title: Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial.
abstract: BACKGROUND
  Evolocumab (AMG 145), a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein cholesterol (LDL-C) in phase 2 studies of 12 weeks' duration. The longer-term efficacy and safety of PCSK9 inhibition remain undefined.
  
  
  RESULTS
  Of 1359 randomized and dosed patients in the 4 evolocumab phase 2 parent studies, 1104 (81%) elected to enroll into the Open-Label Study of Long-term Evaluation Against LDL-C (OSLER) study. Regardless of their treatment assignment in the parent study, patients were randomized 2:1 to receive either open-label subcutaneous evolocumab 420 mg every 4 weeks with standard of care (SOC) (evolocumab+SOC, n=736) or SOC alone (n=368). Ninety-two percent of patients in the evolocumab+SOC group and 89% of patients in the SOC group completed 52 weeks of follow-up. Patients who first received evolocumab in OSLER experienced a mean 52.3% [SE, 1.8%] reduction in LDL-C at week 52 (P<0.0001). Patients who received 1 of 6 dosing regimens of evolocumab in the parent studies and received evolocumab+SOC in OSLER had persistent LDL-C reductions (mean reduction, 50.4% [SE, 0.8%] at the end of the parent study versus 52.1% [SE, 1.0%] at 52 weeks; P=0.31). In patients who discontinued evolocumab on entry into OSLER, LDL-C levels returned to near baseline levels. Adverse events and serious adverse events occurred in 81.4% and 7.1% of the evolocumab+SOC group patients and 73.1% and 6.3% of the SOC group patients, respectively.
  
  
  CONCLUSIONS
  Evolocumab dosed every 4 weeks demonstrated continued efficacy and encouraging safety and tolerability over 1 year of treatment in the largest and longest evaluation of a PCSK9 inhibitor in hypercholesterolemic patients to date.
  
  
  BACKGROUND
  http://clinicaltrials.gov. Unique identifier: NCT01439880.
authors.affiliation: Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (R.P.G., M.S.S.); Carbohydrate and Lipid Metabolism Research Unit, Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (F.J.R.); Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Camperdown, Australia (D.S.); Bethesda Health Research Center, Bethesda, MD (M.B.); Lipid Clinic, Oslo University Hospital, Oslo, Norway (G.L.); Hospital Universitario Miguel Servet, Zaragoza, Spain (F.C.); and Amgen Inc, Thousand Oaks, CA (R.S., P.N., T.L., R.S., S.M.W.).
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Koren
authors.forename: Robert P
authors.initials: RP
authors.lastname: Giugliano
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Raal
authors.forename: David
authors.initials: D
authors.lastname: Sullivan
authors.forename: Michael
authors.initials: M
authors.lastname: Bolognese
authors.forename: Gisle
authors.initials: G
authors.lastname: Langslet
authors.forename: Fernando
authors.initials: F
authors.lastname: Civeira
authors.forename: Ransi
authors.initials: R
authors.lastname: Somaratne
authors.forename: Patric
authors.initials: P
authors.lastname: Nelson
authors.forename: Thomas
authors.initials: T
authors.lastname: Liu
authors.forename: Rob
authors.initials: R
authors.lastname: Scott
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wasserman
authors.forename: Marc S
authors.initials: MS
authors.lastname: Sabatine
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D008078:Cholesterol, LDL / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000378:metabolism; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D059039:Standard of Care; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D008078:Cholesterol, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C577155:evolocumab
keywords: cholesterol, LDL; hypercholesterolemia; randomized controlled trial; serine proteases