Abstract 16265: Inhibition of Proprotein Convertase Subtilisin/Kexin Type 9 With a Monoclonal Antibody REGN727/SAR236553, Effectively Reduces Low-Density-Lipoprotein Cholesterol, as Mono or Add-on Therapy in Heterozygous Familial and Non Familial Hypercholesterolemia
Since 2003 understanding of proprotein convertase subtilisin/kexin type 9 (PCSK9) has advanced from discovery to in vitro, animal, genetic and observational studies to suggest that inhibition of PCSK9 should result in up regulation of hepatic LDL receptors and decrease in LDL cholesterol (LDLc). We report a randomized, double-blind, placebo-controlled, multiple ascending dose trial (NCT01161082) to determine if REGN 727/SAR236553 (REGN727), a fully human monoclonal antibody to PCSK9 was safe and effective in patients with Heterozygous Familial Hypercholesterolemia (FH) or other forms of primary hypercholesteremia (nonFH). The study enrolled 61 adults with either FH (n=21) or nonFH (n=30), both on diet plus stable atorvastatin therapy (atorvaRx), or nonFH (n=10) on diet alone. AtorvaRx patients received doses of 10-40 mg and had LDLc ≥ 100 mg/dL; those on diet alone LDLc ≥ 130 mg/dL. REGN727 was administered subcutaneously at doses of 50, 100 and 150 mg on days 1, 29 and 43. The primary endpoint was the incidence and severity of treatment emergent adverse events (TEAEs). Of 109 patients screened 61were randomized (14 placebo, 47 REGN727) with 100% completing 148 +/−7 days of treatment and follow up. FH were younger than nonFH patients (mean 40 vs 52 yrs), and were on higher doses of atorvastatin (52% on 40 mg). Baseline LDLc was 134, 111, and 179 mg/dL in the FH atrovaRX, nonFH atorvaRx and nonFH diet only groups respectively. No serious adverse events were seen and treatment was generally well tolerated. No drug-related adverse effects were seen on liver function testing or other laboratory parameters. TEAEs that occurred in > 5% of REGN727 treated patients were Headache (n=8), Nasopharyngitis (n=5), and Upper Respiratory Infection (n=3). On day 57, 14 days after the 3rd dose of REGN727, mean % reductions in LDLc on top of statins were 35.6%, 50.2% and 57.5% at the 50, 100 and 150 mg doses, respectively in the combined FH and nonFH populations. There were no apparent differences in response between FH and nonFH or those on or not on statin therapy. Favourable changes were observed in HDLc and apoA1. We conclude that the PCSK9 inhibitor, REGN727/SAR236553, appears to be a promising therapeutic option for patients with or without FH and elevated LDLc on atorvastatin therapy.
- © 2011 by American Heart Association, Inc.