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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

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February 20, 2008

What You Become Known For

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Posted by Derek

A recent item from InVivoBlog about Merck which brought up some interesting points. They aren’t cheerful ones. The article is largely about Merck’s reputation, which has taken some dents in recent years, to put it lightly. The Vioxx debacle is the main reason for this, but the hits have kept on coming, such as the latest controversy over the release of the disappointing Vytorin study data.

So, although this is a painful question, perhaps it needs to be asked: remember when Merck was above all that stuff? Maybe there should be a “seemed” in that sentence somewhere; that might take some of the sting away. But the company really did have a singular reputation at one time. Depending on your point of view, you could have used words like “insular” or “arrogant” to describe the culture over there, but they were distinctive.

Merck didn’t merge with anyone. They stuck with targets and projects for years and years if they thought something would come out of them. And (until Vioxx) they avoided the sorts of disasters that seemed to hit other companies. That’s gone. Not all gone – they still seem to run on longer timelines over there – but one of the most distinctive things about the company was how it guarded its reputation, and that seems to have slipped down the list. They didn't have to do ad campaigns like this one. The company's trying to convince people, or convince themselves, that things haven't changed, but they're wrong.

The other thing that struck me about the article was about the development of the company’s CB-1 antagonist. That’s the same mechanism as rimonabant, Sanofi-Aventis’s failed wonder drug for obesity. (OK, it’s on the market as Acomplia in several countries, but considering what people had thought it would do, it’s a failure, all right). I question Merck’s judgment in pushing another compound into that area, although these programs do take on a life of their own. And as the In Vivo post points out, Merck’s current reputation of pushing every drug as hard as possible won’t help it when it comes to getting the drug through the FDA.

The biggest problem with rimonabant was the comparison of its side effects to its efficacy. It does seem to help people lose weight, although not to any startling extent, but in a large patient population various psychiatric side effects showed up. Taranabant's side effect profile isn't yet clear. Merck is going to have to tread lightly, but can they? The situation is a bit too much like Vioxx, with a huge, lucrative market out there if you can just expand the patient population. And we can argue about just how bad Vioxx really was, and about its risk/benefit ratio, but that won't change the fact that it was a catastrophe for Merck. The last thing they need is another one. I don't think I would have picked this time to push another CB-1 antagonist forward, but I suppose we don't get to pick that sort of thing. . .

Comments (20) + TrackBacks (0) | Category: Diabetes and Obesity | Drug Development | Drug Industry History | The Dark Side


COMMENTS

1. Vioxx victim on February 20, 2008 9:42 AM writes...

Thank you for this great article, too bad this is a realty with Merck. It is really scary when we can't trust big pharma to do the right thing, such as release information form the trial study in a timely manner. After taking vioxx and suffering a MI my family is still realing from that drug. Hopefully the FDA and Congress can keep this from happening again.

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2. Chemist on February 20, 2008 11:16 AM writes...

What, did merck turn you down for a job?

and, NO I don't work for Merck

Your blog shouldn't be allowed on sites like biospace, you make chemists look like idiots. You are a nobody who was drummed out of all your past positions and wound up at shithole Vertex.
GO AWAY! your commentary is worthless....

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3. Derek Lowe on February 20, 2008 11:45 AM writes...

I've never interviewed with Merck.

"Chemist", your two comments so far have been remarkably useless - you'll note that the usual signal/noise is a lot higher around here, thanks to this site's readers.

And, as is usual in cases like this, I invite you to start a site more in line with your own opinions. I'll promise not to babble in your comments section if you won't in this one.

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4. Analytical Scientist on February 20, 2008 12:32 PM writes...

I'm a veteran (victim?) of Vioxx era Merck, though I work elsewhere now. I have to say, that having seen Merck from the inside, I have a greater respect for the ethics and quality of this organization. I remain very fond of Merck and respectful of the passion of its people for developing drugs that help people.

The PR nightmare that was Vioxx is tremendous for the industry, and I think that Merck managment mishandled the whole thing. However, I think they did so out of well intentioned masochism rather than any sinister motives. The public really has an over-alarmed view of the issues associated with this drug. In my humble opinon after having looked at the data from the study that sunk Vioxx, this drug is appropriate to market with a black box warning (like Celebrex) and a suggestion of baby asprin coadministration (again like Celebrex used in it's safety trial). Many patients who valued the benefits of Vioxx would have thanked Merck for such a move. Instead, the vultures circled and everyone wanted their peice of the billion$ Merck was sure to have to pay out.

