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Briefing Summary: US FDA Posts Advisory Committee Materials for Review of Merck’s Cardiovascular Outcomes Trial for Vytorin (IMPROVE-IT Trial) – DEC 14, 2015 (EMDAC)

Background

The US FDA has posted details, including company and FDA Briefing Materials, for the Monday, December 14, 2015 Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) meeting. The Committee will discuss the results of the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT). IMPROVE-IT was a clinical trial that studied the effect of Vytorin (ezetimibe/simvastatin) compared with simvastatin on the occurrence of cardiovascular (CV) events in patients with recent acute coronary syndrome. The results from this trial have been submitted to support supplemental new drug applications (sNDAs) 21445/S-038, for Zetia and 21687/S-054, Vytorin by MSD International GmbH (Merck). The proposed indication for Zetia (in combination with a statin) and Vytorin is to reduce the risk of cardiovascular events in patients with coronary heart disease.

Summary of Company Briefing Materials

In its Briefing Materials, Merck explains that it is seeking the addition of the following indications to the ezetimibe/simvastatin and ezetimibe tablet approved labels:

-VYTORIN® is indicated to reduce the risk of cardiovascular events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, or need for revascularization) in patients with coronary heart disease (CHD).

-ZETIA®, administered in combination with an HMG-CoA reductase inhibitor (statin), is indicated to reduce the risk of cardiovascular events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, or need for revascularization) in patients with coronary heart disease (CHD).

The applications are based on the results from the IMPROVE-IT trial, a large, multicenter, long-term trial designed to assess the cardiovascular (CV) outcomes benefit of further lowering of low-density lipoprotein cholesterol (LDL-C) through the addition of the cholesterol absorption inhibitor ezetimibe to statin treatment in subjects at high risk for recurrent CV events. It says the IMPROVE-IT results provide substantial evidence of a CV benefit attributable to ezetimibe and support a new outcome indication in patients with coronary heart disease.

Efficacy

Merck says that, in IMPROVE-IT, treatment with Vytorin, compared to simvastatin alone, reduced the risk of the first occurrence of the primary composite endpoint by 6.4% (HR 0.936; 95% CI 0.887 - 0.988; p=0.016), with the effect of treatment being statistically significant and similar across the primary composite endpoint and the three secondary composite endpoints.

The results were also consistent across the exploratory endpoints studied, and the treatment effect of ezetimibe in the >20 subgroups assessed was generally consistent across the subgroups and in the overall cohort. They say that the outcomes benefit was consistent with that of statins seen in the treatment analysis.

Safety

Merck says that ezetimibe has a well-established safety profile: it is well-tolerated and associated with minimal risk. It claims that more than 37,000 subjects have been exposed to ezetimibe in the clinical development program, with similar overall adverse event (AE) rates for ezetimibe plus statin and statin monotherapy. It also points to postmarket experience that includes more than 36 million patient years of treatment with ezetimibe in more than 80 markets.

Summary of FDA Briefing Materials

In its Briefing Materials, the FDA notes that the primary endpoint was a composite CV primary endpoint, which included CV death, nonfatal myocardial infarction (MI), documented unstable angina (UA) requiring admission to the hospital, all coronary revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) at least 30 days after randomization, and nonfatal stroke. They say that the results for the primary CV endpoint were statistically significant, with an estimated hazard ratio for the primary endpoint from the primary analysis of 0.94, with a corresponding 95% confidence interval of (0.89, 0.99). They found that the differences in the number/rate of events for two of these components, MI and non-fatal stroke, are the events that drive the results. They note that the secondary endpoints, which are similar composites of CV events, have similar findings, with either one or both MI and non-fatal stroke driving efficacy. The secondary endpoints are: 1. A composite of all-cause death, non-fatal MI, documented UA requiring admission to a hospital, all coronary revascularization with PCI or CABG at least 30 days after randomization, and non-fatal stroke; 2. Coronary heart disease death, non-fatal MI; and urgent coronary revascularization with PCI or CABG at least 30 days after randomization; and 3. CV death, non-fatal MI, documented UA requiring admission to a hospital, All revascularization (coronary and non-coronary) at least 30 days after randomization, and non-fatal stroke.

