title: Safety and efficacy of LY3015014, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9): a randomized, placebo-controlled Phase 2 study.
abstract: The objective of this study was to evaluate the efficacy, safety, and tolerability of LY3015014 (LY), a neutralizing antibody of proprotein convertase subtilisin/kexin type 9 (PCSK9), administered every 4 or 8 weeks in patients with primary hypercholesterolaemia, when added to a background of standard-of-care lipid-lowering therapy, including statins.
  
  
  
  Double-blind, placebo-controlled trial randomized 527 patients with primary hypercholesterolaemia from June 2013 to January 2014 at 61 community and academic centres in North America, Europe, and Japan. Patients were randomized to subcutaneous injections of LY 20, 120, or 300 mg every 4 weeks (Q4W); 100 or 300 mg every 8 weeks (Q8W) alternating with placebo Q4W; or placebo Q4W. The primary endpoint was percentage change from baseline in low-density lipoprotein cholesterol (LDL-C) by beta quantification at Week 16. The mean baseline LDL-C by beta quantification was 136.3 (SD, 45.0)mg/dL. LY3015014 dose-dependently decreased LDL-C, with a maximal reduction of 50.5% with 300 mg LY Q4W and 37.1% with 300 mg LY Q8W compared with a 7.6% increase with placebo maintained at the end of the dosing interval. There were no treatment-related serious adverse events (AEs). The most common AE terms (>10% of any treatment group) reported more frequently with LY compared with placebo were injection site (IS) pain and IS erythema. No liver or muscle safety issues emerged.
  
  
  
  LY3015014 dosed every 4 or 8 weeks, resulted in robust and durable reductions in LDL-C. No clinically relevant safety issues emerged with the administration of LY. The long-term effects on cardiovascular outcomes require further investigation.
authors.affiliation: Department of Vascular Medicine, Academic Medical Center of the University of Amsterdam, Meibergdreef 9, Room F4-159.2, 1105 AZ Amsterdam, The Netherlands J.J.Kastelein@amc.uva.nl juliesherman@lilly.com.
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.affiliation: Cleveland Clinic Heart and Vascular Institute, Cleveland, OH, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Nissen
authors.affiliation: University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.affiliation: Department of Vascular Medicine, Academic Medical Center of the University of Amsterdam, Meibergdreef 9, Room F4-159.2, 1105 AZ Amsterdam, The Netherlands.
authors.forename: G Kees
authors.initials: GK
authors.lastname: Hovingh
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Ming-Dauh
authors.initials: MD
authors.lastname: Wang
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Shen
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Krueger
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D004311:Double-Blind Method; D005060:Europe; D006801:Humans; D007564:Japan; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D013381:Subtilisins; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; C000610655:frovocimab; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D013381:Subtilisins
keywords: Hypercholesterolaemia; Lipid-lowering therapy; Low-density lipoprotein cholesterol