The cloud hanging over Merck & Co and Schering-Plough’s Vytorin has darkened after the firms released information on a long-delayed study which shows that their blockbuster combination cholesterol treatment is no more effective than Zocor.

The ENHANCE study involved 720 patients with heterozygous familial hypercholesterolemia, a rare condition, and the data demonstrate no “statistically significant difference'' in slowing the progression of atherosclerosis between those on Vytorin (10mg ezetimibe + 80mg simvastatin) versus the now-genericised Zocor (simvastatin 80mg) alone. However it did find a significant difference' in ‘bad’ low-density lipoprotein cholesterol among Vytorin patients and those on simvastatin (58% versus 41%).

The study has been mired in controversy for some time. ENHANCE was actually completed in April 2006 and the long delay before publication has led to raised eyebrows among some observers who feel the firms had something to hide. Furthermore, in November, Merck and S-P announced plans to narrow the trial's primary endpoint as a result of “technical difficulties”, though they did a U-turn following criticism that the changing of endpoints was a breach of scientific protocol.

Vytorin, which combines Zetia (ezetimibe) is a $5 billion-a-year drug and vital to the fortunes of both firms, especially S-P. as It was first approved by the US Food and Drug Administration in July 2004, but was regarded with suspicion by some cardiologists due to the lack of long-term outcomes data.

Now that some data has come out, the critics of Vytorin are once again queuing up. Steven Nissen, chairman of cardiology at the Cleveland Clinic, told The Washington Post that “this wraps it up. That's all there is. There just isn't any evidence that adding ezetimibe to simvastatin produces any advantage."

The ENHANCE trial has also caught the eye of Congressmen John Dingell, Chairman of the Committee on Energy and Commerce, and Bart Stupak, Chairman of the Subcommittee on Oversight and Investigations, who have been investigating the case since the primary endpoint U-turn in November.

Congressmen suspicious
They said the announcement that the Enhance study “failed to find any positive benefit from the addition of Zetia to a common, inexpensive, generic therapy raises concerns that attempts were made to mask the minimal value of this new drug”. Rep Dingell added that Merck and S-P’s delay in releasing study results, “as well as their attempt to manipulate the data is, quite frankly, suspicious”. Rep Stupak went on: “It’s currently unclear whether these companies knew that adding a new expensive drug accomplished nothing more than an established, cheaper, generic. But it is clear that our investigation is far from over”.

Analyst at Merrill Lynch were also unimpressed and downgraded their rating on S-P to ‘neutral’ from ‘buy’. In a research note, they said: “We anticipate further pressure on Vytorin and Zetia prescription trends. We do not see S-Pl stock as a ‘buy' when the momentum of the key financial driver is uncertain''.

Investors are not impressed either. Merck shares ended the day down nearly 1.3% at $59.78 while S-P was down almost 8% at $25.52.