The Controversial Vytorin Trial Ends In Failure

[Pharma Newshound]

Source: Pharmalot

Since November, Schering-Plough and Merck have scrambled to explain a two-year delay in releasing results of a trial designed to boost the profile of their Vytorin cholesterol med. Meanwhile, the drugmakers took a beating for changing the primary endpoint, failing to include the lead investigator in the decision and a reluctance to name members of an allegedly independent panel to review the data (and it wasn’t really independent, either).

Today, they released the results and the findings are hardly surprising - There was no statistically significant difference between treatment groups on the primary endpoint, including the common carotid artery, according to a statement. And key secondary imaging endpoints showed no statistical difference between treatment groups. The study was designed to determine whether Vytorin - which combines Zetia and Zocor - was more effective in reducing the growth of plaque in blood vessel walls more than Zocor.

Initially, the companies had said they would measure the thickness of plaque in two arteries - the carotid, which runs through the neck and supplies the brain with blood, and the femoral, which runs through the hips and supplies the legs. However, the alleged difficulties in assessing ultrasound techniques and images was the reason given for the delays and change in endpoints. [UPDATE: Cleveland Clinic’s Steve Nissen tells Bloomberg News there should be a moratorium on using Vyotrin: “Compared with generic simvastatin, Vytorin is expensive and it adds no benefits.”]

Known as the Enhance trial, an abstract will presumably be on display at the American College of Cardiology meeting in March. A belated note: There was a consolation prize for the drugmakers - Vytorin did show a statistical difference in lowering LDL, or bad cholesterol.

[Pharma Newshound]

Source: Schering-Plough News Release

Merck/Schering-Plough Pharmaceuticals Provides Results of the ENHANCE Trial

WHITEHOUSE STATION, N.J. & KENILWORTH, N.J.--(BUSINESS WIRE)--Jan. 14, 2007--Merck/Schering-Plough Pharmaceuticals announced today the primary endpoint and other results of the ENHANCE (Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia) trial. Merck/Schering-Plough has submitted an abstract on the ENHANCE trial for presentation at the American College of Cardiology meeting, which will be held in March 2008, and is awaiting notification of acceptance from the College.

ENHANCE was a surrogate endpoint trial conducted in 720 patients with Heterozygous Familial Hypercholesterolemia (HeFH), a rare condition that affects approximately 0.2 percent of the population. All analyses were conducted in accordance with the original statistical analysis plan. The primary endpoint was the mean change in the intima-media thickness (IMT) measured at three sites in the carotid arteries (the right and left common carotid, internal carotid and carotid bulb) between patients treated with ezetimibe/simvastatin 10/80 mg versus patients treated with simvastatin 80 mg alone over a two year period.

There was no statistically significant difference between treatment groups on the primary endpoint. The change from baseline in the mean carotid IMT was 0.0111 mm for the ezetimibe/simvastatin 10/80 mg group versus 0.0058 mm for the simvastatin 80 mg group (p =0.29). At baseline, the mean carotid IMT measurement for ezetimibe/simvastatin was 0.68 mm and for simvastatin 80 mg was 0.69 mm. There was also no statistically significant difference between the treatment groups for each of the components of the primary endpoint, including the common carotid artery. Key secondary imaging endpoints showed no statistical difference between treatment groups.

The overall incidence rates of treatment-related adverse events, serious adverse events or adverse events leading to discontinuation were generally similar between treatment groups. The incidence of consecutive elevations of serum transaminases (greater than or equal to 3x ULN) was 10 out of 356 for ezetimibe/simvastatin (2.8 percent) as compared to 8 out of 360 for simvastatin (2.2 percent). Incidence of elevated creatine phosphokinase (greater than or equal to 10xULN) was 4 out of 356 (1.1 percent) in the ezetimibe/simvastatin group and 8 out of 360 (2.2 percent) in the simvastatin group and two cases (0.6 percent) of CPKgreater than or equal to 10xULN associated with muscle symptoms in the ezetimibe/simvastatin group and one case (0.3 percent) in the simvastatin group. There were no cases of rhabdomyolysis. Both medicines were generally well tolerated.

Overall, the safety profiles of ezetimibe/simvastatin and simvastatin alone were similar and generally consistent with their product labels.

After washout, patients enrolled in the study had baseline LDL cholesterol levels of 319 mg/dL in the group randomized to ezetimibe/simvastatin and 318 mg/dL in the simvastatin group. Approximately eighty percent of the patients enrolled in the ENHANCE trial had previously been treated with statins.

In the trial, there was a significant difference in low-density lipoprotein (LDL) cholesterol lowering seen between the treatment groups -- 58 percent LDL cholesterol lowering at 24 months on ezetimibe/simvastatin 10/80 mg as compared to 41 percent at 24 months on simvastatin 80mg alone, (p<0.01).

