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

Derek Lowe The 2002 Model

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

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

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« The Torcetrapib Catastrophe | Main | Bigger And Greasier »

December 4, 2006

Too Near the Sun?

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Posted by Derek

One thing that the Pfizer debacle makes you wonder about is: were they trying too hard? Torcetrapib seems to have done a fine job raising HDL on its own - so it was only natural to think of combining it with an LDL-lowering statin. If it turns out, though, that the fatal problems that have turned up were the result of the combination therapy, what then? Will the story be that Pfizer brought the roof down on itself by trying to extend the profitable lifetime of Lipitor?

It turns out that we can answer that question. What if the compound had been developed by a company that didn't have a statin of its own to promote? We don't have to wonder: that's the situation with the Roche/JTT compound. Roche has no statin in its stable. But when you look at the trials they they've been running, well. . .

. . .patients will be randomized to receive either CETP inhibitor (900mg po) or placebo po daily for 24 weeks, with concomitant atorvastatin 10 to 80 mg daily. . .

. . .This study will evaluate the efficacy and safety of three doses of CETP Inhibitor when co-administered with pravastatin. . .

. . .Patients eligible to participate in the extension study will continue on the treatment they were originally assigned to ie CETP inhibitor (900mg po) or placebo daily, with concomitant daily atorvastatin (10 to 80mg po). . .

So why the constant statin drumbeat? There's actually a good reason. As it happens, monotherapy trials of torcetrapib seemed to show that it could lower LDL a bit on its own - but only in patients without high triglycerides. Unfortunately, most of the patient population for the drug has high triglycerides, so there you are. You could always try to make the argument that HDL elevation alone might be beneficial, but no one's quite sure if that would be enough, especially given that lowered LDL has been shown to be beneficial in cardiac outcomes.

Roche, of course, is at the moment just packed with people who'd like to know what (if anything) there is about the statin/CETP combination that could turn awful. I wonder how long it'll be before we find out?

Comments (10) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Toxicology


1. BCP on December 4, 2006 11:18 PM writes...

Interesting post Derek. The other angle is what are the chances that someone will come in to see their doc and get prescribed a CETP inhibitor, without already being on a statin? Pretty much zero, I'd think. Having a drug to treat low HDL that has a negative interaction with a statin would seem to be a commercial non-starter to me.

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2. Morten on December 5, 2006 8:27 AM writes...

Maybe Pfizer should just cut the whole R&D department and buy whatever new blockbuster patents they need. They are quite effective at shifting pills after all.

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3. burt on December 5, 2006 12:50 PM writes...

"Maybe Pfizer should just cut the whole R&D department and buy whatever new blockbuster patents they need. They are quite effective at shifting pills after all."

I beg to differ. What they need to do is RETAIN the good PEOPLE they buy through acquisition.

Torcetrapib was a train wreck waiting to happen, from the structure. Most people wouldn't dream of proposing, let alone MAKING a compound with NINE fluorine atoms unless it was intended as an anesthetic or an inhibitor of nuclear receptors.

Maybe they never heard of Lipinski? ;)

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4. MolecModeler on December 5, 2006 1:59 PM writes...

Good post Derek.

BTW GSK is having a job/career fair in New Haven, Dec 13-14th. It's at the Omni hotel on 155 Temple St. They're looking for everything.

If you're interested, drop a note here and I can send you more details.

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5. ruth on December 5, 2006 6:44 PM writes...

Sorry this is late, but I want to tell you I'm sorry to hear of the loss of your position.

I'm not a scientist, but I thoroughly enjoy reading your site and want to add that your site has provided a lot guidance to my husband when he finished grad school. It was invaluable to his job search.

I am a firm believer that when one door closes another one opens. Here's to the door opening to a wonderful opportunity for you, Derek.
Best Wishes, Ruth

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6. Anon on December 5, 2006 11:38 PM writes...

Torcetrapib had demonstrated a significant BP elevation in recent studies (if I recall, about 5-6mmHg systolic and 3-4mmHg diastolic). Estimates by some experts suggested that this could translate into a 20-25% increase in stroke and 12-15% increase in overall mortality; perhaps that is the effect seen in this trial (ILLUMINATE). Hopefully Pfizer will be open enough to reveal all the relevant data, in the interests of science.

If the Roche candidate demonstrates any sort of BP elevation, or a hint of something close, I suspect there is going to be some real hesitancy to proceed with further testing.

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7. Kay on December 6, 2006 6:38 AM writes...

I have some slides from LaMattina indicating that it's the most hydrophobic drug they have ever developed. If Pfizer doesn't listen to Lipinski, why should anyone else?

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8. Phil-Z on December 6, 2006 9:13 AM writes...

Kay, One of the reasons is "A prophet is without honor in his own country". It doesn't help that Chris is kind of a troll. He's a hard guy to love, and most of his coworkers kinda rolled their eyes when people started talking about the value of partition coefficients. Their loss.

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9. S Silverstein on December 7, 2006 10:43 AM writes...

Sorry this is late, but I want to tell you I'm sorry to hear of the loss of your position.

For a person who writes as well as Derek, and through that writing exhibits such a superb level of common sense, rational thinking, and an understanding of what's truly strategic in R&D, it is perhaps pathognomonic of the industry's problems that Derek lost his position.

S. Silverstein

(former Director of Published Information Resources & The Merck Index, lost my position in 11/2003. The VP who made that decision, an IT person with no background in biomedicine or science, suffered a non-renewal of contract not long after, and now works in a field closely related to pharmaceutical R&D -- in a computer-game hardware company.

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10. Srikanth on December 7, 2006 5:55 PM writes...

Pfizer will move to far East as it should. Americans cost too much and all you really need is pair of hands to move chemicals around the lab. One big brain comes up with the idea, fifty hands put molecule to together. There are many willing hands in China/India. There is no such thing as 'medicinal chemist'. You have a big problem in america that chemists talk too much, thinking they are biologists. Pfizers drug died by bad ADME, studied by toxicologist/ pharma guys. Chemists did their job, but should not be blamed. They are just humble servants.

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