Skip to main content

Diabetes and Obesity

More On Merck and Taranabant

My piece on Merck last week seems to have touched a few nerves, if some of the comments and e-mails I’ve received are any sign. To clarify things: I agree that Merck is still doing some excellent science, as they always have. And they still have a lot of good people there, as they always have. Those aren’t the problems. And they’re still introducing some innovative drugs, arguably more than a lot of other companies, and that’s not the problem, either. These are all are admirable things.
And Vioxx, as I said here at the time, was not, in my opinion, necessarily a bad drug. It and the other COX-2 inhibitors have a real place in the pharmacopeia. The problem is that Merck – or, to put the usual face-saving perspective on it, Merck’s marketing department – oversold the stuff. The prospect of an aspirin-sized market was too much for them to resist, so the company pushed Vioxx just about as hard as they possibly could.
Yep, Vioxx was for all kinds of patients, all kinds of pain, all the time – and under those conditions, whatever side effects were there were finally revealed. It’s the company’s bad luck (not to mention the bad luck of their patients) that those effects were as potentially severe as they were. Even so, the increased risk of a heart attack with Vioxx use is extremely small in any absolute sense. For people with severe pain who can’t get relief with other drugs, I think a COX-2 inhibitor is absolutely worth it.
But that’s not what you’d think from reading the newspapers, or from listening to the lawyers. It was expedient to paint the company as a bunch of callous poisoners; Merck’s reputation has been hooked to the back of a pickup truck and pulled through a swamp. (They didn’t always do themselves much good during that period, either). And while the good name was bouncing off the tree stumps and scooping up the mud, the company had to spend vast amounts of money to deal with all those lawsuits, which is money that presumably could have been used for something else. (OK, some of that is coming from insurance – but think of how much more they’ll be paying for that coverage now).
Which is what worries me about taranabant. I realize, as several commenters to the previous post pointed out, that it may well differ in selectivity and CB-1 receptor activity from rimonabant. If the compound is an inverse agonist instead of an antagonist at the receptor, that could well be good news. Or, you know, it might not be, since we have no idea of what an inverse agonist will do, either. (More on the difference between those terms in a future post). At any rate, discovering new things about human CNS functions while a bunch of lawyers watch doesn’t sound like a good idea. If Merck does end up going down the Vioxx path again, another run through the swamp will do it no good at all.

26 comments on “More On Merck and Taranabant”

  1. MTK says:

    Derek, you are spot on here, both in terms of Merck’s rep and Vioxx.
    Remember back in the 80’s when they would consistently be at or near the top of the “Most Admired Company” lists? Well, in both 06 and 07 Merck failed to crack the Top 300 in Fortune’s list. Talk about a fall from grace.
    Of course, Merck’s fall mirrors that of the pharma industry as a whole. We are the corporate baddies, right up there with oil and tobacco. Regardless of whether it’s causal, symptomatic, or just coincidental, it’s never good when your erstwhile standard bearer goes down.

  2. sroy says:

    Note to pharma companies-
    Ignoring human system pharmacology will lead to therapeutic failure.
    Merck, Pfizer, BMS, J&J, AstraZeneca etc are learning this the hard way.
    Seriously, if you looked at the bad target selections made by big pharma in the past decade and a half, one has to wonder if there was any due diligence on the role of those targets in the human versions of diseases. Then again big organizations tend to favor group think (aka drinking the tainted kool-aid).

  3. MedinformaticsMD says:

    Merck destroyed its culture from within when the Equinox layoffs of 2003 occurred. Thousands laid off from a company that had valued its employees for over 100+ years and not had mass layoffs.
    And this was before the VIOXX problem was a blip on the radar when several late stage compounds were withdrawn.
    Merck did not have to lay off anybody. By doing so they saved a few hundred million while pushing up the stock price a bit. However, the hit to morale of Merck’s joining the “people are assets, but expendible assets” club caused a further exodus of talent, and the cost of lost opportunity is incalculable.
    It would also help them if they’d get their recruiting IT working properly. As it is, it’s likely good talent remains essentially invisible.

