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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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May 15, 2014

The Daily Show on Finding New Antibiotics

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Posted by Derek

A reader sent along news of this interview on "The Daily Show" with Martin Blaser of NYU. He has a book out, Missing Microbes, on the overuse of antibiotics and the effects on various microbiomes. And I think he's got a lot of good points - we should only be exerting selection pressure where we have to, not (for example) slapping triclosan on every surface because it somehow makes consumers feel "germ-free". And there are (and always have been) too many antibiotics dispensed for what turn out to be viral infections, for which they will, naturally, do no good at all and probably some harm.

But Dr. Blaser, though an expert on bacteria, does not seem to be an expert on discovering drugs to kill bacteria. I've generated a transcript of part of the interview, starting around the five-minute mark, which went like this:

Stewart: Isn't there some way, that, the antibiotics can be used to kill the strep, but there can be some way of rejuvenating the microbiome that was doing all those other jobs?

Blaser: Well, that's what we need to do. We need to make narrow-spectrum antibiotics. We have broad-spectrum, that attack everything, but we have the science that we could develop narrow-spectrum antibiotics that will just target the one organism - maybe it's strep, maybe it's a different organism - but then we need the diagnostics, so that somebody going to the doctor, they say "You have a virus" "You have a bacteria", if you have a bacteria, which one is it?

Stewart: Now isn't this where the genome-type projects are going? Because finding the genetic makeup of these bacteria, won't that allow us to target these things more specifically?

Blaser Yeah. We have so much genomic information - we can harness that to make better medicine. . .

Stewart: Who would do the thing you're talking about, come up with the targeted - is it drug companies, could it, like, only be done through the CDC, who would do that. . .

Blaser: That's what we need taxes for. That's our tax dollars. Just like when we need taxes to build the road that everybody uses, we need to develop the drugs that our kids and our grandkids are going to use so that these epidemics could be stopped.

Stewart: Let's say, could there be a Manhattan Project, since that's the catch-all for these types of "We're going to put us on the moon" - let's say ten years, is that a realistic goal?

Blaser: I think it is. I think it is. We need both diagnostics, we need narrow-spectrum agents, and we have to change the economic base of how we assess illness in kids and how we treat kids and how we pay doctors. . .

First off, from a drug discovery perspective, a narrow-spectrum antibiotic, one that kills only (say) a particular genus of bacterium, has several big problems: it's even harder to discover than a broader-spectrum agent, its market is much smaller, it's much harder to prescribe usefully, and its lifetime as a drug is shorter. (Other than that, it's fine). The reasons for these are as follows:

Most antibiotic targets are enzyme systems peculiar to bacteria (as compared to eukaryotes like us), but such targets are shared across a lot of bacteria. They tend to be aimed at things like membrane synthesis and integrity (bacterial membranes are rather different than those of animals and plants), or target features of DNA handling that are found in different forms due to bacteria having no nuclei, and so on. Killing bacteria with mechanisms that are also found in human cells is possible, but it's a rough way to go: a drug of that kind would be similar to a classic chemotherapy agent, killing the fast-dividing bacteria (in theory) just before killing the patient.

So finding a Streoptococcus-only drug is a very tall order. You'd have to find some target-based difference between those bacteria and all their close relatives, and I can tell you that we don't know enough about bacterial biochemistry to sort things out quite that well. Stewart brings up genomic efforts, and points to him for it, because that's a completely reasonable suggestion. Unfortunately, it's a reasonable suggestion from about 1996. The first complete bacterial genomes became available in the late 1990s, and have singularly failed to produce any new targeted antibiotics whatsoever. The best reference I can send people to is the GSK "Drugs For Bad Bugs" paper, which shows just what happened (and not just at GSK) to the new frontier of new bacterial targets. Update: see also this excellent overview. A lot of companies tried this, and got nowhere. It did indeed seem possible that sequencing bacteria would give us all sorts of new ways to target them, but that's not how it's worked out in practice. Blaser's interview gives the impression that none of this has happened yet, but believe me, it has.

The market for a narrow-spectrum agent would necessarily be smaller, by design, but the cost of finding it would (as mentioned above) be greater, so the final drug would have to cost a great deal per dose - more than health insurance would want to pay, given the availability of broad-spectrum agents at far lower prices. It could not be prescribed without positively identifying the infectious agent - which adds to the cost of treatment, too. Without faster and more accurate ways to do this (which Blaser rightly notes as something we don't have), the barriers to developing such a drug are even higher.

