Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody.

BACKGROUND: Patients with PCSK9 gene gain of function (GOF) mutations have a rare form of autosomal dominant hypercholesterolemia. However, data examining their clinical characteristics and geographic distribution are lacking. Furthermore, no randomized treatment study in this population has been reported. METHODS AND RESULTS: We compiled clinical characteristics of PCSK9 GOF mutation carriers in a multinational retrospective, cross-sectional, observational study. We then performed a randomized placebo-phase, double-blind study of alirocumab 150 mg administered subcutaneously every 2 weeks to 13 patients representing 4 different PCSK9 GOF mutations with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL on their current lipid-lowering therapies at baseline. Observational study: among 164 patients, 16 different PCSK9 GOF mutations distributed throughout the gene were associated with varying severity of untreated LDL-C levels. Coronary artery disease was common (33%; average age of onset, 49.4 years), and untreated LDL-C concentrations were higher compared with matched carriers of mutations in the LDLR (n=2126) or apolipoprotein B (n=470) genes. Intervention study: in PCSK9 GOF mutation patients randomly assigned to receive alirocumab, mean percent reduction in LDL-C at 2 weeks was 62.5% (P<0.0001) from baseline, 53.7% compared with placebo-treated PCSK9 GOF mutation patients (P=0.0009; primary end point). After all subjects received 8 weeks of alirocumab treatment, LDL-C was reduced by 73% from baseline (P<0.0001). CONCLUSIONS: PCSK9 GOF mutation carriers have elevated LDL-C levels and are at high risk of premature cardiovascular disease. Alirocumab, a PCSK9 antibody, markedly lowers LDL-C levels and seems to be well tolerated in these patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01604824.

Effect of a monoclonal antibody to PCSK9 on LDL cholesterol.

BACKGROUND: Proprotein convertase subtilisin/kexin 9 (PCSK9), one of the serine proteases, binds to low-density lipoprotein (LDL) receptors, leading to their accelerated degradation and to increased LDL cholesterol levels. We report three phase 1 studies of a monoclonal antibody to PCSK9 designated as REGN727/SAR236553 (REGN727). METHODS: In healthy volunteers, we performed two randomized, single ascending-dose studies of REGN727 administered either intravenously (40 subjects) or subcutaneously (32 subjects), as compared with placebo. These studies were followed by a randomized, placebo-controlled, multiple-dose trial in adults with heterozygous familial hypercholesterolemia who were receiving atorvastatin (21 subjects) and those with nonfamilial hypercholesterolemia who were receiving treatment with atorvastatin (30 subjects) (baseline LDL cholesterol, >100 mg per deciliter [2.6 mmol per liter]) or a modified diet alone (10 subjects) (baseline LDL cholesterol, >130 mg per deciliter [3.4 mmol per liter]). REGN727 doses of 50, 100, or 150 mg were administered subcutaneously on days 1, 29, and 43. The primary outcome for all studies was the occurrence of adverse events. The principal secondary outcome was the effect of REGN727 on the lipid profile. RESULTS: Among subjects receiving REGN727, there were no discontinuations because of adverse events. REGN727 significantly lowered LDL cholesterol levels in all the studies. In the multiple-dose study, REGN727 doses of 50, 100, and 150 mg reduced measured LDL cholesterol levels in the combined atorvastatin-treated populations to 77.5 mg per deciliter (2.00 mmol per liter), 61.3 mg per deciliter (1.59 mmol per liter), and 53.8 mg per deciliter (1.39 mmol per liter), for a difference in the change from baseline of -39.2, -53.7, and -61.0 percentage points, respectively, as compared with placebo (P<0.001 for all comparisons). CONCLUSIONS: In three phase 1 trials, a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels in healthy volunteers and in subjects with familial or nonfamilial hypercholesterolemia. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT01026597, NCT01074372, and NCT01161082.).