A Phase I Randomized Study of a Specifically Engineered, pH‐Sensitive PCSK9 Inhibitor RN317 (PF‐05335810) in Hypercholesterolemic Subjects on Statin Therapy

• Published in: Clinical and translational science Vol. 10; no. 1; pp. 3 - 11
• Main Authors: Levisetti, M, Joh, T, Wan, H, Liang, H, Forgues, P, Gumbiner, B, Garzone, PD
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.01.2017; John Wiley and Sons Inc
• Subjects: Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - blood; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized - pharmacokinetics; Antibodies, Monoclonal, Humanized - therapeutic use; Bioavailability; Cardiovascular disease; Cholesterol; Cholesterol, LDL - blood; Consent; Demography; Dosage; Dose-Response Relationship, Drug; Drug dosages; Drug Therapy, Combination; Female; Humans; Hydrogen-Ion Concentration; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Hypercholesterolemia - blood; Hypercholesterolemia - drug therapy; Immunoglobulins; Injections, Intravenous; Injections, Subcutaneous; Intravenous administration; Kexin; Low density lipoprotein; Male; Middle Aged; Monoclonal antibodies; Mutation; PCSK9 Inhibitors; pH effects; Pharmacodynamics; Pharmacokinetics; Phase Forward; Proprotein Convertase 9 - metabolism; Proprotein convertases; Protein Engineering; Randomization; Statins; Studies; Subtilisin
• ISSN: 1752-8054; 1752-8062
• DOI: 10.1111/cts.12430

This phase I study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of RN317 (PF‐05335810), a specifically engineered, pH‐sensitive, humanized proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibody, in hypercholesterolemic subjects (low‐density lipoprotein cholesterol (LDL‐C) ≥ 80 mg/dl) 18–70 years old receiving statin therapy. Subjects were randomized to: single‐dose placebo, RN317 (subcutaneous (s.c.) 0.3, 1, 3, 6, or intravenous (i.v.) 1, 3, 6 mg/kg), or bococizumab (s.c. 1, 3, or i.v. 1 mg/kg); or multiple‐dose RN317 (s.c. 300 mg every 28 days; three doses). Of 133 subjects randomized, 127 completed the study. RN317 demonstrated a longer half‐life, greater exposure, and increased bioavailability vs. bococizumab. RN317 was well tolerated, with no subjects discontinuing because of treatment‐related adverse events. RN317 lowered LDL‐C by up to 52.5% (day 15) following a single s.c. dose of 3.0 mg/kg vs. a maximum of 70% with single‐dose bococizumab s.c. 3.0 mg/kg. Multiple dosing of RN317 produced LDL‐C reductions of ∼50%, sustained over an 85‐day dosing interval.