Merck Cholesterol Pill Passes A Big Hurdle
10 CommentsBy Ed Silverman // November 17th, 2010 // 9:40 am
One of the most closely watched drug development stories just got a little more interesting. A study of 1,623 people with coronary heart disease or an equivalent risk found that a new pill from Merck - which is called anacetrapib - lowered LDL, which is bad choleserol, while also raising HDL, so-called good cholesterol, to impressive levels.
At 24 weeks, the pill decreased LDL by 40 percent and increased HDL by 138 percent in patients already treated with a statin. And there were no significant differences from placebo in the primary safety measures studied, such as blood pressure. The pre-specified adjudicated cardiovascular endpoints were defined as cardiovascular death, myocardial infarction, unstable angina or stroke, occurred in 16 patients treated with anacetrapib, or 2 percent, compared with 21 people on placebo, or 2.6 percent (see the Merck statement and complete study results in The New England Journal of Medicine).
The findings, which were presented this morning at the annual American Heart Association meeting, are significant for several reasons. For Merck, of course, this is a rare bit of good news, given that its cardiovascular franchise has been hurt over the past couple of years by the Vytorin scandal (recent background) and FDA rejection of an earlier cholesterol pill called Cordaptive (see this).
Moreover, the new Merck pill is a CETP-inhibitor, the same type of drug that Pfizer was developing a few years ago before it crashed and burned among data that unexpectedly caused several deaths and cast a pall over the wisdom of plowing valuable research dollars into developing similar drugs (back story). Both Merck and Roche, however, persisted (Roche has not yet released clinical results). The Merck data revealed no changes in levels of the aldosterone hormone, which may have caused problems with Pfizer’s drug, prompting suggestions CETP-inhibitors may become bigger than statins.
“If what we are seeing now is born out in larger studies, this could be the next big thing that could benefit hundreds of millions of people,” Christopher Cannon, the lead researcher and a cardiologist at Brigham and Women’s Hospital in Boston, tells Bloomberg News at the AHA meeting. “The bad cholesterol goes down to the level you are born with and good cholesterol gets up to twice what you are born with. This is totally unprecedented territory.”
The key phrase, however, is if the same results are ‘born out in larger studies.’ As always, enthusiasm must give way to evidence.
EddieVos
A quick P value for clinical benefit is 0.66, not 0.4 as promoted. The P for deaths 0.5 is correct. Wow!! Where can I get the stuff??
Another tidbit: Oxford’s pharma contracting arm just announced it’s getting another near 100 million pounds from Merck to do a massive anacetrapib trial [current total for the Oxford contractors from Merck is 1/4b$ for cholesterol lowering studies.
The truly curious fact is that they will piggyback the Merck -cetrapib onto lipitor, a Pfizer drug. So, Merck’s paying the bill and “to control LDL cholesterol” they use Pfizer’s statin. The trial is called the REVEAL trial.
contact: press.office@admin.ox.ac.uk
Insider: what do YOU make of this?
industry insider
Eddie, I have never been a strong believer in the HDL hypothesis. Epidemiologically there may be a protective role for higher HDL and even a beneficial role for raising HDL in diabetics who get severe atherosclerosis, but you don’t need the double whammy of a statin and a CETP inhibitor. Niacin or a fibrate will do the job just fine.
To me it’s a moot point. I don’t think that this drug will ever meet the requirements for both efficacy and safety of a combination product: 1) that the combo is more effective than the individual components and 2) the combo is no worse than the individual compaonenents safety wise. I think that the hurdle is insurmountable.
EddieVos
Insider, I totally agree. Not only that, 18% was kicked out because of LDL <25, a level I believe incompatible with long term healthy life.
I take flush type niacin for many reasons, none established with great certainty.
Merck is banking ~$m130 on that Oxford trial since at n=30,000 even the smallest ‘benefit’ becomes significant, or deadly. Why atorva in a Merck trial?
Re fibrate: it’s a killer drug without mortality benefit so for once, we disagree!
HDL is a particle in which over 80 proteins have been detected presumably most with happy roles so I think a good level of HDL is a health benefit. E.
Condor
Most importantly, here Merck’s discussant at AHA this morning used a “smokin’ hot” photo of Ms. Eva Mendes (in only a black lace bra, no less!), in his slides, to make the point about how small changes in molecules make big differences — in results. So true. Do click the link!