  4. Jan Lyons says:

    Vioxx wasn’t bad, as stated it was the marketing and the decision to hide the risk factors. Any drug has side effects along with the benefits. Each individual needs to decide if the negative out weighs the positive. If we had known the risks would my husband have taken Vioxx? No, he would have gone forward with knee replacement, instead of putting it off for a year. Now he is dead with no prior heart history. Someone else that has no quality of life without Vioxx would be willing to take the risk. That is their right. Merck’s culpabilty was in hiding the risks, not in the drug. Be honest, don’t cover side effects to increase profit margins. In the long run even after all the pay outs Vioxx will still be a money maker for Merck. It made 12 billion the settlement is 4.85 billion plus legal expenses for the cases tried.

  5. PharmaToAcademe says:

    “Note to pharma companies-
    Ignoring human system pharmacology will lead to therapeutic failure.

    Seriously, if you looked at the bad target selections made by big pharma in the past decade and a half, one has to wonder if there was any due diligence on the role of those targets in the human versions of diseases. …”
    Good and bad targets are always far easier to discern in hindsight. I’m pretty sure no one saw the glorious fall of Cox-2 and stroke/MI coming all that obviously through pre-clin pharmacology – at least to my knowledge.
    As for MedinformaticsMD, I have to chuckle. Equinox, much like any “restructuring”, occurs largely as a horse and pony show, nothing more nothing less. Since it sounds like you might have been a part of this restructuring (by the way, I might take a guess at your identity), I wouldn’t take it personally.
    Ultimately, I agree with Jan Lyons. Any drugs –by definition– have risks. You’re adding molecules into a body for a desired effect – that effect is almost never 100% constructive. I do however disagree with the profit. You’re missing a huge chunk of money for R&D over nearly a decade. I’d certainly say it’s a black scar on Merck’s reputation and in the books.

  6. Chuck Pelto says:

    TO: Derek Lowe, et al.
    RE: Yeah….Right….
    “Yep, Vioxx was for all kinds of patients, all kinds of pain, all the time – and under those conditions, whatever side effects were there were finally revealed.” — Derek Lowe
    ….for those who died as a result.
    Oh. But I guess the greater good is all that should be of importance here.
    I look forward to the day you report that you’ve been perscribed a drug that makes your very life miserabe.
    I look forward to it with great anticipation.
    Because I was perscribed such that put me into central sleep apnea. [Note: For the ignorant, central sleep apnea is when your brain forgets to tell your lungs to breath in the middle of the night. You’re in a situation where you can go to sleep and (1) wake in a crashing rush gasping for breath (consider the bedroom scene in He Said/She Said) or (2) wake up dead the next morning.]
    A wonderful experience. Makes you appreciate God so much more. I recommend it to everyone….who has taken their doctors word as sacrosanct.
    These people—doctors—play to the lowest common denominator. Lest ye forget, each of us is ‘different’.
    [Mechanics have to fix their mistakes. Doctors bury theirs.]
    P.S. Oh….Yeah….
    When I called the maker of this ‘wonder drug’ about side effects they said, “Yes. Some people experience SLEEP DISORDERS.” When I asked if one of those disorders involved waking up dead, they didn’t answer.]

  7. Dennis says:

    Your sarcasm detector is broken.

  8. Anonymous says:

    TO: Dennis
    RE: Yeah…
    “Your sarcasm detector is broken.” — Dennis
    Sorry about that.
    Blame the vaunted pharms and the FDA and the doctors.
    P.S. I think it got broke the second night I woke up gasping for breath. Guess it got knocked onto the floor from the nightstand.

