Straight story on Vytorin Cholesterol trials? Fat Chance

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  • 11/26/2007
Here's the right question to ask: Would Merck and Schering-Plough knowingly try to cover up data about their drugs? The logical answer is no. Are delays common in producing results. Yes. Have some of the people that Matt Herper and Alex Berenson been involved in scrubbing or tossing out or re-analyzing clinical trial data? Yes. Must we remind the MSM about Nissen's role in the Atherogenics trial or Matt's coverage of that story?

Well here goes:

But AGI-1067 has been dogged by controversy ever since AtheroGenics released interim results from a phase II study known as CART 2 in late September. While AtheroGenics claimed that the interim analysis was positive, critics charged the company with manipulating results in the drug's favor. It was hoped that final data from the CART 2 study would settle the argument.

Data Are Final, but There's More Debate

Monday, those final CART 2 study results were made public, but it doesn't appear as if the controversy over AGI-1067 will subside any time soon.

AtheroGenics said that AGI-1067 was able to reduce the level of arterial plaque by an average of 2.3% over 12 months, a statistically significant amount when compared with the patients' own baseline measurements. Patients in the placebo arm of the study saw only 0.8% reduction in their plaque levels from baseline.

While patients taking AGI-1067 did better than patients in the placebo arm of the study, the relative benefit between the two groups was not statistically significant, AtheroGenics said.

Furthermore, the data from the final analysis were worse than what was reported previously. In the interim analysis, conducted on fewer patients, AGI-1067 produced a 3.8% reduction in arterial plaque.

AtheroGenics said that treatment with AGI-1067 also produced a statistically significant reduction in levels of myeloperoxidase (MPO), an inflammatory biomarker that correlates with future cardiovascular events. High levels of MPO have been linked to increased risk of heart attack, the company said.

But the company did not present any data linking AGI-1067 to reductions in C-reactive protein, a much more widely recognized clinical biomarker for inflammation and cardiovascular risk.

As with the interim analysis, the final analysis was conducted at two leading hospitals -- Montreal Heart Institute and the Cleveland Clinic. The confirmatory analysis conducted by the Cleveland Clinic, not prespecified in the study's protocol, was one of the reasons some critics felt the AGI-10687 data were misleading, especially because doctors at Cleveland Clinic eliminated some patients from the study because their arterial scans were not readable.

In September, Dr. Steven Nissen of the Cleveland Clinic defended his role in analyzing AGI-1067, calling the drug promising if data could be verified in a late-stage study. But Dr. Eric Topol, another leading cardiologist from the Cleveland Clinic, criticized AtheroGenics and the way CART 2 data were analyzed.

There was no comment Monday from Nissen in AtheroGenics' press release and he was missing from the company's conference call. But Dr. Jean Claude Tardif of Montreal Heart, the lead investigator in the CART 2 study, was supportive.

Here's how Herper handled the Nissen involvement in the Atherogenics trial

AtheroGenics first rose to prominence by touting AGI-1067 as a treatment for inflammation of the arteries. The small biotech rushed into its late-stage study, at a cost of more than $40 million, to try to prove the drug reduced heart attacks, strokes, deaths and surgical procedures.

"But the company badly handled its midstage data, eroding investors' trust. One study, called CART-2, was designed to show that AGI-1067 prevented the buildup of cholesterol plaque in the arteries, as measured by an ultrasound probe. For some reason, Medford and his team were troubled by the results.

AtheroGenics brought in a second scientist, Steven Nissen of the Cleveland Clinic, to do a new analysis of the data. Nissen's analysis seemed to show that the drug worked at clearing out artery plaque, but an analysis by Jean-Claude Tardif of the Montreal Heart Institute, who collected the ultrasound data, was inconclusive."

As for Berenson who quoted Nissen and Psaty who was rebuked by NCI for scaring people about the cancer risks of calcium channel blockers, the failure to handle the difficulties about conducting randomized clinical trials with all the scans, blood samples, etc and then adding in a comparative element, well....par for the course. At least this garbage is now in the business section.

But all this speaks to is the pressure to sell papers rather than report on "boring" science.The Atherogenics data could use some re-analysis of subpopulations but when you are trying to be a blockbuster you try to be all things to all people and wind up showing no difference.

So in the end the real story is the limited value of randomized clinical trials in an era of personalized medicine. That's not sexy cause it's science and doesn't have good guys or bad guys or advance Nissen's career. But it's closer to the truth. Which is often boring.

Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.

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