And the development of resistance would surely take such a drug out of usefulness even faster, since the resistance plasmids would only have to spread between very closely related bacteria, who are swapping genes at great speed. I understand why Blaser (and others) would like to have more targeted agents, so as not to plow up the beneficial microbiome every time a patient is treated, but we'd need a lot of them, and we'd need new ones all the time. This in a world where we can't even seem to discover the standard type of antibiotic.

And not for lack of trying, either. There's a persistent explanation for the state of antibiotic therapy that blames drug companies for supposedly walking away from the field. This has the cause and effect turned around. It's true that some of them have given up working in the area (along with quite a few other areas), but they left because nothing was working. The companies that stayed the course have explored, in great detail and at great expense, the problem that nothing much is working. If there ever was a field of drug discovery where the low-hanging fruit has been picked clean, it is antibiotic research. You have to use binoculars to convince yourself that there's any more fruit up there at all. I wish that weren't so, very much. But it is. Bacteria are hard to kill.

So the talk later on in the interview of spending some tax dollars and getting a bunch of great new antibiotics in ten years is, unfortunately, a happy fantasy. For one thing, getting a single new drug onto the market in only ten years from the starting pistol is very close to impossible, in any therapeutic area. The drug industry would be in much better shape if that weren't so, but here we are. In that section, Jon Stewart actually brings to life one of the reasons I have this blog: he doesn't know where drugs come from, and that's no disgrace, because hardly anyone else knows, either.

Comments (58) + TrackBacks (0) | Category: Drug Development | Drug Industry History | Infectious Diseases


COMMENTS

1. Ben T on May 15, 2014 8:11 AM writes...

What are the chances of getting you on the Daily Show, Derek?

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2. henry's cat on May 15, 2014 8:12 AM writes...

Is it just me, or does anyone else's hackles rise whenever someone (who should know better) says 'a bacteria'? Ugh.

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3. zzlangerhans on May 15, 2014 8:17 AM writes...

Also note the concept that these new antibiotics are supposed to come from the federal government, to be funded by tax dollars. That's a virtual guarantee that any drug to come from the initiative will have no commercial or public health value whatsoever. Blaser seems to be unaware that almost all new drugs come from the private sector and the free markets.

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4. Wifool on May 15, 2014 8:28 AM writes...

Enanta seems to be making an effort:
http://www.enanta.com/research/antibiotics/

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5. lynn on May 15, 2014 8:47 AM writes...

I'm glad you brought this up. I was seething a bit while watching the Daily Show that night. Blaser, indeed knows little about antibiotic discovery. You've laid it out pretty well, Derek [although you've overlooked the two main target areas for antibacterials, cell wall (peptidoglycan)synthesis and protein synthesis]. The GSK paper emphasizes that their chemical libraries were poor [very true]- but even when specific enzyme inhibitors are found, they are hard to turn into good drugs. Can I recommend my own review on why antibacterial discovery is so hard? http://cmr.asm.org/content/24/1/71.abstract

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6. JAB on May 15, 2014 8:47 AM writes...

I have to agree that narrow spectrum antibiotics are a tall order, and that they wouldn't be cheap. Our effort needs to be focused much more on conserving the effectiveness of what we already have in hand. Blazer also seems unaware of how much effort went into microbial genome-driven antibiotic discovery, with no results.

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7. antibi on May 15, 2014 8:48 AM writes...

zzlangerhans - this is so far from being correct but I see it all the time on the comments section on here. Yes the private sector/free market is responsible for the final part of the process. But it would be an unfair assessment to say that most antibiotic agents started there. In fact, many of them started in academia. Somewhere along the line, a company came in a bought the rights to an advanced lead and they take all the credit? No, that's not how it works. In the end, the tax dollars went into the initial work and this model has worked just fine.

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8. Michael Bower on May 15, 2014 8:50 AM writes...

Because the need is still there for new antibiotics, and because the market reasons for leaving the field are so compelling (as illustrated in that GSK article), government-funded antibiotic discovery does seem like one of the only options left. Who else will do it? Hopefully they won't put Blaser in charge of their strategy . . .

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9. Anonymous on May 15, 2014 9:00 AM writes...