The incidence rates of cardiovascular clinical events in ENHANCE for the ezetimibe/simvastatin and simvastatin groups, respectively, were as follows: cardiovascular death 2 out of 357 vs. 1 out of 363, non-fatal myocardial infarction 3 out of 357 vs. 2 out of 363, non-fatal stroke 1 out of 357 vs. 1 out of 363 and revascularization 6 out of 357 vs. 5 out of 363. There were no non-cardiovascular deaths or incidents of resuscitated cardiac arrests in the ENHANCE trial. This surrogate endpoint study was not powered nor designed to assess cardiovascular clinical event outcomes.

Merck/Schering-Plough Pharmaceuticals is currently conducting three large outcomes trials with ezetimibe/simvastatin, which involve more than 20,000 high-risk patients, including the more than 10,000 patient IMPROVE-IT trial. No incremental benefit of ezetimibe/simvastatin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.

About The ENHANCE Trial

ENHANCE was a multinational, randomized, double-blind, active comparator trial that used digitized single-frame ultrasound technology for imaging purposes. There were 357 HeFH patients randomized to ezetimibe/simvastatin and 363 HeFH patients to simvastatin. The study collected more than 30,000 carotid artery and 10,000 femoral artery images from these patients. HeFH is characterized by markedly elevated plasma concentrations of LDL cholesterol; typically well above the 95th percentile for age and sex.(1)

Single-frame ultrasound images were analyzed from the right and left carotid arteries at three sites (the common carotid, the internal carotid and the carotid bulb) and at numerous time points (baseline, 6, 12, 18 and 24 months). Images from the right and left common femoral arteries were analyzed at these same time points as well.

[Pharma Newshound]

Source: Bloomberg.com

By Michelle Fay Cortez and Shannon Pettypiece

Jan. 14 (Bloomberg) -- Merck & Co. and Schering-Plough Corp. said their best-selling combination cholesterol drug Vytorin worked no better than an older, generic medication in reducing the buildup of artery-clogging fat in a key study.

Steven Nissen, head of cardiology at the Cleveland Clinic in Ohio, immediately called for a ``moratorium'' on the use of Vytorin and Zetia, citing consumer costs. Vytorin combines Zetia and simvastatin, the generic form of Merck's Zocor used in the trial. Vytorin and Zetia generated $1.3 billion in the third- quarter for Merck and Schering.

The study, run by the companies, examined the carotid arteries and found ``no statistically significant difference between treatment groups,'' the companies said in a statement. If that artery is blocked, it can cut blood supply to the brain and cause a stroke. The trial looked at the highest dose of Vytorin used over two years for patients with a genetic predisposition to high cholesterol.

``In the absence of any evidence of a clinical benefit, these drugs should now be used as a last resort,'' said Nissen, who wasn't involved in the study, in a telephone interview. ``This is a $5 billion-a-year drug, and there are almost 1 million prescriptions written for it weekly. Compared with generic simvastatin, Vytorin is expensive and it adds no benefits.''

Schering-Plough spokesman Lee Davies said the study wasn't definitive on whether the drug improves outcomes because it was looking at a rare population of patients with extremely high artery-clogging LDL cholesterol, the bad form. Because patients had such high cholesterol levels, it may have been difficult to show a change in arterial thickness, he said.

Shares Fall

Merck, based in Whitehouse Station, New Jersey, fell $1.10, or 1.8 percent, to $59.45 at 10:28 a.m. in New York Stock Exchange composite trading, after rising 31.8 percent in the year before today. Schering-Plough, of Kenilworth, New Jersey, dropped 65 cents, or 2.3 percent, to $27.08.

``It was never intended to be a definitive study on outcomes,'' said Schering-Plough's Davies. ``They both started at incredibly high LDL levels so the patients were not brought to goal. If they were brought to goal, they might have had different outcomes.''

Merck spokesman Skip Irvine didn't immediately return a call requesting comment.

The trial, called Enhance, tested the drugs on 720 patients and found the drugs studied had similar safety profiles, the companies reported. The results were submitted to the American College of Cardiology for presentation to a meeting in March.

Bad Cholesterol

The study also found a ``significant difference'' in so- called bad cholesterol among Vytorin patients and those on Zocor, with 58 percent reduction in Vytorin patients compared with 41 percent on Zocor, according to the company statement.

While several studies found Vytorin lowers cholesterol levels more than some other medicines currently available, none have shown that the difference leads to longer, healthier lives. Merck and Schering-Plough have three additional studies involving more than 20,000 patients under way that should resolve those issues, the companies said.

In November, Schering-Plough and Merck said they planned to change the main goal of the study because a review of the data was taking longer than expected. The decision to change the study, which the companies later reversed, spurred criticism from some doctors and caused investors to speculate that the findings would be unfavorable.

Simvastatin costs as little as three cents a pill, compared with $2.84 for the same dose of Vytorin and $2.63 for Zetia, said analyst John Boris, of Bear Stearns in New York, citing a listing of the average wholesaler acquisition costs in a December note to clients.

To contact the reporter on this story: Robert Greene in Washington at rgreene2@bloomberg.net