: Academia (vs. Industry) | Drug Development


1. Palo on September 13, 2007 9:19 AM writes...

Oh, here we go again. A lot of small little truths making a big misleading claim. Derek, I never heard anyone claiming that "pretty much all drugs come right out of from publicly funded research", as you said. Much less the "NIH funding discovers all the new drugs". I do hear a lot of people claiming that public funding makes a huge contribution to drug research, and that very often, in brochures, industry blogs or Pharma-funded articles by Joe DiMassi, that contribution is downplayed or simply ignored. Yes, the little compound that Dr. X found and thought to be a potential cure for disease might not have the right druggable properties, but it might also be a great lead into a similar compound with the right druggable properties, saving you and your company a lot of time and money. And that would be the right combination of academic research and industry development. There is a right balance between academia and industry interests and contributions, but it is often hard to find it when you take on these issues by drawing straw men.
You know, but never seem to included to the discussion, that this controversy around academic contributions to drug research usually arises from the discussion about drugs prices, prices that Pharma defends on the grounds on the cost of developing a new drug, as if it is developed from ground-up by the industry, from research to development. Sometimes it is true, very often it is not. Sometimes a company does scoop up a fully druggable compound from academia, most often does not.

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2. Derek Lowe on September 13, 2007 10:04 AM writes...

Palo, all I can say is that, to the best of my knowledge, never once in my career (1989-present) have I worked on a project where the lead compound (or any chemical matter at all) came from academia. Nor can I recall any such project going on at any of the companies I have worked for. All of the compounds have come from internal screening, subsequent internal SAR, or from chemical motifs gleaned from other industry work (patents, etc.)

There are examples of academic compounds turning into early lead molecules, drug candidates, or full-fledged marketed compounds. But these cases are - at least in my experience - quite rare. Rare enough that I have not seen one myself, nor been down the hall from one, in almost twenty years.

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3. Wavefunction on September 13, 2007 10:38 AM writes...

I think the number of academia-discovered "drugs" are increasing, and my advisor is a good example of someone who discovered a really good bonafide drug in academia. I agree that such examples are rare. But again, we really have to go back to what we were saying about the difference between ligands and drugs. A molecule which just kills the parasite is more of a good ligand than a drug.

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4. Jose on September 13, 2007 10:43 AM writes...

Dennis Liotta is the *only* academic to have ever gotten anything into trials and market, aside from huge collaborations on molecules like taxol, Ect-543 and discodermolide. Can anyone name any others?

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5. Harriet on September 13, 2007 10:53 AM writes...

Ted Taylor with Alimta. Eli Lilly's med chemists couldn't improve upon the original structure.

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6. Device R Us on September 13, 2007 11:02 AM writes...

Certainly Pete Schult'z non native amino acid work commercialized by AMBRX is being put into the clinic by Merck-Serono

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7. qetzal on September 13, 2007 11:20 AM writes...

Palo, re:

You know, but never seem to included to the discussion, that this controversy around academic contributions to drug research usually arises from the discussion about drugs prices, prices that Pharma defends on the grounds on the cost of developing a new drug, as if it is developed from ground-up by the industry, from research to development.

What, in your opinion, is the issue here? Is it just a matter of credit? I.e., pharma should better acknowledge how essential basic academic research (on biology, diseases, targets, etc.) really is?

Or are you implying that pharma somehow tries to include academic research costs in the overall drug development cost equation, as part of pharma's justification for high prices? I.e., pharma is trying to count costs it doesn't actually pay?

Or do you think that since pharma builds on publicly funded basic research, the public should have some degree of ownership of the resulting drugs?

Or others? I hope this doesn't sound snarky. I'm genuinely curious in your view here.

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8. qetzal on September 13, 2007 11:44 AM writes...

Another thing I'm curious about is how we define "drug research" (as opposed to basic research before hand, and drug development afterwards).

I mean, if you're screening a compound library for activity against a known target that has a proven role in a given disease state, most people would probably agree that's drug research.

But what about finding new possible targets for a given disease? Or taking a putative target and trying to prove it really has a role in disease? Or trying to understand the molecular and biochemical basis for that role? What about research on the disease itself (rather than molecular targets that may have a role in the disease)?

Things like that are obviously hugely valuable, and can be the basis for successful drug R&D. But are they drug research?

If we're going to argue about how much drug research is done by industry versus academia, we need some agreement on what drug research is. Depending on where you draw the line between basic research and drug research, you could argue that academia does only a tiny fraction of drug research, or you could argue they do the vast majority.

