Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab.
OBJECTIVE
This study sought to evaluate the efficacy and safety of subcutaneous evolocumab compared with oral ezetimibe in hypercholesterolemic patients who are unable to tolerate effective statin doses.


BACKGROUND
Statin intolerance, which is predominantly due to muscle-related side effects, is reported in up to 10% to 20% of patients. Evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), demonstrated marked reductions in plasma low-density lipoprotein cholesterol (LDL-C) in a phase 2 study in statin-intolerant patients.


METHODS
The GAUSS-2 (Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects) trial was a 12-week, double-blind study of randomized patients (2:2:1:1) to evolocumab 140 mg every two weeks (Q2W) or evolocumab 420 mg once monthly (QM) both with daily oral placebo or subcutaneous placebo Q2W or QM both with daily oral ezetimibe 10 mg. Co-primary endpoints were percent change from baseline in LDL-C at the mean of weeks 10 and 12, and at week 12.


RESULTS
Three hundred seven patients (age 62 ± 10 years; LDL-C 193 ± 59 mg/dl) were randomized. Evolocumab reduced LDL-C from baseline by 53% to 56%, corresponding to treatment differences versus ezetimibe of 37% to 39% (p <0.001). Muscle adverse events occurred in 12% of evolocumab-treated patients and 23% of ezetimibe-treated patients. Treatment-emergent adverse events and laboratory abnormalities were comparable across treatment groups.


CONCLUSIONS
Robust efficacy combined with favorable tolerability makes evolocumab a promising therapy for addressing the largely unmet clinical need in high-risk patients with elevated cholesterol who are statin intolerant. (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2; NCT01763905).
Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands. Electronic address: e.s.stroes@amc.uva.nl.
Erik
E
Stroes
Wesley Medical Centre, Auchenflower, Australia.
David
D
Colquhoun
Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Camperdown, Australia.
David
D
Sullivan
Hospital Universitario Miguel Servet, Zaragoza, Spain.
Fernando
F
Civeira
Cardiometabolic Disorders Department, Icahn School of Medicine at Mount Sinai, New York, New York.
Robert S
RS
Rosenson
Lipid Disorders Clinic, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.
Gerald F
GF
Watts
Hopital Pitie-Salpetriere, Paris, France.
Eric
E
Bruckert
Preventive Cardiology and Rehabilitation, Cleveland Clinic, Cleveland, Ohio.
Leslie
L
Cho
Amgen, Thousand Oaks, California.
Ricardo
R
Dent
Amgen, Thousand Oaks, California.
Beat
B
Knusel
Amgen, Thousand Oaks, California.
Allen
A
Xue
Amgen, Thousand Oaks, California.
Rob
R
Scott
Amgen, Thousand Oaks, California.
Scott M
SM
Wasserman
Cardiovascular Medicine Department, Cleveland Clinic, Cleveland, Ohio.
Michael
M
Rocco
D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000097:blood / Q000187:drug effects* / Q000276:immunology; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis; D002784:Cholesterol / Q000097:blood*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004361:Drug Tolerance; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors* / Q000276:immunology; D012697:Serine Endopeptidases / Q000276:immunology; D016896:Treatment Outcome; D055815:Young Adult
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C577155:evolocumab
LDL-cholesterol; evolocumab; ezetimibe; hypercholesterolemia; statin intolerance