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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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October 16, 2013

The First PCSK9 Phase III

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Posted by Derek

Some long-awaited clinical data has appeared in the cardiovascular area: Sanofi and Regeneron have the first Phase III numbers for their PCSK9-blocking antibody alirocumab. (Here's some background on this area from John LaMattina).

This was a monotherapy trial, run head-to-head against Merck/Schering-Plough's Zetia (ezetimibe). Patients in the alirocumab arm started at a low dose, injected every two weeks, and had to the option to increase it if their LDL had not hit the target levels. Three quarters of them didn't have to. Their LDL levels went down 47% on average, compared to 15.6% in the daily Zetia group, so I think we can call that one a solid success. There are other Phase III trials ongoing in different patient populations and with different regimens (for example, taking alirocumab along with a statin), but these results bode well. No significant toxicity has been observed, which, needless to say, also bodes well.

That's the thing to watch. This is a new mechanism of action, and if there's one thing that the history of drug discovery tells us, it's that we don't know as much as we need to about mechanisms of action (both good and bad). It's good news that PCSK9-blocking therapies have been as clean as they have so far, but everyone in the field (Amgen is right behind Sanofi and Regeneron, and others are behind them) will be scrutinizing the data closely as more and more patient reports come in. These drugs could be used very widely indeed, and for many years at a time, so it's important to look for all sorts of things that might be down in the weeds. But so far, so good.

Comments (6) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials


1. anon-ymous(e) on October 16, 2013 6:55 PM writes...

Fabulous LDL lowering!!!! That said, it will be a fascinating exercise in drug discovery/pharmacology/human health improvement to see whether PCSK9 inhibition improves cardiovascular morbidity and mortality (i.e., CV outcomes). I can't wait (but will have to for a long time I guess) !! IF (and I repeat IF) it does NOT, strike another one for (those dirty???) statins. Science, not to mention drug discovery, is so very cool (yes, despite all the extraneous B-llsh-t).

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2. william check on October 16, 2013 10:08 PM writes...

zetia is not used as monotherapy. it is used along with simvastatin in combination (vytorin). I don't think we can assume that PCSK9 plus a statin will be superior to zetia plus a statin based on the monotherapy results. in fact, I wonder why the trial was designed this way. i'm waiting to see combination results. or even PCSK9 vs. atorvastatin, which can exceed this degree of lowering, depending on dose (as do high doses of other statins).

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3. ScientistSailor on October 16, 2013 10:22 PM writes...

#1 is right, lowering LDL is great, but not sufficient to improve outcomes. I'll not be holding my breath...

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4. businessscientist on October 17, 2013 9:47 AM writes...

#2, this trial was designed for patients who can't take statins.

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5. Wake up on October 20, 2013 2:12 AM writes...

And the phase 2 data is already reason to assume it + statin will outperform zetia + statin. Assumptions can be wrong, but plenty of reason to assume in this case.

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6. VA on December 9, 2013 7:06 PM writes...

This product class has a great deal of hype. It has several negatives - injectable which means it will always be 2nd or 3rd line option after orals, small population that can't take stains or are not controlled with other meds, large trials required.

The market projections of $3B seem a little optimistic!

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