Vioxx could have happened to any company--it just happened to Merck. This should (and did) humble Merck, but it would also be arrogant to think that it couldn't happen at your company, too.

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5. A-non-y-mous on February 20, 2008 2:04 PM writes...

Isn't Rimonobant an inverse agonist, as opposed to an antagonist? This small distinction really helps to explain its psych profile. Perhaps Taranabant is a true antagonist, and is why Merck is plowing ahead? Any idea?

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6. milkshake on February 20, 2008 2:22 PM writes...

We have a number of ex-Merck biologists and chemists in top positions here. Even though they hold their chin high when tthey are alking about their experience at Merck, I was surprised to find that they had generally more nuanced view of the company, especially its management. I heard a comments from a ex-Merck chemist that went like this: "They treat you like mushrooms. They keep you in dark and they feed you shit" Part of the bitternes was undoubtedly due to the fact that he spent more than two years of his productive life on a research project that was kept alive for purely political internal reasons (it was somebody's pet project) and from the beginning there was an internal opposition to the project and a quiet decision that is was not going to be advanced into clinic no matter how succesful the project would turn out.

Also, the way Meck transformed Sibia in San Diego (only to close it down later entirely) resonates with me - I had a similar experience with SUGEN and Pfizer.

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7. Analytical Scientist on February 20, 2008 3:22 PM writes...

A-non-y-mous,

Taranabant is the same target as rimonabant, with all the same potential class effects.

Which is not to say that it will have the same safety profile...but it might.

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8. Chrispy on February 20, 2008 3:49 PM writes...

Analytical Scientist,

I have to disagree here a bit. An inverse agonist could push the system to an extreme you'd not see with a simple antagonist. Sortof the difference between applying the brakes and throwing it intto reverse. I do agree, though, that since the both operate in the same axis you'd be right to worry.

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9. CMC guy on February 20, 2008 4:12 PM writes...

#2 Chemist peak in a mirror to see who making chemists look like idiots. Derek I find this Blog insightful with wide ranging topics and opinions plus often spawns memories of grad school or lab work.

Unfortunately what you say about Mercks loss of preeminent reputation, apart from the particular damaging events, is illustrative of what has happen to Pharma Industry as a whole in past 20 years with publicly view that we are now “bad guys”. Drug companies seemingly were more focused and productive but certainly did also have an air of arrogance compared to other industries. Science Research & Development and aim of promoting Health was more a core activity (with inherent rewards) rather than a profit generation tool. Mergers have impacted innovation mostly negatively in eliminating viable target projects or personnel or whole organizations but as pointed out Merck has faired no better on their own. Smaller Biotechs may not capable in filling the void unless appropriate experience can be found internally or externally. Regulatory (Global), Legal and Sales Marketing are more powerful forces to deal with and have greater influence or consequences. Wish had some encouragement or answers but for most part there appear downward momentum in perception and productivity from Pharma.

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10. Mark M on February 20, 2008 4:49 PM writes...

To this day, scaleup protocols coming out the Merck Process group are still regarded as having a high likelihood of reproducability.

So, the tarnish hasn't affected the reputation of everyone over there. Granted, a lot of good folks from the glory days have moved on (eg, Paul, Jerry)

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11. merckrmurderers on February 20, 2008 5:43 PM writes...

MERCK SHOULD BE SHUT DOWN AND IT ASSETS SIEZED /DISTRIBUTED AMOUNGST THE VICTIMS

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12. Taranabant on February 20, 2008 5:55 PM writes...

Actually, I think A-non-y-mous has it backwards. Rimonabant is the antagonist, and Taranabant is the inverse agonist. Also, Merck has been testing Taranabant in Phase III at a far lower dosage than the dose of Rimonabant submitted to the FDA and on sale in Europe. Whether any of this makes a big difference in the side-effect profile remains to be seen.

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13. Jose on February 20, 2008 6:06 PM writes...

A believe "victim" implies not having had a choice in the matter. But, logical consistency might not be a forte for our poster....