  9. sroy says:

    In the case of COX-2 inhibitors, internal documents show that they were aware of the CVD risk even before it was launched.
    Do you realize that many of the NSAIDs approved in the 80s(meloxicam, diclofenac) before COX-2 was discovered have been now found out to be fairly COX-2 selective. Diclofenac (the prototypical low GI side-effects NSAID) had been associated with an increased risk of CVD even before celecoxib came to the market. Rofecoxib’s fault was that it was very COX-2 selective, hence the substantially higher MI risk.
    If you do not believe this look at the pharmacophore requirements for COX-1 and COX-2 inhibitors. You will see that the last NSAIDs developed before COX-2 inhibitors have features that would make them COX-2 selective.
    Merck should have followed up on such previously published data. It is called ‘due diligence’ though I suspect that the management there (and in other big pharma companies) does not understand that concept. After all who care what happens to a drug 5 years after it was released as long as everyone in management have cashed in their stock options and have golden parachutes.
    Lets us consider CETP inhibitors (Torcetrapib)- So is increased HDL (or a lower HDL/ LDL ratio) the cause or the proxy for CVD? Think about it – why don’t 20-30 year old men who eat a lot of pub food drop dead from MI? Is it simply a cholesterol input/ output problem? And while we are at it – do old calcified plaques cause MI or is it new unstable plaques?
    So what is behind the new unstable plaques – small changes in cholesterol transport or increased systemic inflammation?
    About Ezetimibe – is there any strong correlation between dietary fat intake in european countries (large population studies) and rate of heart disease?
    While I am at it, let’s look at antagonist/ inverse agonists of the THC receptor. If an agonist (THC) makes people eat more, increases the threshold for vomiting and makes most people feel calm, is it not rational to consider that blocking the function of this receptor (especially for a chronically administered drug) might cause the reverse? All of that for a medically insignificant few pounds of weight loss?
    And now let’s consider varenicline- given that Ach receptors (muscarinic, nicotinic) form some of the basic subsystems in many parts of the brain, is it not possible that a partial agonist might cause problems? You must be aware that selective nicotinergic agonists have shown a lot of promise in treating ADHD and cognitive deficits in schizophrenia. Nicotinergic partial agonists might therefore adversely affect cognition, mood and motivation.
    It all boils down to ‘due diligence’ aka not drinking your own toxic kool-aid.
    Merck made it’s reputation on innovation, excellent science and due diligence. Then they got MBAs to run the company in the last 15 years and you know the rest..
    I also think that they should use names starting with ‘V’ for any future drug- Vioxx, Vytorin.. come to think about it.. varenicline (Chantix).
    Might also want to stop pushing newer COX-2 inhibitors and not license and develop more gaba agonists or modulators for treating insomnia (I follow the news).
    Though I am finishing my PhD in computational chemistry (drug design stuff), my first love has always been Pharmacology.

  10. Anonymous says:

    P.P.S. I understand that a woman died on an American Airlines flight from Haiti to New York.
    Something about not being able to BREATH.
    Guys and gals….
    ….I KNOW EXACTLY HOW THAT FEELS. And it ain’t much ‘fun’.

  11. Skeptic says:

    The medicinal chemists here can complain all they want about the crook MBA’s and such but the consumers/investors are the source of the problem.
    The FDA will kill the US pharmaceutical industry simply because of the fact that in front of every computer sits an idiot looking for an easy buck. Do you think these fools give a crap about human rights and labor laws in China? The FDA is a hassle and they don’t want that.

  12. DrSnowboard says:

    sroy –
    Sounds like you’re not planning to join the pharmaceutical profession anytime soon then? I admire the excellent hindsight skills your PhD is bestowing on you. My recollection is that celecoxib as FIC is very moderately COX-2 selective hence diclofenac approaches it. Also very assay dependent.
    Name me a target you do want to work on, please.
    As for Merck, my feeling is they still get respect for the science and for pursuing targets they believe in. HIV integrase since 1994 and through a couple of clinical hiccups ie non-products to Isentress.
    And no, I’ve never worked for Merck.

