Vytorin Trial Misses Goal & Shows Cancer Risk
15 CommentsBy Ed Silverman // July 21st, 2008 // 1:56 pm
The so-called SEAS trial of 1,873 patients unexpectedly suggests an increase in cancer among those on the controversial cholesterol drug - 39 on Vytorin compared with 23 on placebo, according to researchers who presented their findings today. Want to watch the replay? Then click here.
This was a “disturbing finding,” says Terje Pedersen of Ulleval University Hospital in Oslo, Norway, the lead researcher, although he stressed the trial involved a small number of patients and the findings could have been due to chance. In other words, it may not be conclusive. Here is the official release.
In fact, the investigators say two larger, ongoing Vytorin trials - the SHARP and IMPROVE-IT trials with more than 20,000 patients combined - so far haven’t shown such a risk. “There is no good, no credible evidence, when you look at these studies, of an increased risk of cancer,” says Richard Peto, professor of medical statistics and epidemiology and co-director of the clinical trials service unit, University of Oxford.
“This is a rather bizarre hypothesis…What matters is that we have drugs that seriously lower cholesterol…” Peto continued, noting that he compared data from all three trials. “Again, they do not confirm the hypothesis that treatment increases the overall risk of getting cancer. The SEAS, SHARP and IMPROVE-IT trials do not provide any credible evidence of developing cancer.”
The Data Monitoring Committee unanimously supports Peto’s conclusion. The results, by the way, have been provided to regulators, according to Peto.
Beyond this sobering news, the cholesterol med failed to meet the main goal of improving cardiovascular outcomes for patients with aortic stenosis, which is an irregular thickening of the main valve to the aorta. No significant difference was seen between the patients who received Vytorin and those who received a placebo.
However, the drug did meet a secondary goal - there was a statistically significant 22 percent reduction in non-fatal heart attacks and coronary artery bypass surgery. And Vytorin patients also had much lower LDL than patients on placebo. The trial was designed to determine whether aggressive cholesterol lowering can lessen the need for surgical replacement of aortic valves, reduce cardiac death and reduce cardiovascular events, including heart attacks.
In an investor note this afternoon, Wachovia Capital Markets analyst Larry Biegelsen writes: “Although the increase in cancer risk may have been due to chance and this outcome has not been seen with other ongoing Vytorin trials, we think the media and competition will likely highlight this risk which could put additional downward pressure on Zetia and Vytorin prescriptions.”
“As scary as this sounds, the truth of the matter is that it is likely a red herring,” writes Sanford Bernstein analyst Tim Anderson in his own investor note. “There is no plausible mechanism by which Vytorin should cause this, and analyses of other, larger ongoing trials (i.e. SHARP and IMPROVE-IT) shows no link.” He adds that Merck and Schering-Plough can now claim to have “at least semblance of outcomes data, although he concedes how much comes from Zocor versus Zetia is unclear.
CV MD
I’m not sure how anything important can be coming out of the IMPROVE-IT experience at this point. Just how many of the total patients are enrolled? Also, how many patient years of exposure exist in that trial? However many are in, they cannot average much more than 6 months. SEAS was a longer trial. In addition, if I remember correctly, SHARP is in another specialized population - patients with renal disease. Will it be three strikes and you’re out? Or will they get an extra pitch come 2012-2014? Will MSP provide any update on when they project results from IMPROVE-IT will be known?
Paul G
“Vytorin was significantly better than placebo in reducing atherosclerotic events, defined as non-fatal heart attacks, need for coronary artery bypass surgery or artery-clearing procedures, hospitalization due to chest pain and strokes.”
Practicing MD
So! What’s your point? Vytorin beat placebo for CV events. That’s because simvastatin is the active ingredient! And it can be had for pennies a day!
Big Pharma Guy
Let’s see - cancers up by 50%. What was the percent reduction in CV events? What was the overall benefit if you take all serious consequences into consideration? Please -can we have the whole story?
Jeffrey Clark, CEO of Beaker.com - The Online Community for Life Sciences Professionals
Merck & Schering Plough can’t seem to get out of their own way with this one. Even if they can justify its benefit & mitigate its risks, they are losing the PR battle with doctors, patients and the general public.
If you understand the power of direct-to-consumer marketing, you probably also understand that negative news works in exactly the same way.
LeftPharma
“Vytorin was significantly better than placebo in reducing atherosclerotic events, defined as non-fatal heart attacks, need for coronary artery bypass surgery or artery-clearing procedures, hospitalization due to chest pain and strokes.”
Don’t we have a far more cost effective class that accomplishes this?
Hint: One example is the half of Vytorin that’s not ezetimibe.
Reality Bites
One word for Merck and Schering-Plough - disasterous!
Bad News
Cancer man! We’re talking cancer man! Cancer incidence was up 43%. Cancer deaths were up 69%. CV events down 22%. if you look at all the numbers in the trial for overall benefit/risk, less than 12 patients did better with Vytorin in an almost 1900 patient trial in which patients were foillowed for four years. Bad, really bad!
Day Trader
Cancer concerns came up with pravastatin some time ago and no causal relationship was ever determined. Considering that the other Vytorin trials aren’t showing increased incidence of cancer, it’s reasonable to conclude that the cancer rates were not drug related. As for the other data, the drug lowers cholesterol as it is indicated to do and prevented heart attacks in a sick population. This does not spell disaster for MSP but it gives their competitors something to distract physicians with… Remember, lipitor showed no benefit over placebo in post-menopausal women’s CIMT nor did it show any benefit over placebo in aortic stenosis. No-one ever speaks to these concerns about Pfizer’s blockbuster medication… Bias against Merck, perhaps?
Justice in MI
Does anyone now see a pt. population for which Vytorin would make sense, even as third line, _at this time_?
Insider
I wonder if SP will apply for a pediatrics licence?
Lisa Van S
Geee, This surprises’ folks!!!!
Ron Kavanagh
In contrast to what Dr. Peto says I do not believe that inducing cancer is a ‘bizarre hypothesis’. In fact I believe that there may be a biologically plausible mechanism that also may underlie those aspects of FDA’s critical path initiative and personalized medicine being used for treating or preventing cancer. The problem is that the possible mechanism can cut both ways and is one of the problems with using biomarkers for many drugs. Another problem is that it may be a factor with other drugs or drug classes. (N.B. people with many forms of severe mental illness have high comorbidity of diabetes, lipid disorders, and cardiovascular disease, yet low incidences of cancer.) Having said that either statistical variability, population size or differences in patient populations (e.g. genetics) might also underlie differences between trials.
Big Pharma Guy makes a valid point and is the first thing I would look at, what is the net effect. Unfortunately based on what Bad News says, prima facies it appears that the net effect is not to Schering’s advantage.
I hope that subgroup analysis is performed. In addition an examination of genetics, drug metabolites, and their effects on various receptors that might be involved, as well as possible drug interactions are also looked into.
This is what FDA calls a signal for a serious risk.
Ron Kavanagh
Piper
Regarding the pediatrics question - both Zetia and Vytorin were approved for pediatric use last month….
Unsupported Opinion
It is my understanding that some scientists believe that high levels of cholesterol serve to block the development of cancer. If that is true it might stand to reason that a drug, such as vytorin, that radically reduces cholesterol levels, may give rise to the development of cancer by reducing the blocking agent. Admittedly, this is pure speculation, but it may be worthy of scientific inquiry.