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14. NJBiologist on February 20, 2008 8:29 PM writes...

I understand the point about Merck having fallen, but are they really doing that poorly? After all, they came from behind and beat Novartis to market with a DPP-IV inhibitor, and may yet get a CETP inhibitor on the market where Pfizer pfailed.

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15. Eli on February 20, 2008 9:40 PM writes...

Someone needs to explain the difference between what an antagonist does and what an agonist does in vivo - it seems to me that the antagonist is a mere inhibitor, while the agonist works to illicit the opposite pharmacological effect, but how?

Thanks.

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16. srp on February 20, 2008 10:18 PM writes...

If Merck is really a worse place than it used to be, then I would shed no tears for a declining reputation--that's an important disciplinary device. To the extent that the reputation hit is undeserved, it is sad, but problably far from fatal.

When you say "Exxon" all kinds of negative associations are stirred up in much of the public, and they certainly have a reputation for "arrogance" vis a vis critics, but Exxon has continued to be the best-managed, most technologically progressive firm in the oil industry, and they have not suffered on their income statement or in the stock market.

Popularity is overrated, if you can get used to being unpopular. If you think everyone still loves you when in fact they don't, though, you could make some bad decisions. I suspect that's the biggest risk for Merck. Their hardball strategy of fighting the Vioxx suits seriatim instead of instantly settling suggests, however, that they may have avoided that risk.

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17. weirdo on February 20, 2008 11:15 PM writes...

Eli:

An agonist is a molecule that activates a receptor to do its "normal" action. (Confusingly, sometimes that means blocking some effect, but whatever).

An antagonist, simply, blocks the action of an agonist.

An inverse agonist not only blocks the action of an agonist, but also blocks any constituitive activity of a receptor. Hence, it does the opposite of an agonist -- "inverse agonist". Some people believe this to be, in many cases, an artefact of recombinant in vitro systems. But clearly, there are some receptors that have constituitive activity in vivo.

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18. Eli on February 21, 2008 8:15 AM writes...

A dual comment:

Weirdo: Thanks for the explanation - THC is the agonist and taranabant (supposedly) is the exact opposite of it?

Srp: Exxon can afford to be unpopular because we have no power over whether or not to use their products - they'll do what they do and we can't stop them. You can stop buying gas at Exxon, but they are so entrenched, that it makes little difference. Oil products are like an orgy in that way. The big difference between the two companies is that at the end of the day, Merck is in the people business, and there is a healthy bit of competition. Sure if they make a "miracle drug" it would help, but if people think they are the devil, doctors and patients would probably go out of their way to avoid their products, no? Also, "miracle drug" is a b.s. pipedream - everything is eventually toxic at some level.


This blog is the greatest.

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19. I hate to be picky but....... on February 21, 2008 10:07 AM writes...

Taranabant and a-non-y-mous:
Rimonabant is an inverse agonist in recombinant systems (see PNAS 2007 Dec 18;104(51):20588-93)
It is also not particularly specific; it is an antagonist/inverse agonist at the closely related GPR55 (see Proc Natl Acad Sci U S A. 2008 Feb 8; [Epub ahead of print]. Merck's Taranabant may be alot cleaner and may therefore have a better safety/side effect profile.

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20. been there on February 21, 2008 7:27 PM writes...

With all due respect to those who have been harmed from cox-2 inhibitors... consider a contrarian point-of-view i.e., there is a preponderance of evidence (clinical etc) supporting the notion that the selective and potent inhibition of cox-2 is, for some folks, a highly safe & effective means of combating inflammation.

The fact that an army of litigators could not prevail against such an easy target i.e., the "Evil Empire" that is Big Pharma Merck, speaks volumes about any alleged negligence on the part of Merck. Why those compounds were being given out like candy is deserving of its own commentary.

I respectfully disagree with Derek re Merck losing its reputation; the rapid development & approval of Januvia and Janumet again speaks volumes, especially in the current FDA climate. In case you are wondering, I have never worked for Merck although I have competed against them. In my opinion their R&D remains something to emulate. I can't speak for their marketing & sales, though I suspect that is where their recent troubles have originated; to be fair, I could be completely wrong about that. One thing that always puzzled me was the Rosetta purchase many years ago. At the time it seemed to me they paid way too much; it still does.

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