  13. sroy says:

    To DrSnowboard,
    I am actually very interested in joining a biotech/pharma company, infact I worked for one between my MSc (Pharmacology) and PhD (Comp Chem).
    Given that I have almost finished writing my Thesis, I am actively looking for a job.
    My experience with companies (worked and interacted with) has been that the scientists are usually very competent. But the management misallocates resources for what ever is hot at that moment (kinda like a child with ADHD).
    One of the result of this short-sighted management style is that teams are created and destroyed at will. Therefore a deep base of knowledge about a given disease is hard to create and maintain. Since the first targets for a disease might not be the right one, many companies prematurely exit a field/ disease.
    Target selection is an extremely important and neglected area. It requires a very good understanding of the science and logistics of a given target. The ability to not drink your own kool-aid is very important. One has to be dispassionate and utterly realistic when doing it. However this decision is often made by people who are not scientists (sales, consumer research) or based on whatever is in the news.
    An other problem is the shortage of scientists with a good interdisciplinary training. Often the med chem guys speak a different language from the comp chem guys (synthetic accesibility vs filling the pocket by any means). Pharmacologists often cannot convey the full implications of assay results to med chem and comp chem. While I not suggesting that we should require double PhDs, a good understanding of another field certainly helps with communication.
    The end result is that we end up creating drugs that are very effective in treating rats and mice (as opposed to humans).
    About your other question. I have quite a few ideas for targets.
    Class I – Easy and very low Risk [Use existing drugs (combinations) or close analogs to treat a few conditions].
    2-3 years.
    a] Traumatic Brain Injury Rehabilitation [Think of the market for people involved in automobile accidents and Iraq Vets]
    Could also be marketed as a treatment to decrease hospital and rehab stays for stroke patients.
    I am not predicting a complete return to normal function – just a quicker return to a measurably better quality of life. Though the liars in marketing can easily spin that into the second coming of christ.
    Class II – Medium Risk [Development Required]
    3-5 years
    a] Anti-bacterial compounds (including inhibitors of toxins and other targets involved in pathogenesis as opposed to normal growth)
    b] Selective Androgen Receptor Modulation. (Modulation not modulators)
    Class III – High Risk [of failure]
    3-5 years
    a] Stopping the progress of Alzheimer’s and coexisting Vascular Dementia [injectable].
    b] Treating Lewy Body Dementia [injectable].
    c] CVD modification [speculative mechanism].
    I have more speculative ideas, but that is an other story

  14. MolecModeler says:

    sroy: Pfizer was hiring like mad recently, maybe they still are. Not sure I’d want to work there given the impending Lipitor patent loss.
    Interesting that as you’re seeking to enter the field (comp chem), I’m seeking to leave it.
    You appear to have an ideal background for a successful comp chemist though (i.e. someone who knows about the realities of drug development and not just 6-31G*)

  15. sroy says:

    To MolecModeler,
    I had applied to Pfizer and a few others. I think the problem is the trolls in the HR department.
    I am not sure whether directly contacting someone in the departments (from publications) is a better idea.

  16. Haggis says:

    I find you reply to Dr Snowboard most touching in it’s naivety. Especially your comments on anti-bacterials as being medium risk and taking 3-5 years. Sorry, but those of us who have worked in that field might suggest that it will take much much longer. Some relatively recent publications by GSK and their utter failure despite buckets of cash might educate you as to the difficulties we face here. I suggest you multiply your timescales 5 fold! Compounds make drugs not targets.

  17. sroy says:

