Org Prep Daily

April 22, 2009

blockbuster drugs

Filed under: industry life, lit highlights — milkshake @ 7:12 pm

I would like to direct the readers here to the excellent project-and-career story from Bruce Maryanoff in the most recent J. Med. Chem ASAP. It is very illuminating on how the drug discovery and development works, and it describes in some detail what a bright chemist can hope to achieve in this profession -with the necessary motivation and a decent employer (and tremendous amounts of luck).  

It is also an illuminating story on how the process does not work. For example, the currently most popular, target-driven rational-design-based approach can be pretty futile in CNS drug projects . The author also suggests that the management mantra about focusing on the discovery of the next “blockbuster drug” actually bankrupts the industry – financially and scientifically; his drug Topiramate (which has been making 2 billions a year for the company) would have not been discovered or developed under the management methods currently prevalent in the industry. Few things stand out: 1) It seems that having a blind luck and testing the compounds in a realistic animal model is more important than having a correct mechanistic understanding how the drug candidate actually works.  2) Few independent-minded individuals in their pharmacology and chemistry have made a good use of their lucky break. They stubbornly kept the research program going – even as their managers were lukewarm and would not support the compound development for a long time. It also goes to the credit of the management that allowed their researchers to pursue this as their hobby. The story shows that the progress in pharma research does not really happen by imposing some management-theory-derived reporting structure on the research department, by drafting the flowcharts and aligning the teams. For medchem research to succeed, the projects should be allowed to self-organize around the bright individuals rather than being planed out from top down, with red tape and micromanagement.

In this context it is entertaining to read rather disingenuous remarks made by the Merck chief strategy officer Merv Turner at the pharma management conference. He explained that they are currently sacking lots of people in research because  “Seventy-five cents of every dollar we spend on R&D goes to fund failure” and “the future results must come at a lower cost”.  

The actual drug discovery cost makes only few percent of the final drug development cost. By far the most expensive part is the clinical trials and namelly the late-stage clinical trials. What the Merck management poseurs do not tell in public is that it was the Merck top management decisions that cemented their company’s commitment to these “the next blockbuster” projects –  which eventually led to a string of stunningly expensive late-stage failures. When the top executives receive massive stock option bonuses, they become mercenaries of the stock prices. Their wishful thinking baloney percolates from top down through the management layers, etc.

There are many parallels between the state of pharma industry and the recent financial sector collapse, and it is always the executives who run their companies to the ground that are rewarding themselves most obscenely. Remember this whenever the pharma companies claim that the freedom to price their drugs is essential for the innovation.

_________________________________________________________

Update:  Here are additional two great articles from Bruce Maryanoff on the subject

18 Comments »

  1. I like your turning into this comments style, Milshake. You seem to be somehow tired of the undergraduate basic organic synthesis colsulting… I can understand you.
    Anyhow, it is always a pleasure to read from privileged minds like Derek and you.

    Comment by Vasili — April 23, 2009 @ 1:51 pm

  2. A privileged mind, no less – are you trying to borrow money off me? In fact I like discussing chemistry so any reasonable synthetic question is welcome.

    Regarding this article – it used to puzzle me how come in the old days (with so few tools and less money and fewer people) the drug discovery was cheaper and more productive. I think it is helpful to read stories about successful projects and compare that with what one can see around – because how can one decide for himself what is normal and what’s insane if there is no reference.

    Comment by milkshake — April 23, 2009 @ 2:12 pm

  3. Well said milkshake.

    It seems to me (as a Big Pharma outsider) that all these companies are far too busy spinning their latest “discovery model” as being uniquely fit to prosper in future years – despite the fact that to outsiders such as myself all their discovery models seem essentially identical.

    They try very hard to make thier bullshit look different, but it all smells the same.

    Comment by Ed — April 24, 2009 @ 2:19 am

  4. Nice topic. I attended for a lecture given by Bruce in the Smissman award symposium at spring ACS. It looks like he summarized it in the publication you mentioned.

