FDA panel votes against new indication for ezetimibe, combination therapy

Issue: January 2016

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted against recommending approval of supplemental new drug applications for ezetimibe and ezetimibe/simvastatin.

Based on results of the IMPROVE-IT study of patients with recent ACS, Merck is seeking new indications for reduction of risk for CV events in patients with CHD for ezetimibe (Zetia, Merck) administered in conjunction with a statin and ezetimibe/simvastatin (Vytorin, Merck). Five members of the committee voted that efficacy and safety data from IMPROVE-IT provided enough evidence to approve the new indications, and 10 members voted that the data did not provide enough evidence.

In IMPROVE-IT, compared with simvastatin alone, simvastatin plus ezetimibe was associated with a 6.4% reduction in the composite primary endpoint of CV death, nonfatal MI, nonfatal stroke, unstable angina requiring hospitalization or coronary revascularization at least 30 days after randomization (HR = 0.936; 95% CI, 0.887-0.988; absolute risk reduction, 1.8%).

Those who voted against approval cited the small magnitude of benefit demonstrated in IMPROVE-IT; missing data that occurred more frequently in the ezetimibe/simvastatin arm, casting doubt on the robustness of the result; the clinical relevance of the majority of nonfatal MIs and nonfatal strokes that drove the main results; and the broadness of the claim sought by Merck, with many panelists saying IMPROVE-IT did not provide direct evidence that the result would be applicable to those with stable CHD.

“I do not believe [IMPROVE-IT] provided substantial evidence in terms of supporting the approval claim for two reasons,” John R. Teerlink, MD, director of HF and director of echocardiography at San Francisco Veterans Affairs Medical Center and professor of medicine at the University of California, San Francisco School of Medicine, said. “I don’t think it was substantial in terms of proving statistical and clinical meaningfulness in terms of the endpoints and also in terms of the claims. Specifically, the claim was much too broad for the population that was studied.”

Panelist Michael J. Blaha, MD, MPH, assistant professor of cardiology and epidemiology and director of clinical research at Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins Hospital, said he voted yes because “there is a modest unmet need for add-on LDL-lowering therapy for patients with coronary disease, specifically patients with ACS. This is an important space we’re talking about. In my view, we’ve waited a long time for evidence that a drug added onto a statin therapy works, and now we have it.”

FDA staff asked the panel to discuss two subgroup analyses indicating that adding ezetimibe was more beneficial to those with diabetes (HR = 0.85; 95% CI, 0.78-0.94) than to those without it (HR = 0.98; 95% CI, 0.91-1.04; P for interaction = .021) and to those aged 75 years and older (HR = 0.8; 95% CI, 0.7-0.9) than to those younger than 75 years (HR = 0.97; 95% CI, 0.92-1.03; P for interaction = .005). Most panelists said that subgroup analyses should not carry great weight in the FDA’s decision.

The panel was asked to discuss the safety findings from IMPROVE-IT, and some panelists expressed concern that the ezetimibe/simvastatin group had a numerically higher rate of hemorrhagic stroke (HR = 1.38; 95% CI, 0.93-2.04).

Panelist Milton Packer, MD, distinguished scholar in cardiovascular science at Baylor University Medical Center, Dallas, who voted no, said that while there was not enough evidence to support a new claim, there was enough to remove the provision in the labels of ezetimibe and ezetimibe/simvastatin stating that their effects on CV events and mortality have not been studied.

“Everyone who wants to use this drug for risk reduction in CVD can do that right now, based on the current label,” he said. “If you think that the LDL hypothesis is valid … you have a label right now for this drug that says you can use it for cholesterol-lowering, and if you believe that that cholesterol-lowering lowers CV risk, then IMPROVE-IT supports that and you don’t need a label change. However … the current label for this drug says there is no evidence that the effects of this drug change CV outcomes. I might suggest that we have enough evidence to take that line out.”

Ezetimibe alone or in combination with a statin and ezetimibe/simvastatin is currently approved for reduction of total cholesterol, LDL and other lipid parameters in patients with hyperlipidemia or familial hypercholesterolemia.

The FDA is not required to follow the recommendations of its advisory panels, but it usually does. – by Erik Swain

For more information:

EMDAC Briefing Document. NDA 21445/S-038 and 21687/S-054.

Disclosure:The members of the Endocrinologic and Metabolic Drugs Advisory Committee report no relevant financial disclosures.