    Hi Haggis,
    3-5 years to know if the thing is worth developing for human use (discovery + animal model + tox/ ADME + Phase I).. and another 3-4 years to push it through the red tape (Phase II and Phase III)..
    GSK and many other pharma companies spend too much time trying to make better macrolide mimics, nucleotide analogues, lipid synthesis or gyrase inhibitors.
    I am not talking about killing bacteria. Just making them incapable of sustaining a disease process in humans. Remember infection, colonization and disease are three separate processes.
    Think about it- The majority of mortality and morbidity from bacterial infections in developed countries is due to infections by rather common bacteria in older hospitalized patients.
    How do you think S.auerus or P.aeruginosa kill people, when you also can readily find them in a healthy nasopharynx and a hot tub? What makes a commensal into a deadly pathogen? Do bugs in these two states express the same sets of genes? Why not hit only those genes products expressed during pathogenesis? Such proteins are better targets since the chance of finding mammalian homologs is even less than most other bacterial proteins.
    The trick is a] understanding the relative importance of each gene product in the web of pathogenesis b] identifying similar systems in other bacterial species so that you have a broad spectrum drug that screws up the pathogenic phenotype feedback loop of more than one bacterial ‘species’.
    Then again if you just want bacterio -static/cidal drugs why not just crystallize any bacterial enzyme you can find (regardless of what you know about its function) -> identify pharmacophore requirements for binding -> test compounds in binding assay -> leads -> test in culture -> test for toxicity -> refine compounds till you are satisfied. A shotgun approach for sure – but doable.
    The real problem is most management types like projects that develop analogs/ homologs/ improvements of existing drugs (low risk) or develop inhibitors for some speculative target without ‘due diligence’ (so that they can appear to be on the cutting edge).
    On an other note many people say that new antibiotics will not be used as a treatment of first choice in patients. I suggest that problem can be rectified by using proper re-education techniques for doctors.
    You can get doctors to publish glowing reviews about the great therapeutic advances awaitimg introduction of torcetrapib, rofecoxib, ezemtimibe and get them to prescribe risperidal, zyprexa, topamax for of-label indications. The question therefore is – does pharma think it is profitable to pay and get doctors to conform to their guidelines for new antibacterials.

  18. weirdo says:

    Best of luck finding a job at a real company. Your attitude is not going to help.

  19. processchemist says:

    5 years maximum from hit2lead to phase I included sounds like pure science fiction. Also in small/mid sized companies only tox+phase I takes 2-3 years, even with the most rabid management breathing on the back of the project manager.

  20. PharmatoAcademe says:

    Your enthusiasm is commendable. I think the criticism you are receiving here are probably somewhat exaggerated, however, I think your views are overly idealistic. They contrast with the many jaded scientists struggling with the challenges of drug discovery. The fact of the matter is science isnt’ at a point yet to really know what happens *to humans* when you block/enhance a known target. Even the most ‘low risk’ targets are crapshoots until they reach Phase I trials – which is more than a handful of years in preclin development. The problem is, you just don’t hear about these failures and so they unconsciously get taken out of the denominator when people consider Drug Discovery.
    In addition, I can’t for the life of me see how brain trauma can be reliably treated pharmacologically – the science there is orders of magnitude less established than in fields such as cardiovascular or pain/inflammation.
    Your view sadly runs parallel with the public’s view, which might be (over)simplified with, “You morons.. you’ve got so much money and so much talent and you can’t even throw together drug X. You must either be a bunch of money-grubbing corrupt scientists/business people or just dumb” I hate to break it to everyone, but to get a drug that 1)works, 2) is safe enough relative to its efficacy, and 3) makes money is a challenging highly risky proposition. The process and its many potential pitfalls are taken for granted – even by bright scientists. In order to stay competitive, pharmas are forced to push candidates through before they understand the science (this is true in nearly any business or industry – push products before policies/theories are in place to regulate those products). Even then, the science does not always apply from molecule to cell to tissue to preclin to humans.
    As to your comment on breaking into the industry, definitely having a PI battle for you from the inside will get you further than knocking on the front door. Conferences also are a good place for pharma contacts. Searching for any job, you have to kind of put your pride down and consider that the worst thing that could happen is the receiver laughs at your CV and dumps it in the trash. At least you never hear about it. You’ll likely get more mileage in a job search that way, than by being demure about who you can/should contact.

