FDA Reviewer Gives Merck’s Vytorin A Thumbs Up
14 CommentsBy Ed Silverman // October 31st, 2011 // 8:53 am
In what may be an anticlimatic end to a controversy that has hovered over the Vytorin cholesterol pill, an FDA medical reviewer is endorsing the largely positive findings of a study that indicates the drug could be used safetly to treat patients with chronic kidney disease. An FDA advisory committee is scheduled to meet this Wednesday to review the data.
The clinical trial, known as Sharp, found that Vytorin - which combines Zetia and simvastatin, otherwise known as Zocor - reduced the risk of “major vascular events” among adult subjects with CKD, or chronic kidney disease, who did not have a history of myocardial infarction or coronary revascularization by 16 percent compared with a placebo. Merck sells all three meds.
The drugmaker claims by “lowering low density lipoprotein-cholesterol (LDL-C) level, Vytorin is effective in reducing cardiovascular risk in CKD patients. My review of the statistical evidence suggests support for the claim,” writes James Smith, of the Division of Metabolism and Endocrinology Products in the FDA Center for Drug Evaluation and Research, in briefing documents posted on the FDA web site. “However, the treatment effect appears to be heterogeneous among patients with different renal function status…Whether it could be claimed that Vytorin is effective in reducing cardiovascular risk in all patients with CKD is a question up for discussion at the advisory committee meeting.”
There were also no safety matters, particularly regarding cancer, which had been an issue surrounding Vytorin a couple of years ago, when an earlier study suggested a link. Two years ago, the FDA stated an interim finding did not indicate a link existed (read this) and the latest agency review found the incidence rate was 9.4 percent compared with 9.5 percent among those on a placebo (see Table 52 on page 99 of the briefing document). However, there were 18 more deaths resulting from the incidence of cancer in those randomized to Vytorin compared with placebo (see page 100). [You can read the Merck briefing document here and the questions the panel must answer here].
Not surprisingly, the FDA review was interpreted as a plus by one Wall Street analyst. In an investor note this morning, Leerink Swann analyst Seamus Fernandez noted that the key question the agency panel will review is the extent to which Vytorin at 10 to 20 mg is effective in patients before dialysis -where the pill showed a 22 percent drop in major vascular and atherosclerotic events - compared with dialysis patients - where Vytorin showed a 6 percent drop in MVE and 10 percent drop in MAE.
“We believe these data should help lay to rest investor concerns about Vytorin/Zetia’s safety,” he wrote. “We also believe the efficacy data from SHARP strongly suggest that reducing LDL with Vytorin/Zetia is consistent with the efficacy demonstrated with statins over time.” The next key test for Vytorin will be the results of yet another trial called Improve-It that compared the pill with simvastatin. He expects interim results early next year.
The findings, by the way, were published last June (read here), but the FDA endorsement potentially removes a cloud over Merck, which has struggled to overcome the lingering effects of a scandal that have plagued Vytorin research, as well as the competitive threat of generic statins. So far this year, Vytorin sales are down 3 percent compared with a year ago, according to recently released Merck sales data (look here).
Last year, University of Oxford researchers, who were running the Sharp trial, attempted to change the composite endpoint, which would make it easier to show positive results. Merck, however, resisted and both later issued press releases about the favorable results. However, the Oxford researchers caused a flap by trumpeting findings that were skewed - they never mentioned the primary endpoint and compared Vytorin favorably with simvastatin alone, when the trial compared the drug only to a placebo. The ruckus was yet another stain on Vytorin and, by extension, Merck (read here).
You may recall that Merck was at the center of a huge scandal involving a trial called Enhance, which found the costly combination of Zocor and Zetia - which was sold by Schering-Plough, now part of Merck - failed to show a benefit over the much cheaper Zocor in reducing plaque in the carotid artery, and even showed a statistically insignificant buildup, although it did a better job of lowering LDL in patients with an inherited form of high cholesterol. However, the drugmakers delayed releasing the study for nearly two years; never appointed an independent board, and briefly changed the primary endpoint without consulting the key investigator (see this).
thumbs up thx to reid on flickr
Marilyn Mann
The rest of the materials are here:
http://www.fda.gov/AdvisoryCommittees/WhatsNew/default.htm
Angry Pharm.D
What about cancer? what about the negative CIMT data?? This is a bad idea.
Its just one more in a series of dozens of missteps and cases of corruption for Eric Colman and the rest of Division of Metabolism and Endocrinology.
They are either all mental midgets or accepting bribes from Merck.
john
“Two years ago, the FDA stated an interim finding did not indicate a link existed (read this) and the latest agency review found the incidence rate was 9.4 percent compared with 9.5 percent among those on a placebo (see Table 52 on page 99 of the briefing document).”
Marilyn Mann
I am also concerned that there were more cancer deaths in the Vytorin group.
Moreover, there is no way of knowing what ezetimibe contributed to the result. The entire benefit could have been due to the simvastatin.
Angry Pharm.D
“I am also concerned that there were more cancer deaths in the Vytorin group.”
–very unlikely. no other study with simvastatin has shown a cancer risk to the best of my knowledge…..
Marilyn Mann
@Angry Pharm.D Vytorin also contains ezetimibe, so it could be due to the ezetimibe. As you know, the SEAS trial had an excess of cancer cases and cancer deaths in the Vytorin group.
Angry Pharm.D
…right…I mis-wrote….I blame ezetimibe too.
Ezetimibe is a BS drug and the efficacy data sucks. Additionally, the cancer data really shouldn’t be ignored.