    Comment by Samsleshana — April 24, 2009 @ 11:11 am

  5. milkshake while I think you make some good points there is danger is saying “Remember this whenever the pharma companies claim that the freedom to price their drugs is essential for the innovation”. I know you are emphasizing executives exorbitant pay, too which I hardly agree is mostly ridiculous relative to other workers/contributions, however also must account that within the current system it is Sales/Profits is what directly funds R&D (even VC funding is predicated on anticipated future ROIs). I don’t see how introduction of Drug Price Controls in US will not do damage to innovation since having a “Free Market” allows companies to counterbalance the great risks involved with potential for great rewards. Part of the problem, IMO, is that US is covering a disproportionate cost for supporting new drug so are fueling Global effort. Alternate funding mechanisms I have seen involve huge Academic and/or Government programs that largely try to exclude Industry (except to distribute products) so likely would end up being much slower, more closely and less efficient that current Model even with its many flaws. I won’t discuss Regulatory aspects which it probably most uncertain and expense laden factor in the process but can not ignore the messy situation there.

    Although I do see (mis)Management, particularly Blockbusteristis, as chiefly responsible for current situation in pharma, the Scientists areas are not without some blame as have too long tolerated inefficiency and/or did not focus own efforts and/or overly resisted changes that could be useful (unfortunately majority of these came force feed as “ultimate solutions” rather than tools). In the end in addition to the serendipity and persistence it does take the convergence of many disciplines to bring a drug to patients in need.

    Comment by CMCguy — April 24, 2009 @ 2:49 pm

  6. I think the industry is ridiculously ineffective – it reminds me of the East Bloc of the Brezhnev era. I was with three companies before the current job and I think lean times could benefit the industry and especially its management. And someone ought to look at the FDA approval process as well. The problem as I see it is that the current system of how the drugs are developed is astronomically expensive even when things work as supposed, and no-one seems to be motivated to make it any cheaper. Look at the story of Paul Janssen: He might have been extremely lucky but still – it is unthinkable that in these times some young medical graduate would use his parents money to hire few technicians without a chemistry degree, and soon discover several revolutionary drugs. These guys operated on a shoestring budget and they even did not have an NMR.

    Comment by milkshake — April 24, 2009 @ 3:04 pm

  7. I also agree pharma is extremely poor at what should be first mission: bringing new safe and effective treatments to reality. However reminds me more of Churchill Quote “It has been said that democracy is the worst form of government except all the others that have been tried.” Plenty of room for improvement in drug R&D but in spite of all complexities it can be successful. Concur as I am not sure Janssen story could have happened in modern era which is sad thought.

    Problem with lean times is (back to a common management criticism) that most companies react to not just trim the fat but will cut out muscle and bone that are needed for future. There has to be critical mass and the correct expertise to address to get things done or it can make a difficult process even worse to implement.

    Comment by CMCguy — April 24, 2009 @ 5:43 pm

  8. Milkshake, i’ve read your blog with great admiration.. and I’ve always found the info here useful… since there seems to be no contact information for you (probably due to privacy reasons), I was hoping to get your attention here (feel free to email me).

    I was hoping you or others might have knowledge of how best to deal with excess strong alkylating agents in the lab… e.g. propargyl bromide / MeI / benzyl Iodide, etc. This often comes up when using excess agent as is required in some alkylations, but i’ve not been able to find a good universal way to quench these safely. Should I reach for the ethanol amine or the Et2NH to quench out the excess in my reactions ? I’d rather not put them on the rotovap and vaporize these nasties. I was sort of hoping you might put up a post with your knowledge on the subject (a la your ethanol amine story a couple years back).

    Thanks, Adam

    Comment by Adam L. — April 26, 2009 @ 6:39 pm

  9. I suppose adding some methylamine (Fluka sells 33% solution in ethanol) should do it. Methyl iodide or benzyl bromide are not that terrible – never heard of anyone quenching them. Just make sure you clean rotavap after the use, and wash the glass in the hood (one always gets some inconsiderate colleague washing benzylbromide flask with hot water in the sink…) By the way I have had a better experience with using propargy chloride instead of bromide, in alkylation reactions.

