title: Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial.
abstract: BACKGROUND
  Statin intolerance has been a major limitation in the use of statins, especially at higher doses. New effective treatments are needed for lowering low-density lipoprotein cholesterol (LDL-C) in patients who cannot tolerate daily statin doses.
  
  
  OBJECTIVE
  ODYSSEY ALTERNATIVE (NCT01709513) evaluates efficacy and safety of alirocumab, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody, in patients with well-documented statin intolerance and moderate to very high cardiovascular risk.
  
  
  METHODS
  This is a phase 3, multicenter, randomized, double-blind, double-dummy study in statin-intolerant patients. Intolerance was defined as inability to take at least 2 different statins because of muscle-related adverse events (AEs), 1 at the lowest approved starting dose. Patients first received single-blind subcutaneous and oral placebo for 4 weeks, and were withdrawn if they developed muscle-related AEs after the placebo treatment. Continuing patients were randomized (2:2:1 ratio) to alirocumab 75 mg self-administered via single 1 mL prefilled pen every 2 weeks or ezetimibe 10 mg/day or atorvastatin 20 mg/day (statin rechallenge), for 24 weeks. Alirocumab dose was increased to 150 mg every 2 weeks (also 1 mL) at week 12 depending on week 8 LDL-C level. The primary endpoint is percent change in LDL-C from baseline to week 24 by intent-to-treat analysis. Muscle-related AEs were assessed by spontaneous patient reports and clinic queries.
  
  
  RESULTS
  A total of 314 patients have been randomized.
  
  
  CONCLUSIONS
  This is the first and only study of a new class of LDL-C-lowering agents in patients selected with a rigorously documented intolerance to statins, using a placebo run-in and statin control arm.
authors.affiliation: Division of Clinical Pharmacology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA. Electronic address: PMORIART@kumc.edu.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Moriarty
authors.affiliation: Emory University, Atlanta, Georgia, USA.
authors.forename: Terry A
authors.initials: TA
authors.lastname: Jacobson
authors.affiliation: Hôpital de la Pitié-Salpêtrière, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Bruckert
authors.affiliation: Hartford Hospital, Hartford, Connecticut, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Thompson
authors.affiliation: Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Guyton
authors.affiliation: Sanofi, Montpellier, France.
authors.forename: Marie T
authors.initials: MT
authors.lastname: Baccara-Dinet
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gipe
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000069059:Atorvastatin; D001384:Azetidines / Q000008:administration & dosage / Q000009:adverse effects; D002170:Canada; D002318:Cardiovascular Diseases / Q000175:diagnosis / Q000188:drug therapy*; D008078:Cholesterol, LDL / Q000097:blood; D054796:Drug Dosage Calculations; D005060:Europe; D000069438:Ezetimibe; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D063806:Myalgia / Q000209:etiology / Q000517:prevention & control; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000276:immunology*; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects; D012306:Risk; D012697:Serine Endopeptidases / Q000276:immunology*; D014481:United States
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001384:Azetidines; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D000069438:Ezetimibe; C571059:alirocumab
keywords: Alirocumab; Ezetimibe; Hypercholesterolemia; Muscle symptoms; PCSK9; Phase 3 clinical trial; Statin intolerance; Statin myopathy