A lot of the argument on narrow spectrum development was supported by people with an interest in continued DNA sequencing efforts as they would be the diagnostic gatekeepers. It feeds mostly off the triclosan/efflux pump resistance story where a mechanism of broad resistance develops then spreads from ubiquitous use of an antibiotic.

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10. NMH on May 15, 2014 9:12 AM writes...

I would like nothing better to see over-paid (meaning 100% salary from hard money) academic dead-wood (meaning, they no longer get a grant and are bored to tears) be placed in some kind of government sponsored bacteria/ bacteria resistance learning boot camp and then given sufficient (but not excessive, we are talking potentially lazy academics here) funding to drive antibiotic drug discovery.

But then again, none of my other hypothesis have worked.

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11. Anonymous on May 15, 2014 9:16 AM writes...

"Blaser seems to be unaware that almost all new drugs come from the private sector and the free markets."

To me it seems more that he would like something "new" to be tried, a large scale, governement funded research program. It's not like pharma's overall economic model is very efficient these days.

In addition, +1 to #5, lots of game-changing ideas come from academia. Luckily there are still bright people trying to find new ways to fight bacteria out there.

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12. PJ Hansen on May 15, 2014 9:22 AM writes...

Very good points. I look forward to DL's visit to the show during his book tour.

There has been much discussion of broad-spectrum oral antibiotics killing off helpful bacteria in the gut when prescribed for infections of the lung, skin or where ever. Would switching to more common use of i.v. or i.m. administration be a better approach? Besides the doctor/patient inconvenience and likely sore arm.
A generally knowledgeable friend of mine keeps suggesting this as a prior good practice and I am too young to have experienced it. Is it too impractical for modern medicine?

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13. Hap on May 15, 2014 9:32 AM writes...

Tax dollars fund lots of leads, and interesting ideas (that is why we spend them there, after all), but leads and ideas != drugs. There's still lots of optimization on activity and pharmacokinetics, and then lots of trials, which tend to be the expensive part of finding a drug. In terms of the money and work that goes into finding actual drugs, almost all of it has and probably will come from private companies.

Other than penicillin (maybe), has a drug been put into use where the development (not just discovery) was managed or performed by a government? The absence of experience does not assure that a government can't develop drugs, but it seems unreasonable (and potentially counterproductive, if you implement policy based on on the misconception) to assume that the government already posseses the capacity to develop drugs.

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14. Andrew D on May 15, 2014 9:49 AM writes...

@11 cephlosporins were developed by a UK government development company and licensed to Industry. I expect neorandian propaganda about government research programs on political blogs, not here on an evidence based blog

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15. anon on May 15, 2014 9:49 AM writes...

I'm pretty sure we have narrow spectrum agents, but no one wants the endless compromises of dealing with phages when blister packs of broad spectrum small molecules are getting the job done.
You might have been able to develop a phage drug in 1960's Soviet Russia, but what about 2014 USA?

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16. LittleGreenPills on May 15, 2014 9:51 AM writes...

Hap - I believe Taxol went through a lot of development work at the NCI before being sold to BMS.

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17. Calvin on May 15, 2014 10:01 AM writes...

#5, #12,#14. Let's be realistic. 2 products in 60 years isn't really a good advert for saying that most things come from academia. The reality is that academia can and does do some really useful early stage stuff. But the numhber of groups that can do much past hits-to-leads without serious CRO help is vanishingly small. It's much better than it was but I'd suggest that's because of a substantial influx of people from industry.

Academia does research (and the value here is tremendous don't get me wrong). Academia even dose some translation. But industry discovers drugs >95% of the time. It's that simply.

However, I do think that this field (which is very small) could do with some novel thinking and the best idea might be a better partnership between academia and industry. Who might be willing to fund that?

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18. Hap on May 15, 2014 10:06 AM writes...

From the NCI's article on Taxol, NCI did Phase I trials on Taxol, and mechanism of action studies but they don't note any later trials (when trials get expensive), and the development of methods to get it in quantity had to be done by others.

@12: Did they actually do any trials on the cephalosporins? I wasn't arguing that governments didn't help find potential drugs, but that most of the money and work in drug development is in trials (where most drugs fail), and most of that is spent by businesses.

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19. lynn on May 15, 2014 10:06 AM writes...