The FDA statistical reviewer notes that subgroup analysis results suggest a more favorable treatment effect for the diabetic and elderly (at least 75 years old) patients in this study, with no effect seen among the under 75, nondiabetic subgroup, a majority of the study population.

The FDA also looked at the diversity of the study population. Of the 18,144 patients randomized into the study, they found that 4,416 (24.3%) were female and 13,728 (75.7%) were male, with an overall mean age of 63.6 years. Approximately 84% were Caucasian, 4.3% were Asian, 4.5% were of Spanish descent, 2.8% were Black, and 4.3% were Other. There was a history of previously documented MIs in 21% of patients, and 26.6% had a history of CHD, with 29.2% showing disease in 3 vessels. A history of diabetes mellitus was reported by 27.2%, 61% had hypertension, and 4% of patients had a previous history of stroke.

The intent-to-treat (ITT) population included 9,067 patients in the ezetimibe/simvastatin treatment arm and 9,077 patients in the simvastatin treatment arm. Approximately 13.6% patients in the ezetimibe/simvastatin arm and 13.8% patients in the simvastatin arm did not complete the study.

In addition, the FDA says that 11% of patients were censored for the primary endpoint prior to May 1, 2014, with most of the censoring occurring in the first year of a subject’s participation. They note that more patients in the ezetimibe/simvastatin arm missed follow-up times earlier in the trial than patients in the simvastatin arm. The FDA says this timing could be important, because there was also a much higher event rate during the first year after randomization (approximately 13.5%) than during the rest of the study (range, 5.3% to 2.6%). It is possible that, by more ezetimibe/simvastatin missing follow-up times during that period, some primary endpoint events may have been missed in the ezetimibe/simvastatin arm, leading to an overstated benefit of ezetimibe contribution to treatment.

Questions for Committee Members

1. DISCUSSION: In the IMPROVE-IT trial, 2,572 (28.4%) of 9,067 patients in the ezetimibe/simvastatin arm and 2,742 (30.2%) of 9,077 patients in the simvastatin arm had at least one primary composite endpoint event, defined as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, documented unstable angina requiring hospitalizations, or coronary revascularization (at least 30 days after randomization). According to the primary analysis (intent-to-treat), this yielded a 6.4% relative risk reduction for ezetimibe/simvastatin compared with simvastatin (HR 0.94; 95% CI, 0.89-0.99; p=0.016).

Provide your interpretation of the efficacy results from the IMPROVE-IT trial. Specifically discuss the magnitude of the observed treatment effect; the robustness of the result of the primary composite endpoint (considering, for example, the extent and pattern of missing follow-up time); and any comments you may have regarding observed effects on components of the primary composite endpoint or secondary endpoints.

2. DISCUSSION: Multiple subgroup analyses of the primary composite endpoint were specified in the statistical analysis plan. The most notable differences in treatment effect were observed in subgroups defined by diabetes status or age (using a threshold at 75 years), as summarized in the table below.

Provide your interpretation of these subgroup findings.

3. DISCUSSION: The applicant has proposed that the results from IMPROVE-IT, which tested the addition of ezetimibe to simvastatin among patients with very recent acute coronary syndrome, can be extrapolated to other clinical situations, such as adding ezetimibe onto any statin among patients with stable coronary heart disease. Discuss the extent to which such extrapolation is reasonable.

4. DISCUSSION: Discuss the safety findings of the IMPROVE-IT trial.

5. VOTE: Do the efficacy and safety data from the IMPROVE-IT trial provide substantial evidence to support approval of a claim that adding ezetimibe to statin therapy reduces the risk of cardiovascular events?

a. If yes, please comment on your rationale and whether such claim should carry any limits (e.g., whether the data support use in only certain clinical situations or subgroups).

b. If no, provide your rationale and comment on what additional data would be needed to support approval.

What’s Next?

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Merck Drug Name: ezetimibe; ezetimibe/simvastatin Drug Class: cholesterol absorption inhibitor; statin Indication: reduction of cardiovascular risk


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