Now, should we call it Vytorin® 2.0?
That is what the Motley Fool just called it.
Why?
Because 30,000 patients will take perhaps 8 years to reach the event driven endpoint. That makes it much like Vytorin/Zetia’s IMPROVE-IT trial. So, look for revenue (if at all) after 2018 at Merck, in my estimation.
Don’t get me wrong, this safety signal is good news, it is simply the case that way too many otherwise level-headed science writers have “caught the vapors” — about Merck’s Anacetrapib — this CETP inhibitor candidate.
Namaste
industry insider
I would have killed this drug the minute Zocor went generic. Knowledege of CETP has been around for at least 40-50 years (used to be known as LCAT [lecithin cholesterol acyl transferase] or ACAT [Acyl CoA acyl transferase]. Knowing the old guard at Merck and their expertise in developing and commercializing enzyme inhibitors, I would guess that this project’s tires have been kicked around more than a few times. You won’t be able to sell this product into a genericized statin market, except for the few hundred patients with Tangier Disease (congenital HDL deficiency).
M Helm, MD
I’m skeptical that there will be benefit shown. Sure there are improvement in lab values, and no immediate serious indication of problems. Still there is no guarantee that problems won’t appear in the longer term (I’d be particularly concerned about neurologic problems - esp. Parkinson’s).
Additionally, the exact nature of what causes the statins to have benefits for long-term CV event reduction are not really known. The drugs that confer benefits have potent antioxidant, anti-proliferative and other direct effects. These effects correlate with potency in LDL reduction of the available products. I can’t recall how cerivastatin which lowered LDL like nothing else compared to other statins on the antioxidant, anti-proliferative and other effects.
I predict that if this “new” class doesn’t prove to have anti-oxidant and anti-proliferative effects that the real benefit (CV event reduction) will not equal what the statins already offer (regardless of how much they can monkey with the cholesterol particle markers).
If it takes 8 years to have real outcomes data, I would say this product won’t really be ready for “prime-time” until after real world comparative effectiveness trials are completed, published, and sufficient paitents have been treated for a sufficient duration to detect all of the unrecognized problems. That could be a long time.
Still, I wish them luck.
EddieVos
Dr Helm, it was all a dream after all, a reporting benefit only. Statins imitate nitroglycerin. This makes red cells and arterial walls more compliant, clotting a little less excessive and heart attacks a little less noticeable in patients and therefore, de toute évidence, in clinical studies and thereby turning it into a marketing miracle. The combined p values are tiny as are the Absolute Risk reductions while effectively nobody lives longer.
Evidently, when statins have never extended the lives of older men or of a woman of any age, we are dealing with a useless family of drugs, diverting our attention from the real causes of arterial decline. The bulk of the benefit in most trials was in interventions not done and in non fatal anything.
Ceriva was simply mg for mg the most powerful statin and that was its demise;, it worked too well, cutting most of the root system and skinning the bark of the mevalonate biochemical tree. Biochemistry 101.
Condor
“From the sublime to the ridiculous,” then gentlemen:
It seems Merck has “censored” Dr. Thomas Lüescher’s AHA-presented DEFINE results discussant slide deck of yesterday!!!
Don’t leap out of your seat, just yet, though — Merck removed a rather racy “black-lace bra (only)” image — of the lovely Ms. Eva Mendes — from his slides.
Can anyone ID the other “gentleman” Dr. Lüescher depicted — the one giving the middle finger salute (it is not Enrico, FYI!)?
It’s a trivia contest — do go take a guess!
First correct answer in my comment box wins. . . sumthin’ fabulous! Have at it!
Heh! [I actually have no problem -- at all --with the original slide (assuming Ms. Mendes cleared the use of her image in that way).]
Namaste
EddieVos
Insider you said: “I would have killed this drug the minute Zocor went generic. That is what Merck did with lovastatin / Mevacor in most of the western world when Zocor became their on-patent higher profit drug.
Try and get a prescription for lovastatin in most European countries [U.K., Holland, other] … My guess, it’s buried in the shallow grave near head office with some of the EXCEL trial authors. That was the trial halted in the nick of time [p=0.11] before excess mortality became significant.
As one author said: mortality, what mortality? We proved lovastatin does not cause eye damage and is well tolerated.
Then again, the brilliant beauty of statins has made many a proponent go blind in the process.
roger coutts
send me any information on this pill. it is interesting to me.