#5 antibi - It is true that some of the early antibacterial agents and natural products that were later developed into antibacterial drugs were discovered in academic laboratories, but industry was also very active in natural product discovery in those days. However, one is hard pressed to find academically derived antibacterials since those early efforts that have made it to market. Can you give some examples? I can give some counterexamples: naphthyridines and fluoroquinolones, oxazolidinones, cephamycins, carbapenems, fosfomycin, daptomycin, lipiarmycin [fidaxomicin], chloramphenicol, chlortetracycline, gentamicin, lincomycin, rifamycin, vancomycin, erythromycin...etc. All discovered, optimized and developed by pharma.

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20. Puff the Mutant Dragon on May 15, 2014 10:06 AM writes...

Thanks for this. I saw this interview just the other day and I was kind of blown away by his claim that "we have the science" to make narrow-spectrum antibiotics...it sounded to me like he has no idea how difficult that is. You would need targets specific to certain species or genera of bacteria. Even assuming there ARE such targets and we knew what they are, the market for a drug of this kind would be very limited. I've worked on antibiotic drug development and frankly I find his comments about development of new narrow spectrum agents kind of baffling.

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21. antibi on May 15, 2014 10:13 AM writes...

2? You cannot be serious. There were two name here but there MANY examples and you know it. It's like once people go to industry, they have to become vehemently loyal to the idea that only industry can discover drugs.

SAHA, AZT, cisplatin, alimta, geldanamycin, Byetta, and several biologicals in clinical trials

And add Darunavir (the best HIV-1 protease inhibitor out there) to the list.

http://en.wikipedia.org/wiki/Darunavir

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22. Brett on May 15, 2014 10:14 AM writes...

I'd support more funding for antibiotics research from the government, even if it did just lead us to discover that there's nothing new that works without killing the patient. Mostly because in general I support some subsidies to defray the costs of bringing a drug to market, especially the expensive clinical trials.

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23. leftscienceawhileago on May 15, 2014 10:16 AM writes...

"...rejuvenating the microbiome that was doing all those other jobs..."


Unfortunately we barely have any idea what is in that microbiome, and very little idea what "rejuvenating" means past maybe eating some yogurt after a course of antibiotics....

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24. Barry on May 15, 2014 10:21 AM writes...

In 1773, John Harrison received £8,750 from parliament (albeit not the full "Longitude Prize" of £20,000 [about $4.25million today] that had been offered in 1714) for the chronometer he delivered. Until the advent of GPS in the 1970s, it was descendants of his timepieces that permitted navigators for 200 years to know where they were in the world.
The U.S. embraced a different model, preferring to let the market drive innovation, rather than waiting for our Legislature to post a prize for solving a problem that it deems worthy. For 200yrs, this patent system of granting a period of market exclusivity in exchange for educating your competitors in your innovation has driven a lot of medicine.
But the emergence of antibiotic resistance has revealed the limits of market-driven drug discovery. Twenty years of market exclusivity is a weak incentive to spend the time and money to research and develop a drug that our FDA will reserve for only the direst cases. The drug company will never recuperate its costs that way unless each dose were astronomically expensive. And so we return to the age of government prizes driving innovation at best--or, if our government doesn't act--to a world in which we all risk death from a trivial injury or infection.

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25. Chemjobber on May 15, 2014 10:27 AM writes...

Merrill Goozner* is a big fan of the "NCI was responsible for a lot of drugs before Big Pharma kneecapped them" theory. I don't really buy it, but I don't have the historical knowledge to know if it's true or not.

*Not exactly a fan of pharma, one notes.

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26. Hap on May 15, 2014 10:32 AM writes...

@19: What part of "lead != drug" don't you get, exactly? If you want a drug, even if you know the exact compound, you have to prove that it works; hence lots of expensive trials, where the money comes across. Did the (US) government do any of those trials for those compounds? How many were P2 and P3 (the costs of trials go up exponentially with phase)?

The point of (federally funded) research is to find interesting biology, which leads to potential drugs. Research is really useful; however, there's a big difference between a potential drug and an actual one, though. Getting a compound from killing bacteria in cells or rats to killing them in people (without killing people) is not the same as designing a car and building it; the gap between known and unknown for drugs is much bigger than that for cars, and thus the amount of money and effort that have to be expended to surmount that gap (and the likely failure rate) are correspondingly greater. In almost all cases, the money to surmount that gap has come from companies.