I sometimes think management at the FDA was bribed to let this continue on. If you think about it, giving away an extra 1-2 million in cash under the table to an to a few key corrupt indivduals like FDA eric colman is chump change for a company like Merck…
alig
What would Zocor alone do in these patients?
Marilyn Mann
@alig Zocor (simvastatin) would be expected to do about the same.
original industry insider
I’m a dinosaur, I admit, but if you want a fairly effective and safe, non-absorbable cholesterol lowering drug that admittedly tastes like liquid chalk but that you can safely take with a statin I favor simvastain plus cholestyramine, or any other bile acid binding resin. As long as you’re aware of its effects of absorption of other drugs, “liquichalk” isn’t bad. I’ve tried it myself, flavored with a bit of Hershey’s syrup.
NotSoAngryMD
@Angry PharmD. I’m a nephrologist, and frankly it’s a bit encouraging to see that the SHARP results were positive for at least SOME outcome after the failures of 4D and AURORA. Agree that we can’t say anything about ezetimibe from SHARP, although the FDA is saying exactly the same thing…at least in that review. Our guidelines currently suggest treating to LDL goal < 100, but we haven’t had any data to suggest whether that’s worthwhile. If I can prevent a stroke, trips to the cath lab, or maybe a nonfatal MI in some of my patients, I’ll take it. I don’t care that they don’t show a mortality benefit. Morbidity is important, too.
I don’t think SHARP will change my practice. I’ll continue using statins despite what the Merck drug reps will start saying if they gain approval. But I don’t think it’s the place of the FDA to get involved in comparative effectiveness research or guideline development either. It seems they’re evaluating whether Vytorin beats placebo, and it seems that it does. My patients have been excluded from most large statin trials in the past, so I’m personally relieved that we finally have a bit of evidence to back our current practice.
As for Vytorin, the IMPROVE-IT trial will certainly be interesting. From my point of view, however, I do run into problems sometimes when I escalate statin doses in my patients with renal disease…so it certainly would be nice if the LDL hypothesis is correct and ezetimibe is doing something. I could get away with less statin & still get adequate LDL reduction. SHARP at least suggests, to me at least, that my patients aren’t going to be dropping like flies from rhabdo, liver problems, etc. *IF* I chose to use Vytorin.
As for the cancer stuff, the essentially equal incidence of cancer (in fact, the very slight imbalance was in the placebo group) is pretty reassuring. The imbalance of cancer deaths is less meaningful to me since I think that would be hard to define…I mean, really, if my patient has advanced colon cancer, gets malnourished, then gets influenza followed by pneumonia and dies, is that a cancer death? Who the hell knows. Maybe it was, maybe it wasn’t. I don’t see how the adjudicators could determine that stuff. DIAGNOSIS of cancer, however, seems much easier to determine.
Just my 2 cents. I’m not going to start prescribing Vytorin, but it seems this IS reassuring. At least placebo didn’t do worse than Vytorin. ;)
Angry Pharm.D
@NotSoAngryMD: Thanks for your reply, but I do disagree with several points you made:
“It seems they’re evaluating whether Vytorin beats placebo”
“At least placebo didn’t do worse than Vytorin. ;)”
–Surely you dont agree that its ethical to compare eze to pbo in light of the available LDL lowering data in statins! Do you think it is appropriate therapy to kick existing lipid patients off of statin therapy so they can be part of the placebo group in an ezetimibe trial? I’m sure Merck and the FDA believe its OK, but I dont!!
“Our guidelines currently suggest treating to LDL goal < 100…”
what about CARDS PROVE-T and ALLHAT-LLA and LDL’s of 100mg/dL They said it gave additional benefit. Very few patients will even meet goal, let alone exceed it on eze therapy, and chances are they could be give a 4-dollar-a-month statin for that. eze is lots more $$
I hear you re: renal disease, but you can still give low-dose statins in that population, and one cant really challenge outcomes data for drugs like atorva.
Also: you reply conspicuously omits the whole efficacy/negative CIMT data associated with the achieved LDL lowering. That’s kind of the whole idea here…
Just wondering: are your initials J.S.? Dont worry; I wont tell!! :)
NotSoAngryMD
Re: ethical. In the general population, no. In the advanced CKD/ESRD population, yes. At the time SHARP, 4D, and AURORA were being planned, there was no evidence that lipid-lowering helped these folks, they die of heart failure & sudden death primarily, they have vessels that are calcified as hell (instead of shaggy atherosclerotic things), etc. Lots of reasons to think that statins may not work in them….and then when 4D and AURORA were published, it seemed that they may not! So, while I completely agree with you that statins are the go-to therapy for the general population, I disagree that it was obvious that they would work in the advanced CKD/ESRD population.
CARDS excluded Cr > 1.7. PROVE-IT excluded Cr >= 2.0. ALLHAT-LLA excluded Cr > 2.0…and on and on. Even the trials that DIDN’T exclude based on Cr criteria - few and far between…TNT comes to mind…didn’t ENROLL patients with this degree of renal insufficiency. TNT had no Cr cutoff, but only 29 patients had an eGFR < 30.
Agree with the concern about the negative ENHANCE data…but there are plausible reasons.
I don’t know what you’re referring to with regard to J.S., but no, they’re not.
NotSoAngryMD
ha, i just figured out the J.S. thing. Took me a few minutes and had to re-read the article as I sat here puzzled. No, no, no. Just a nephrologist who is contemplating a move to industry and spent some time doing lipid research, so i find this stuff interesting.