Derek, as a pragmatic approach, can you summarize the major types of research activities at your current (&/or former) employer)? Also, do you have any sense of the relative resource allocation between research versus development?

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9. d_orbital on September 13, 2007 11:55 AM writes...

I think there is also Breslow's drug SAHA (vorinostat).

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10. Sigivald on September 13, 2007 12:49 PM writes...

Palo: Maybe you've managed to avoid hearing that, but I've heard it, or things almost identical to it, like "the big evil pharma companies wouldn't even exist without NIH research".

Perhaps you manage to associate with a slightly more clueful set of people.

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11. MikeS on September 13, 2007 1:53 PM writes...

Following up on Palo's and qetzal's comments, I think that the "NIH vs Industry, who makes what contribution?" debate suffers from a lack of clarity about the root issue.

For example, the pharmaceutical industry is criticized over drug pricing, pharma then rebuts by noting that drugs are very expensive to develop. This argument is countered by raising the contributions of public funding to drug development. However, this line of debate obscures the fact that the price of a given drug, post-approval, has almost nothing to do with what development costs were, and everything to do with what the market is willing to pay in light of the severity of the condition treated, the availability of alternative therapies/generics, and the availability of government sanctioned market exclusivity through patents.

The real interaction between pricing and development costs is that creating a legal environment that allows pharma to extract high prices makes development of a broader spectrum of drugs (targeted at smaller markets, more alternatives in larger markets, etc) profitable. Currently, this balance is roughly set as a function of overall patent term, the Orphan Drug Act, and direct gov't/private funding for research into underserved diseases.

However, just as industry arguments that high prices are a consequence of development costs is a misdirection from the reality of how drugs are priced, the critics' argument about the role of the NIH is also somewhat off-point. If the argument is that public money makes a contribution to development that pharma is free-riding off of, then it would follow that pharma patentees are obligated to divest some ownership of their IP corresponding to the contribution of public money/NIH funding back to the public through lower pricing. The problem with critics as I see it is that they never put forth a realistic plan for how this could be done within the patent system as it actually exists.

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12. CMC guy on September 13, 2007 4:31 PM writes...

Like Derek I have encountered many people who think “all drugs” come from NIH or other Public-funded research and in large part most Press reports on the subject mostly portray that view. I likewise (in 20 years)have only come across a few things that did not demand considerable manipulation to go from a prof's promising idea to a pharmacy shelf.

While the "basic research" is often the foundational science and provides tools for the "applied research" needed in ID and proof of drugs however the "translational" activities are often huge, require combination of several "new ideas" and can take decades to bear fruit. It is important to support/fund novel-unproven stuff and if university labs divert their attention to attempt discovering new drugs long-term benefits will suffer (no drugs of tomorrow). Most Profs/Universities now-a-days have learned how to use Patents and/or spawn "companies" to capture some rewards but again these usually don't take you far down the path to a real drug. As was pointed out Academia can be very naive and lack the skills and culture and therefore the Pharma industry should do a better job of educating the educators (and general public) on what is involved in successful drug development.

The issue of “drug pricing” is a quagmire and MikeS has some salient points (i.e. driver what market will bear) although seeing the costs of running even a small Phase III clinical studies is mind-boggling. It is important to realize the US and a few other countries pays seemingly exorbitant costs and other countries with price controls are not contributing to support new drugs. I think the US also pays much extra because of “real and potential Litigation” as even if the drug works a legal suit surely will occur and -help any company that has a harmful side-affect.

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13. Blue Turtle on September 13, 2007 4:40 PM writes...

Did no one go to this session last year? If so, I'm curious if anything resounding came from it.

Drugs from Academia: Marketed Drugs Discovered in Academic Labs

Official: John E. Macor
9:00 AM 204 Invention of SAHA, the first HDAC inhibitor approved by the FDA
Ronald Breslow
9:40 AM 205 Darunavir, a new protease inhibitor to combat drug-resistance: Structure-based design targeting protein backbone
Arun K. Ghosh
10:20 AM 206 The discovery and development of 3'-heteranucleosides
Dennis C. Liotta
11:00 AM 207 Discovery of Alimta, a broadly effective new antitumor agent
Edward C. Taylor
11:40 AM 208 The taxol story
Robert A. Holton

I think this may become a little more common, with academic institutions becoming more saavy with patenting and business development, and with the ever-increasing virtual drug discovery/development companies.

By the way, Horton didn't discover taxol (guys at Research Triangle Institute in RTP are credited with it); he just came up with part of the synthetic process that is used to produce it.


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14. Chuck on September 13, 2007 6:58 PM writes...

