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Preliminary FDA Review Gives High Marks to Cholesterol Drug Alirocumab (Praluent)

Approval decision expected in July

The experimental drug alirocumab (Praluent, Sanofi/Regeneron Pharmaceuticals) effectively lowers “bad” low-density lipid cholesterol (LDL-C) and is generally well tolerated, according to a preliminary review by the FDA.

The review was published on the agency’s website ahead of a June 9 meeting of its Endocrinologic and Metabolic Drugs Advisory Committee, which will discuss the drug and recommend whether it should be approved. A final approval decision is expected by July 24.

The FDA has asked the panel to consider whether Sanofi and Regeneron have sufficiently established that the LDL-C–lowering benefit of alirocumab exceeds its risks to support approval in one or more patient populations.

Alirocumab, a human monoclonal antibody, is a member of a new class of lipid-modifying therapies that inhibit the proprotein convertase subtilisin kexin type 9 (PCSK9), a serine protease that is secreted with the low-density lipoprotein receptor (LDLR) and promotes its degradation. Upon binding to the LDLR, PCSK9 initiates internalization and lysosomal degradation of the LDLR/PCSK9 complex. By inactivating PCSK9, therefore, alirocumab upregulates LDLR, especially on the surface of hepatocytes, leading to increased uptake of circulating LDL-C and a consequent reduction in the plasma LDL-C concentration.

The drug product is presented as a subcutaneous (SC) injection at doses of 75 mg/mL or 150 mg/mL solution for injection in a single-use prefilled pen or single-use prefilled syringe.

The applicants are seeking an indication for alirocumab for the long-term treatment of adult patients with primary hypercholesterolemia (non-familial and heterozygous familial) or mixed dyslipidemia, including patients with type-2 diabetes mellitus, to reduce LDL-C, total cholesterol, non–high-density lipoprotein cholesterol (HDL-C), apolipoprotein B, triglycerides, and lipoprotein (a), and to increase HDL-C and apolipoprotein A1.

The targeted patient populations include patients with heterozygous familial hypercholesterolemia (HeFH); those without FH, but with elevated LDL-C and a high or very high cardiovascular risk on statin therapy; and those who are intolerant of statins because of their muscle-related adverse effects.

Alirocumab was evaluated for efficacy in ten phase III trials that included a total of 5,296 patients: nine of the 10 studies enrolled patients with HeFH and/or patients at high or very high cardiovascular risk. Five trials were placebo-controlled, and five were active-controlled. Two dose regimens were evaluated: eight studies used a starting dosage of 75 mg by SC injection every 2 weeks (Q2W) with up-titration at week 12 to 150 mg Q2W if LDL-C goals were not met, and two trials started all patients on 150 mg Q2W. Eight studies administered alirocumab in patients who were receiving background statin therapy, and two studies administered alirocumab as monotherapy. All ten trials used the same primary endpoint: the percent change in LDL-C from baseline at week 24.

In all of the studies, alirocumab was associated with decreases in calculated LDL-C of 36% to 61% from baseline, and with statistically significant treatment differences of 39% to 62% compared with placebo (all P < 0.0001) and 24% to 36% compared with ezetimibe. Maximal LDL-C–lowering efficacy was observed at week 4 and persisted for the duration of the studies.

Sources: Reuters; June 5, 2015; and FDA Briefing Document; June 5, 2015.

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