title: A Phase I Randomized Study of a Specifically Engineered, pH-Sensitive PCSK9 Inhibitor RN317 (PF-05335810) in Hypercholesterolemic Subjects on Statin Therapy.
abstract: 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.
authors.affiliation: Pfizer, San Diego, California, USA.
authors.forename: M
authors.initials: M
authors.lastname: Levisetti
authors.affiliation: Pfizer, San Diego, California, USA.
authors.forename: T
authors.initials: T
authors.lastname: Joh
authors.affiliation: Pfizer, South San Francisco, California, USA.
authors.forename: H
authors.initials: H
authors.lastname: Wan
authors.affiliation: Pfizer, South San Francisco, California, USA.
authors.forename: H
authors.initials: H
authors.lastname: Liang
authors.affiliation: Pfizer, South San Francisco, California, USA.
authors.forename: P
authors.initials: P
authors.lastname: Forgues
authors.affiliation: Pfizer, San Diego, California, USA.
authors.forename: B
authors.initials: B
authors.lastname: Gumbiner
authors.affiliation: Pfizer, South San Francisco, California, USA.
authors.forename: P D
authors.initials: PD
authors.lastname: Garzone
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics / Q000627:therapeutic use; D008078:Cholesterol, LDL / Q000097:blood; D003710:Demography; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy*; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D000091362:PCSK9 Inhibitors; D000071449:Proprotein Convertase 9 / Q000378:metabolism; D015202:Protein Engineering
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000091362:PCSK9 Inhibitors; C000598888:bococizumab; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; C000625350:ralpancizumab