#4, what about Rick Silverman and Lyrica?

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15. SD Reader on September 13, 2007 7:21 PM writes...

C&EN covered this topic.
# Chemical & Engineering News, 85(16), April 16, 2007
# Chemical & Engineering News, 85(21), May 21, 2007

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16. Petros on September 14, 2007 4:09 AM writes...

I think Derek is right that it's rare

Anotherexample is Malcolm Stevens (in the UK) and temozolomide (Temodar)

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17. Palo on September 14, 2007 11:46 AM writes...

Derek, I was not referring to compounds discovered in academia that ended-up in your hands, but to compounds discovered in academia that gave you ideas and leads into developing your own compounds. We have the whole NF-kB patent litigation that revolves around these issues. To claim that nothing that you worked with in years at Pharma had anything to do with academic discovery is as misleading or false as to claim that "all drugs were developed in academia".

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18. milkshake on September 14, 2007 12:33 PM writes...

The two phosphonate nucleotide antivirals that Gilead is selling were discovered at a academic institute in Prague, in 80s

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19. Kay on September 15, 2007 6:15 AM writes...

Since these are times of excess within our companies, we can and should ignore other potential sources of compounds. We should not help the academics either unless/until they bring us Phase II compounds with no warts. Those with successful business models should be very choosy.

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20. kiwi on September 16, 2007 6:42 AM writes...

Although it is an example of the exact troubles Derek is getting at, the neuraminidase inhibitor zanamivir is another drug with an academic past.

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21. Monica on September 16, 2007 4:54 PM writes...

Another example of non-industry discovered drug is geldanamycin, a natural HSP90 inhibitor, a chemotherapeutic agent; its derivatives are now in clinical studies. Another example is Byetta, an incretin mimetic used for diabetes, it is derived from the saliva of Hila monster..
I am amazed how arrogant one can be talking about the drugs and discoveries mostly done by industry, or academia... pretty much all we use or purify or "synthesize" come from the greatest chemist of all - Nature. From Taxol to vitamin C, all that we use to cure or support our health has a natural base and has to be biocompatible with our physiology and biochemistry. In order to "develop" a drug, any drug, we must have studied thoroughly our own biology, pharmacology ( internal targets), disease states as well as the biology of the potential medicine. That also involves a lot of botany, pharmacognosy, microbiology, and so on.
In other words there is a lot of basic research in many scientific fields (usually done in academia) before anyone can develop a drug.

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22. Chuck on September 16, 2007 11:56 PM writes...

Arun Ghosh is an academic researcher with a drug on the market and two others currently in clinical trials. I have no doubt there are others. However, the vast majority of drugs on the market came from industry.

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23. NIHer on September 17, 2007 8:21 AM writes...

All NIH and NSF funded research and training is eliminated. What is the impact on pharma and biotech?

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24. rhovero on September 18, 2007 7:05 PM writes...

There are many parallel situations between biotech/pharma and the high-tech fields, but I haven't heard anyone insist that Intel or Apple pay fees (other than for patents they license) to academia for basic research that allows their products to be developed, nor that they lower the cost of their products so more people can buy them. Perhaps the better parallel might be with the software industry - again there's a lot of basic research which allows new programs to be developed whether for security, pattern recognition, simulation/prediction, etc. but I don't think software developers pay fees to academia (again other than for patent licensing). However, I have heard calls for lower pricing on software - specifically Microsoft products (can't think of any other examples just now).

I think the resistance to market pricing in both industries partly stems from the low cost to manufacture the products. In the pharma and software industries, manufacturing the final product costs very little once the high startup and development have been incurred. As in the pharma industry, knock-offs are sold around the world - but in software, you can get exact duplicates. But since people don't demand all software be sold cheaply, there's also a little guy vs. big bad pharma/Microsoft mentality. What do people think of this concept underlying the arguments/attacks?

In addition, the pharma industry creates products that in some cases are needed to prevent morbidity or mortality. The software industry hasn't yet had to face that, but perhaps when electronic medical records and expert diagnosis and medical management programs become widely accepted (I'm not holding my breath), then that will be an excuse for people to demand that medical software be sold cheaply too. And similarly, if we take away the high profit margins, then companies that invest to develop really excellent computational health agents will likely suffer.

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25. xchemist on September 20, 2007 11:12 PM writes...

Erik De Clercq anyone? A lot of the pioneering nucleosides from 3TC-lamiviudine on arguably came out of his lab. I think Arun Ghosh is great, but a lot of his ideas were incubated when he worked at Merck/West Point and it's hard to separate him as an academic vs industry scientist.

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