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27. Don B. on May 15, 2014 10:41 AM writes...

In my experience, gram doses of tetracycline are effective against viral pneumonia.

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28. antibi on May 15, 2014 10:46 AM writes...

@ Hap

oh - so what you are saying is that the great contribution of industry is to come in and "optimize" and pay for stuff? Oh well, I cannot argue with you there. But it also makes it sound like industry could be replaced with a banking system?!? This is completely dismissive of how valuable a lead is. But anyway, I'm done arguing here. Keep the blinders on buddy!

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29. JAB on May 15, 2014 10:59 AM writes...

@ChemJobber: my knees are a bit beat up but it was Tonya Harding's thugs done it!

Pharma works with NCI all the time, see the eribulin/Eisai story
Collaborative Innovation in Drug Discovery: Strategies for Public and Private Partnerships
Rathnam Chaguturu
John Wiley & Sons
2014

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30. lynn on May 15, 2014 11:03 AM writes...

#19 antibi
I was speaking of antibacterial agents. You have not named any. Of course there have been academic and government contributions in many parts of drug discovery. Not so much in antibacterials since the days of salvarsan, penicillin, cephalosporin, trimethoprim.

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31. Jose on May 15, 2014 11:37 AM writes...

Re: #11 anon- just a note, using the phrase 'game-changing' in any scientific discourse pretty much negates everything that follows. It's great for MBAs and business dev types, but buzzword bingo doesn't cut it in the scientific trenches.....

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32. Dr. Manhattan on May 15, 2014 11:38 AM writes...

Screening random chemical libraries with lots of "novel targets" has not yielded any new antibacterials. Read Lynn's review (comment 5); it lays out very cogent arguments. Most antibiotics originated in natural products, and most hit a very select subset of essential bacterial physiological processes (peptidoglycan, topoisomerases and ribosomes). Single target compounds quickly engender mutational resistance; the most recent example is the failure, due to resistance development during treatment, of the Anacor/GSK oxaborole compound.

I respect Blaser, but he is mistaken that the science is there to make narrow spectrum compounds.

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33. Kevin on May 15, 2014 11:38 AM writes...

#19 antibi

How many academic labs do you know of that have the following:

GLP assay capability
hERG e-phys setups
Process R&D
Formulation R&D
Packaging and tableting operations
CMC expertise
GMP manufacturing capabilities
Commercialization capabilities
Ability to run GCP clinical trials
Global regulatory expertise
Post-market pharmacovigilance
Competitive market intelligence

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34. Vader on May 15, 2014 11:53 AM writes...

Sigh. So Blaser is the latest victim of Pauling syndrome, in which a person who is brilliant in one field is blinded to his lack of brilliance in other fields.

I've fallen victim to it myself, though I hope I got better. Something for us all to watch out for, in ourselves and our colleagues.

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35. Lactams lament on May 15, 2014 12:07 PM writes...

Hey- Give Blaser a break! At least someone is talking! All the real infectious disease researchers, are worn-out, unemployed,dissipated and disenchanted by the system and can't even utter a sentence without breaking out into tears and crying.
Pharma has drawn way back and its only the small and the warm-blooded that will survive among the cold-blooded dinosaurs. You need to look to works of Yellapragada Subbarow to see how far antibiotic research has evolved since their discovery. He's be rolling in his grave, and not in approval.


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36. Bell4 on May 15, 2014 12:53 PM writes...

Federal research generates tens of thousands of possible areas for new medical therapies every year - that's their purpose. Among these, several hundred seem potentially applicable to the generation of new therapeutics in the reasonably near-term, and formal or informal relationships with industry are established to investigate them. From that cohort, maybe 50-100 trigger significant investment in biotech or Big Pharma companies. On average half a dozen genuinely novel, significant opportunities emerge each year that eventually move to advanced clinical investigation. The vast majority of good new ideas in this domain fail to produce any medicines at all, and industry and its investors bear the cost of these failures.

To be sure, the numbers above are a best guess, but the process by which industry winnows down a torrent of academic ideas into the tiny fraction of programs worth substantial investment is, I think, very under-appreciated by those outside our business. Placing bets and taking on risk is what a market economy is supposed to do. It's gotten harder in the last decade for a number of reasons, but there is no evidence that in the current environment government is capable of taking over the risk-taking and decision-making essential for making important new drugs available.

