Cholesterol Drug Trial Results Mean Bad News for Schering-Plough, Merck

Merck (MRK) and Schering-Plough (SGP) have released the data on a study of genetically high-LDL patients taking a statin alone (Zocor, simvastatin) or the combination of the statin and Schering-Plough's cholesterol absorption inhibitor (Vytorin, simvastatin and ezetimibe). Vytorin has a good share of the market, and has already been shown to lower cholesterol.

And so it did this time: the Vytorin patients showed a 58% decrease in LDL, while the Zocor group showed a 41% reduction. But this trial went further, looking at the growth of atherosclerotic plaques. You'd figure that a greater decrease in LDL would mean a greater decrease in the size and growth of plaques.

You'd be wrong. The Vytorin group's carotid arteries, measured in a standard way (intima-medial thickness, IMT) came out as 0.0111 mm, while the Zocor group's came out as 0.0058 mm. This is making the headlines as "twice as bad as Zocor", but the difference actually isn't statistically significant (p = 0.29). Steve Nissen of the Cleveland Clinic is quoted as saying that this is "as bad a result for the drug as anybody could have feared", but that's not quite right. If that p value had been, say, 0.01, that would be worse. Strictly speaking, you can't call the two groups different. They don't seem to have been different in cardiovascular outcomes.

But here's the real point: that's bad enough. The whole point of Vytorin is that it's supposed to be more effective than a statin alone, and what you can say about this trial is that it sure didn't prove that. But that carotid artery thickness is definitely a concern - the numbers appear to have big error bars on them, but they're certainly not pointing in a good direction. And it's going to be difficult, perhaps impossible, to ever know if that effect is real, because it'll be mighty hard to get another trial of this sort off the ground after results like this. How can you enroll a treatment group for a drug that has been shown to have no benefit?

Well, OK, there's that LDL reduction. But the downstream clinical data (the artery measurements and outcomes) overrule that. The point of taking a cholesterol medication is not to make your lab test numbers go up and down, the point is to have fewer heart attacks and strokes. We use those blood lipid numbers as a convenient surrogate, but it's been obvious for a long time now that we have, to put it delicately, an imperfect understanding of their relevance. Data closer to real mortality and morbidity outcomes will win.

Now what? This is clearly terrible news for Merck and (especially) for Schering Plough. The companies already were under pressure for having taken so long to work up the data for this trial, which delay ended up just drawing even more attention to these bad results. Now, how do you go out and sell Vytorin (or Zetia, the cholesterol absorption inhibitor alone)? Why do insurance companies have motivation to pay for it? And when are we ever going to understand the complexities of human lipid behavior and cardiology?

Comments

[bzshadow]

isis and its lead mipomersen drug are uniquely poised to vill the void left by these failures...

[hmmmmm]

Your article is somewhat imbalanced. This trial is not an outcomes trial as you said early in the piece. The definition of "outcomes" is being used in two different contexts and is confused when the word "outcomes" is mentioned again - "But the downstream clinical data (the artery measurements and outcomes) overrule that." No they don't, at least not yet. The time period was not long enough, there were not enough patients and how can you interpret numbers from this population of cholesterol producers who make cottage cheese for blood to the entire population? You can't.

All of the information is not available as the trial has not been peer reviewed, presented or published. This process is fairly well laid out and will be completed. Scientific discourse should be allowed in this case as well before weighing in and scuttling the whole thing.
We don't even know what the significance of IMT measurements are so to conclude anything from this trial is inappropriate. Does IMT = plaque? (We don't know.) Have there been legitimate outcomes studies with IMT? (Find them.) Are there more than one failed IMT studies out there? (Absolutely)
How can you say there is no benefit to the drug when the LDL's were dropped by 58% and you point out yourself the p value of .01? There is significant data showing the relationship of LDL and cardiac events. I don't think you can settle that this is completely bad info until the rest of the data gets released & reviewed.

It certainly is bad politically for Schering. One might ask more about what is going on behind the scenes? How did this trial get released one day and show up with Katie and the good doctor the next morning? Hmmmmm? Overall, I think there is some strong mischaracterizations here by experts and by writers who do a lot of damage when damage is not warranted.