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FDA Panel Backs Cholesterol Drug Evolocumab (Repatha) for Patients at High Cardiovascular Risk

Monoclonal antibody is administered as subcutaneous injection

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) has recommended approval of the cholesterol-lowering drug evolocumab (Repatha, Amgen), but said it should be used only in patients at high risk of cardiovascular disease, according to a Reuters report.

Evolocumab is designed to be administered as a subcutaneous injection in biweekly doses of 140 mg or in a monthly dose of 420 mg, with both regimens given on top of statins, if patients can tolerate them.

The panel voted unanimously to recommend approval of evolocumab for patients with homozygous familial hypercholesterolemia (HoFH), a hereditary disorder characterized by high low-density lipoprotein (LDL) levels that can cause heart attacks in very young people. The panel also recommended approval of the drug for patients without HoFH who are at high risk of cardiovascular disease and are taking other cholesterol treatments, with an 11-to-4 vote.

Panel members raised questions about what physicians should do if evolocumab, combined with statins, were to cause LDL levels to drop too low, according to Reuters. They feared that if physicians become alarmed by very low LDL levels, they could cut back on the patient’s statin, which would not be desirable since there is a large body of data showing that statins reduce the risk of heart attacks and strokes.

The panelists were reluctant, therefore, to recommend the drug for a wider patient population until Amgen completes a study to assess whether the cholesterol-lowering effect of evolocumab translates into a reduction in cardiovascular risk.

Evolocumab is a human monoclonal antibody that binds to proprotein convertase subtilisin kexin type 9 (PCSK9), a circulating negative regulator of the LDL receptor (LDLR). Upon binding to LDLRs, PCSK9 initiates internalization and lysosomal degradation of the LDLR/PCSK9 complex. By inactivating PCSK9, evolocumab upregulates LDLRs, especially on the surface of hepatocytes, leading to increased uptake of circulating LDL-cholesterol (LDL-C) and the consequent reduction of plasma LDL-C concentrations.

The efficacy of evolocumab was assessed in four double-blind, randomized, placebo- or ezetimibe-controlled phase III trials of 12 weeks duration and in one 52-week placebo-controlled trial. The 12-week studies evaluated evolocumab in four patient populations: 1) as monotherapy in patients at low CV risk (i.e., a 10-year Framingham risk score of 10% or less; n = 614); 2) in combination with statins (n = 1,896); 3) in “statin-intolerant” patients (n = 307); and 4) in patients with HeFH (n = 329). The 52-week DESCARTES trial (N = 901) also evaluated evolocumab in four different patient populations: 1) no drug therapy required (diet alone); 2) low-dose drug therapy required (diet plus atorvastatin 10 mg); 3) high-dose drug therapy required (diet plus atorvastatin 80 mg); and, 4) maximal drug therapy required (diet plus atorvastatin 80 mg plus ezetimibe 10 mg).

Integrated analyses from the four 12-week trials demonstrated statistically significant reductions in LDL-C for both evolocumab dosing regimens (140 mg biweekly and 420 mg monthly) compared with placebo (P < 0.001), with treatment differences ranging from reductions of 60% for the 420-mg monthly dosage to 67% for the 140-mg biweekly dosage compared with placebo.

The persistent efficacy of evolocumab (420 mg monthly) was demonstrated in the 52-week DESCARTES trial. The percent change in LDL-C from baseline to week 52 for monthly evolocumab compared with placebo using ultracentrifugation/directly measured, reflexive LDL-C, or calculated LDL-C values resulted in treatment differences of –57%, –58%, and –59%, (P < 0.001), respectively, when added to background lipid-lowering therapy.

Sources: Reuters; June 10, 2015; and FDA Briefing Document; June 8, 2015.

 

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