For those who are skeptical about the latter contention, step back a minute and have a look at a world map: there are huge areas of the world with well-educated populations which, for historical reasons, have mostly rejected the Western capitalism-based model for the investigation and demonstration of the value of new medicines. What has Brazil, or the former USSR, or India, or China put into the world's medicine chest?

To paraphrase Churchill, profit-motivated groups are the worst possible organizations to come up with new drugs...except for all the alternatives.

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37. will on May 15, 2014 1:03 PM writes...

two things about darunavir

1) arun ghosh is not a listed inventor on the patents claiming the drugs, see, eg us 6248775

2) when those patents were filed he was at merck, so regardless, it was an industry, not academic, discovery

I would add pregabalin and emtracibine as successfully drugs not developed by industry

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38. Anonymous on May 15, 2014 1:12 PM writes...

@28: oh anitbi, antibi...

Your example of Daruavir is quite hilarious. Notice how wikipedia states "the chemist who discovered the molecule at Univ. Illinois at Chicago." The key word is 'discovered'. Drug discovery, while not easy, is nothing compared to the time, resources, effort that goes into drug development.

If only you knew that a "lead" compound from an academic lab is worth nearly zilch. How many lead compounds come out of academic labs that never get to GLP tox studies? I don't know the answer but I'm willing to bet 99+%. Great, you got some positive in vitro data, great you got some positive in vivo efficacy data with N=3. But you know what? That's the case for 1000s of compounds in industry.

Please for the sake of us all, get off your academic high horse and educate yourself on drug development, including clinical development. You'll likely be very surprised at what you find and impressed by the amount of resources, smarts, and hard work that goes into it all.

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39. Anonymous on May 15, 2014 1:25 PM writes...

@37: I feel like it's lala land here today. Pregabalin and Emtricitabine (or possibly a precursor to them) may have been discovered in academia, but please don't say they were developed in academia. See the above post.

Perhaps it would be useful for Derek to write a post on what constitutes drug development...

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40. Hap on May 15, 2014 1:31 PM writes...

I don't think they did many trials on emcitrabine or gabapentin, but they were developed some...enough so that the pharmas who purchased their rights coughed up significant cash to continue their development. (Patent encumbrance probably played a role, too.) If they weren't drugs yet, they were not just "look, this kills E. coli in a dish/makes mice happy!", either.

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41. will on May 15, 2014 1:32 PM writes...

@39 - fair enough, i was careless with my language. i agree the unis did not carry out the trials or even do the formulating work.

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42. Lyle Langley on May 15, 2014 1:43 PM writes...

I do find these academia v. industry dust ups on this site to be very amusing. (It very quickly turns to an us v. them mentality). Industry, yes, over time has been the primary drug discoverer and developer. However, as the industry contracts, the lead/drug discoverer is slowly changing over time. They will still (unless something very drastic happens) be the primary developer of drugs. However, there were a couple points I found pretty humorous. First, #17 Calvin's comment on academics reliance on "serious CRO help" is pretty funny. Why? Because most industrial labs rely on "serious CRO help" whether that be medicinal chemistry labs off-shore, or other CRO's. As a disclaimer, I work in an academic drug discovery unit, but before that worked in industry. We have contracts with Big Pharma and it's nearly daily/weekly that we have an assay that needs to be run and are told, "oh, we just outsource that assay". The second funny post is #33, Kevin's list of "jobs" not available at most academic labs. What so funny? Again, many of those are the same functions that get outsourced by Big Pharma. When we used to have 25+ Pharma companies, things were different, but we are down to what 8? 10? And most, if not all, have some affiliation with academics...makes it hard to say going forward that industry will be "discovering" drugs. Not to mention that many of the academic labs are populated with people that have come from Pharma (and not just the dead weight anymore) that brings extensive experience to academic side. Industry, unfortunately, has lost significant know-how over the past 10 years, so let's drop the charade that only they know how to do this. The main difference I see right now between industry and academia is the access of money to fund the research, and even that is dwindling in industry (see research budgets after mergers, never an additive number).

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43. Anonymous on May 15, 2014 2:08 PM writes...

