Abstract 13322: The Effects of Single Dose Administration of RN316 (PF-04950615), a Humanized IgG2a Monoclonal Antibody Binding Proprotein Convertase Subtilisin Kexin Type 9, in Hypercholesterolemic Subjects Treated with and without Atorvastatin

Abstract

Background: RN316 binds to Proprotein Convertase Subtilisin Kexin type 9 (PCSK9), preventing PCSK9-mediated down-regulation of low density lipoprotein receptor, leading to improved low density lipoprotein cholesterol (LDL-C) clearance in serum and reduction of LDL-C. Three single dose studies were conducted to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of RN316 in hypercholesterolemic (HC) subjects.

Methods: HC subjects with chronic stable medical conditions were randomized into one of 3 studies: a) ascending single intravenous (IV) RN316 doses (0.3 to 18 mg/kg) or placebo (PBO) in diet-managed HC (LDL-C ≥ 130 mg/dL; n=48); b) single RN316 IV doses of either 0.5 or 4 mg/kg added on to ongoing atorvastatin (AT) 40 mg (no LDL-C criterion; no PBO; n=24); or c) fixed, subcutaneous (SC) RN316 doses (100 or 200 mg) or an IV RN316 dose (200 mg) in diet-managed subjects (LDL-C ≥ 130 mg/dL; no PBO; n=49). Subjects were followed from 30 to 90 days.

Results: RN316 PK was well characterized following single IV or SC doses. Exposure to RN316 increased slightly greater than dose-proportionally and clearance decreased with increasing dose reflecting target-mediated disposition. The mean maximum % decreases from baseline LDL-C ranged from -33% (0.5 mg/kg) to -84% (18 mg/kg) in RN316 treated HC subjects vs. -2% in PBO treated subjects. LDL-C reductions were dose-dependent up to 3 mg/kg IV, beyond which the duration of the maximum LDL-C lowering was dose-dependent. In general, high density lipoprotein cholesterol (HDL-C) and triglycerides were not affected by RN316. Adverse events (AEs) were infrequent, transient and not dose-related. Based on a visual analog scale of 0 (no pain) [[Unable to Display Character: –]] 100 mm (very severe pain), the highest mean pain score immediately after a 2 mL SC injection was 3.82 ± 7.75 mm. Across the 3 studies, one serious AE was reported (worsening cephalgia 57 days after IV dose 4 mg/kg) but was not considered to be related to RN316.

Conclusions: Substantial and clinically-meaningful LDL-C lowering occurs in HC subjects treated with RN316 after single IV and SC doses, both as monotherapy and when added on to AT. RN316 was generally safe and well-tolerated in the limited number of subjects exposed to the drug.