Abstract 13524: The Effects of Multiple Dose Administration of RN316 (PF-04950615), a Humanized IgG2a Monoclonal Antibody Binding Proprotein Convertase Subtilisin Kexin Type 9, in Hypercholesterolemic Subjects

Abstract

Background: RN316 binds to Proprotein Convertase Subtilisin Kexin type 9 (PCSK9), preventing PCSK9-mediated down-regulation of low density lipoprotein receptor, improving low density lipoprotein cholesterol (LDL-C) clearance in serum and reduction of LDL-C. A double-blind, randomized, placebo-controlled, multiple dose study was conducted to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of RN316 in hypercholesterolemic (HC) subjects of non-Japanese (NJS) and Japanese (JS) ancestry.

Methods: Sixty seven diet-managed HC subjects, including 9 JS, with chronic stable medical conditions and LDL ≥ 130 mg/dL were randomized to one of 4 intravenous (IV) doses of RN316 (0.25, 0.5, 1 and 1.5 mg/kg) or placebo (PBO). Subjects were treated weekly for 4 weeks and then followed for 8 weeks.

Results: RN316 PK was well characterized in both groups of HC subjects. The t1/2 and AUC after 1.5 mg/kg were 248 vs. 245 hrs and 8637 vs. 7676 µg•hr/mL in NJS and JS subjects, respectively. The maximum mean % decreases from baseline LDL-C were [[Unable to Display Character: –]]60%, -58%, -66%, and -65% and occurred on Days 25, 22, 29, and 43 after 0.25, 0.5, 1 and 1.5 mg/kg, respectively in RN316 treated HC subjects vs. [[Unable to Display Character: –]] 9% on Day 25 in PBO treated subjects; in the JS subgroup maximum mean % decreases were -60% (n=4; 0.5 mg/kg), -98% (n=1; 1 mg/kg), and -64% (n=4; 1.5 mg/kg). The % decrease in LDL-C of ≥ 50% below baseline were sustained for a mean duration of 12, 14, 27 and 56 days after 0.25, 0.5, 1 and 1.5 mg/kg, respectively. High density lipoprotein cholesterol (HDL-C) was generally higher and triglycerides generally lower in RN316 vs. PBO treated subjects. Adverse events (AEs) were infrequent, transient and not dose-related. One subject reported nonserious infusion reactions on 3 occasions, each after 0.25 mg/kg; the subject was discontinued from the study. One serious AE was reported (pulmonary embolism 63 days after last 0.25 mg/kg dose) but was not considered to be related to RN316.

Conclusions: Substantial and clinically-meaningful LDL-C lowering occurs in NJS and JS HC subjects treated with RN316 after multiple IV doses as monotherapy. The PK parameters were similar for both groups. RN316 was generally safe and well-tolerated in the limited number of subjects exposed to the drug.