  21. sroy says:

    Hi PharmatoAcademe,
    I can understand why you would think that my views are idealistic. Given that I am just finishing my PhD, it is very reasonable to assume that I am into the theory stuff (as opposed to reality and business constraints). However I have worked in biotech/ pharma between my MSc and PhD, so I am aware of the ground realities of research in companies.
    You are absolutely right in the remarkable lack of understanding of human physiology and pathology (as opposed to mice and rats). We are very good at treating diseases in mice and rats. Sometimes I feel that the ‘Hitchhikers guide to the galaxy’ is more true than I would want it. I believe that the way to solve this is for companies to do some hard headed research into human systems rather than search through the mountain of questionable data produced by academia.
    The problem with academia is that you cannot get a grant unless you fall behind whichever fellow academic is getting money by selling a new idea (irrespective of it’s connection to reality). Therefore the vast majority of medical research funded by the govt or foundations is useless and misleading if you want to develop a new drug (new mechanism as opposed to a NCE).
    I am also very aware of the very high attrition rates for targets in almost all fields of pharma research. I have spent (too) much time looking though patents of stuff that looked promising but never made it past Phase I/II. What did surprise me back then was the the vast majority of useless targets could have been easily identified with the information available when that project was started. This is because many of the ideas did not pass basic rational scrutiny.
    Even a brief rational look at the concept behind these targets would have identified bad targets over 80% of the time. I think that works to an 80% wastage in pre-clinical development. That is just unacceptable.
    Moreover many of the other 20% were clearly lacking decent therapeutic activity in the animal models used. In the drive to get something working animals models with no relation to the human disease were used to justify future development.
    About the brain trauma stuff – I think it is possible to increase the speed and extent of regaining some function faster than is currently possible with physio- and occupational therapy. My idea has to do with the gaming the functioning of the remaining neural net infrastructure at multiple points to alter the feedback loops such that there is more recovery than is otherwise possible. I am not talking about perfect recovery , just improving the quality of recovery in a statistically quantifiable and significant manner (what is necessary to sell drugs).
    As I have said before the problems with innovation in pharma are systemic. However the major blame has to placed on the high level management practices (in the last 15 odd years) and control of resource allocation by people lacking an understanding of the complexity and risk/ reward inherent in drug research. If everyone in control is just thinking about their next year stock options and golden parachutes – it won’t work. This problem is systemic in the developed world today and is worse in many other industries (auto and finance).
    My issue with this situation is that it is not sustainable (even in the next 5 years). The sad reality that without a significant change in management styles, many big companies are going to implode once major money making drugs come of patent. The top-level management will however loot the place and fire every competent person before they open their golden parachutes. They will destroy whole teams of very competent scientist, managers and salespeople because of their own incompetence. These people have destroyed the public image of the pharma business. It took a long time to creates it but now they have screwed it up for all of us.
    Add this to the monetary issues and political winds in the US economy and you have a situation where it will be very hard for big pharma to be as profitable as they used to be.
    And that is the real reason I am concerned.

  22. Evan says:

    In regards to your comment about how expensive Merck’s insurance now is, here is a statement from their Form 10-K released just last week:
    “The Company has no product liability insurance for products first sold after August 1, 2004. As a result of a number of factors, product liability insurance has become less available while the cost has increased significantly. The Company has evaluated its risks and has determined that the cost of obtaining product liability insurance outweighs the likely benefits of the coverage that is available and as such, has no insurance for certain product liabilities effective August 1, 2004, including liability for products first sold after that date.”
    I would suppose that one of those ‘number of factors’ would be the Vioxx cost, eh?

  23. weirdo says:

    Looks like Derek was correct, again:
    Oh, well.

  24. fez_monkey says:

    Merck has announced it has dropped plans for pursuing Taranabant.

  25. speakertolabanimals says:

    Actually – rimonabant and taranabant *both* are often considered to be inverse agonists instead of antagonists.
    The usefulness of such a distinction is questionable, as is the label, since in a system that is active with endogenous cannabinoids, there is little to no difference in action of an inverse agonist *or* strict antagonist.

  26. speakertolabanimals says:

    Actually – rimonabant and taranabant *both* are often considered to be inverse agonists instead of antagonists.
    The usefulness of such a distinction is questionable, as is the label, since in a system that is active with endogenous cannabinoids, there is little to no difference in action of an inverse agonist *or* strict antagonist.

Comments are closed.