    I would only consider quenching alkylating agents when working with diazomethane, methyl triflate or fluorosulfate ‘magic methyl” or dimethyl sulfate – those are seriously poisonous, and people actually ended up with lung oedema in hospital because of them. Diazomethane is easily destroyed with acetic acid.

    Comment by milkshake — April 26, 2009 @ 6:51 pm

  10. Adam,

    I’ve used liters of methyl triflate and dimethyl sulfate for gram quantity scale-up of an early intermediate in a multi-step synthesis. You can quench either ‘softer’ alkylating agents or the nasties with a 5% solution of aqueous ammonia.

    If you ever do work with the nasty alkylating agents, don’t ever use more than a dilute (5%) solution of a nucleophile to quench. I’ve read of incidents where folks quenched methyl triflate or dimethyl sulfate with conc. ammonium hydroxide – and the reaction exploded due to the exotherm.

    Universally, any strong nucleophile should quench an electrophilic alkylating agent.

    Good luck!

    Comment by T — April 27, 2009 @ 12:40 am

  11. Hi guys, my question is out of topic of this article, but could be important for anybody, I guess. What kind of silica gel do you use for regular/flash chromatography? Does anybody have experience with e.g. Divisil, Merck or Fluka silica?

    Comment by dany — April 30, 2009 @ 7:00 am

  12. It should be Davisil.

    Comment by Dany — April 30, 2009 @ 7:01 am

  13. We buy bulk EMD Merck silica, EM-9385-4 through VWR, in 2.5kg bottles, its a good stuff.
    Other groups here use silica from a company called Silicycle and they buy it in drums.

    I have no experience with Davisil – the only good way to compare it would be to actually run a column.

    Comment by milkshake — April 30, 2009 @ 2:15 pm

  14. Dear Friends in the Blogosphere. I thank Milkshake for the kind remarks about my Perspective article that was just released in J. Med. Chem. The story I presented there is a sort of semi-autobiography that is used as a foil to convey certain impressions about drug discovery, and the pharmaceutical industry, past and present. Most importantly, it is my opinion that the discovery of drugs is less likely to be accomplished effectively by a formulaic, process-oriented approach, which seems to be the gospel of executive management in big-pharma these days. Serendipity and opportunism need to be a sizable component. One cannot say too much about the value added from the insight and intuition of observant, attentive medicinal chemists. When medicinal chemistry is “commoditized”, that value is no longer realized. In any case, the story in JMC is an expansion of the final 15% of my Smissman Award lecture at the ACS Natl. Meeting in SLC. Basically, the “more” part of “Adventures in Drug Discovery: Enzyme Inhibitors, Receptor Antagonists and … More”.

    Comment by bruce maryanoff — May 3, 2009 @ 11:28 pm

  15. Dr. Maryanoff: it is wonderful that you stopped by here – you are an inspiration to us all.

    Comment by milkshake — May 4, 2009 @ 3:06 am

  16. Milkshake,
    I wonder if you have you listed bromination of furan any where in your procedures!

    Comment by Anonymous — May 4, 2009 @ 5:48 pm

  17. Also, I was wondering if you knew any of the grants, and stipends (fellowships) that I can apply for the postdoctoral studies in USA being a non-citizen.

    Thanx ahead for your time.

    Comment by Anonymous — May 4, 2009 @ 5:51 pm

  18. Well I cannot advise you about applying for the scholarships because I never really had to search for it – I just applied to one that I heard about (it was specifically for Czech-born organic chemists).

    I have no experience with brominating furans; I suppose one should probably use very mild conditions. There are two procedures for compounds with bromofurane piece here in Org Prep Daily but these compounds were made from commercial bromofuran starting material.

    I would recommend that you do a structure search in Org Syn – its free online, and the procedures there are usually pretty reliable.

    Comment by milkshake — May 4, 2009 @ 6:15 pm


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