@42, awesome points you raise. It shouldn't be a them vs us mentality and perhaps that is changing due to what you mention. Regardless, the level of experience in academia in regard to drug discovery/development is still small. About 7 years ago, prior to industry I've worked in labs where upon obtaining a IC50 of 5 nM against MDA-231 cells for a targeted taxane derivative, everybody, including the PI, thinks they've almost "cured" cancer. It are these types of events that are laughable, but still likely continue at most universities today.

I do, however, vastly disagree with your statement about funding. Total NIH budget = $30B. How much of that goes into labs doing direct drug discovery? I have no idea. 10%? 20%? Meanwhile, Merck R&D = $7B. Pfizer R&D = $6B. Sum up all the other pharma + biotech + startup companies and I'm sure it's a lot more than $30B.

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44. Anonymous on May 15, 2014 2:16 PM writes...

#40: Great point Hap. Though I think perhaps many people on this site, myself included, play down the role of clinical development in drug development... It's fantastic that somebody somewhere has a compound that works preclinically in vivo, doesn't show liabilities in GLP tox studies, and is formulated into a stable, bioavailable, soluble form. But now what? How to define inclusion/exclusion criteria? Attempt to select subjects via some type of imaging/diagnostic test? What are the parameters for all this? Incredibly important and difficult questions is the compound is in fact going to progress through to commercialization.

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45. Lyle Langley on May 15, 2014 2:38 PM writes...

@43...
Not sure what you are disagreeing with concerning budgets. NIH funding is $30B and a very small amount goes to drug discovery (and I don't count the total NCATs budget as that is still primarily basic research). Industry vastly outspends government/academic labs for drug discovery. What I was trying (and probably failed at) to convey is that industry budgets are dwindling with some of that money coming over to academic research, thus the discovery aspect is growing in academics. Industry is starting to cumulatively decline due to contractions (I think Dr. LaMattina touched on this a bit ago). IF Pfizer/AZ goes through, what comes out of the sausage grinder will have a much lower R&D budget than the combined budget that went in.

I agree, and witnessed it myself, about the professor that thinks they have a drug after screening ChemBridge. However, we all know that is not drug discovery and that is not what is touted as academic drug discovery through consortiums like the ADDC. I know that last statement will get some responses, but it's true.

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46. JT on May 15, 2014 2:59 PM writes...

@21 With respect to darunavir having been invented in an academic lab, it may be of interest to you and the med-chem community that the first description of this molecule can be found in US US 6,248,775
Claim 7 column 221 filed April 8, 1999 and issued June 19, 2001. See also USRE42889 filed April 28, 2007; reissue Nov. 1, 2011.

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47. Anonymous on May 15, 2014 3:09 PM writes...

@45, I misread your statement about industry v. academic drug discovery funding. My apologies. Indeed, consolidation is occurring in pharma, but I'm not convinced R&D budgets are decreasing. Now they are definitely not increasing at a rate they we all would like, but I believe they are either stagnant or slightly increasing (not accounting for inflation) over the last few years: e.g., 3.9% YoY 2014 R&D growth in pharma, 8.2% in biotech.

http://www.prlog.org/12159144-continuing-growth-in-rd-spending-forecast-for-2014.html

As somebody who has worked in huge pharma to a VC-funded startup, I will readily say that I would like to see more drug discovery occurring in academic settings. From bureaucracy in big pharma to impossible timelines from VCs which result in ahmmmm not-so-robust data packages, high quality research is really hard to do in for-profit institutions. Perhaps something will come from the ADDC. I do hope so. To do it right and produce robust, relevant, directly translatable data, it's my belief that many experienced, motivated, non-apathetic scientists with industry experience will need to jump on board.

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48. Lyle Langley on May 15, 2014 3:36 PM writes...

@47...
Was the "non-apathetic scientists" comment really needed? We've already heard from someone above about the "lazy academic scientist". Let's try and keep this a bit more civil than what normally comes out on this blog as soon as someone mentions anyone other than industry personnel can do drug discovery.

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49. NJBiologist on May 15, 2014 3:40 PM writes...

@Hap (40) -- Gabapentin > pregabalin (although Parke-Davis/Warner-Lambert did spend a pile on clinical trials for both of them)

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50. Anonymous on May 15, 2014 3:43 PM writes...

