Effects of RG7652, a Monoclonal Antibody Against PCSK9, on LDL-C, LDL-C Subfractions, and Inflammatory Biomarkers in Patients at High Risk of or With Established Coronary Heart Disease (from the Phase 2 EQUATOR Study).
RG7652 (MPSK3169A), a fully human immunoglobulin G1 (IgG1) monoclonal antibody directed against proprotein convertase subtilisin/kexin type 9 (PCSK9), blocks the interaction between PCSK9 and low-density lipoprotein (LDL) receptor. EQUATOR (ClinicalTrials.govNCT01609140), a randomized, double-blind, and dose-ranging phase 2 study, evaluated RG7652 in patients (1) at high risk for or (2) with coronary heart disease (CHD). The primary end point was change in LDL cholesterol (LDL-C) from baseline to day 169. Patients (n = 248; median age, 64 years; 57% men; 52% with established CHD; 82% on statins) with baseline LDL-C levels of 90 to 250 mg/dl (mean, 126 mg/dl) continuing on standard-of-care therapy were randomized to receive 1 of 5 RG7652 doses or placebo, subcutaneously every 4, 8, or 12 weeks for 24 weeks. Significant dose-dependent reductions in LDL-C levels from baseline to nadir (56 to 74 mg/dl [48% to 60%]) were observed in all RG7652-dosed patients; effects persisted to day 169 with the highest doses (reduction vs placebo up to 62 mg/dl [51%]) with no unexpected safety signals. RG7652 reduced apolipoprotein B and lipoprotein(a) levels. LDL-C subfraction analysis by nuclear magnetic resonance spectroscopy revealed a prominent decrease in large LDL-C and some decrease in small LDL particles. There was significant reduction in mean particle size of LDL-C on day 169 but no significant reductions in systemic markers of inflammation (high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-alpha). RG7652 reduced LDL-C levels and was well tolerated in patients at high risk for or with CHD on standard-of-care therapy. In conclusion, RG7562 treatment affected large LDL-C and, to a lesser extent, small LDL-C particles; RG7562 did not affect systemic circulating pro-inflammatory cytokines or high-sensitivity C-reactive protein.
Genentech, Inc., South San Francisco, California. Electronic address: baruch.amos@gene.com.
Amos
A
Baruch
Genentech, Inc., South San Francisco, California.
Sofia
S
Mosesova
Genentech, Inc., South San Francisco, California.
John D
JD
Davis
Genentech, Inc., South San Francisco, California.
Nageshwar
N
Budha
F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Alexandr
A
Vilimovskij
Genentech, Inc., South San Francisco, California.
Robert
R
Kahn
Genentech, Inc., South San Francisco, California.
Kun
K
Peng
Genentech, Inc., South San Francisco, California.
Kyra J
KJ
Cowan
Genentech, Inc., South San Francisco, California.
Laura Pascasio
LP
Harris
Genentech, Inc., South San Francisco, California.
Thomas
T
Gelzleichter
Genentech, Inc., South San Francisco, California.
Josh
J
Lehrer
Genentech, Inc., South San Francisco, California.
John C
JC
Davis
Genentech, Inc., South San Francisco, California. Electronic address: tingley.whittemore@gene.com.
Whittemore G
WG
Tingley
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood* / Q000187:drug effects; D003327:Coronary Disease / Q000097:blood / Q000175:diagnosis / Q000517:prevention & control*; D016207:Cytokines / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood; D007279:Injections, Subcutaneous; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D000071449:Proprotein Convertase 9 / Q000276:immunology*; D012307:Risk Factors; D055815:Young Adult
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D008078:Cholesterol, LDL; D016207:Cytokines; C000600650:RG7652; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9