@48: perhaps re-read my last sentence. I was referring to the industrial scientist as apathetic. You know, the ones who sit in their office/cube all day, hiding from the boss and team lead, pretending to write emails, while really looking at FB. Or even better, the director/VP level individuals who run from meeting to meeting pretending to talk about "important stuff" when in fact they are just talking about the Bruins game last night for HOURS on end with other directors/VPs.

And I won't say the above hasn't been me on many a day...

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51. johnnyboy on May 15, 2014 4:29 PM writes...

Sad to see the comments so quickly devolve into a tiresome and useless academia vs industry shouting match.
Hey, all you righteous and tireless academic and industry strivers - don't you have some of that important drug discovery work to do today, instead of arguing on a blog comment section ?

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52. Anon on May 15, 2014 7:18 PM writes...

Stewart: "Could there be a Manhattan project?..."

Blaser: "I think it is. We need both diagnostics and narrow spectrum agents and we have to change the economics base of how we assess illness in kids and how we pay doctors so that we really value that more."

So we need diagnostics, medicine, and to pay doctors more?
www.medscape.com/sites/public/physician-comp/2014

...right

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53. wavefunction on May 16, 2014 10:28 AM writes...

We really need to stop comparing every project to the Manhattan Project (click on handle).

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54. Anon2 on May 16, 2014 10:29 AM writes...

@52 I didn't get "pay doctors more money" out of that . I think his point was that the economics of the situation has to change -- currently, it obviously values shotgun-style broad spectrum antibiotic prescription, and there's no incentive for individual doctors NOT to do that.

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55. Vaudaux on May 16, 2014 11:42 AM writes...

"If there ever was a field of drug discovery where the low-hanging fruit has been picked clean, it is antibiotic research.... Bacteria are hard to kill."

Bacteria are actually not hard to kill. Chemical libraries, and your kitchen, are full of compounds that can prevent growth of bacteria on a culture dish and in many cases can kill the bugs. Consider honey, vinegar, dishwashing soap, baking soda, egg whites (lysozyme), as well as drain cleaner, rat poison, bleach.

Whether you are working with natural products or synthetic molecules, finding antibacterial activity is easy if you ignore issues like mammalian cell toxicity and ADME.

This is not a quibble, it is the key issue in antibiotic discovery and often overlooked by academic researchers and small companies. People put a huge effort into screening technology - eg, for inducing production of new molecules by Streptomyces, or for finding inhibitors of a particular bacterial enzyme. That's fine, but it is only the first and easiest step (as described here and elsewhere by Derek, Lynn, et al).

The work begins when you try to determine whether there is a novel drug somewhere in one of your many active natural product extracts. These days, there hardly ever is - see "low-hanging fruit" above.

For synthetic molecules, you have to search through your screening hits and somehow pick out a few to use as starting points for chemistry. You hope to make a good choice, as it will probably take years to make the hits into drugs. This has hardly ever been done.

The list of antibiotic classes that were discovered through medicinal chemistry and went into clinical use is very short. The ones that come to mind are salvarsan, the sulfa drugs, trimethoprim, fluoroquinolones, and linezolid. Probably also some of the tuberculosis drugs. There are a few in clinical trials now.

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56. Vaudaux on May 16, 2014 12:06 PM writes...

A second comment, getting back to the main subject of the post, Blaser's comments about species-specific antibiotics:

There are a few examples. Some of the tuberculosis drugs are prodrugs, converted within bacteria to active molecules by enzymes that are relatively specific to Mycobacterium tuberculosis. For these cases, the activation process was discovered after the drug.

If you wanted to design such a drug, genomic data would definitely help you look for an activating enzyme with the desired bacterial spectrum. A narrow spectrum would probably be easier to identify candidate enzymes. (Loss of the activating enzyme renders the bug resistant to the drug, but that is another issue.)

I don't know whether this way of limiting the antibacterial spectrum of a drug would be easier than finding a pathogen-spectrum target, but it might help.

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57. Roger Zimmerman on May 16, 2014 2:29 PM writes...

It may not be a disgrace that Stewart doesn't understand the drug creation (and regulatory approval) process. However, isn't it a disgrace that he pontificates on it as if he does?

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58. bRUCE on May 16, 2014 7:44 PM writes...

I have a very simple question. EMT Basic a decade ago taught me to put bleach on everything dead and brown iodine on everything red. Any problem with this?

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