A phase 1 study to evaluate the safety and LDL cholesterol-lowering effects of RG7652, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9.
BACKGROUND
Proprotein convertase subtilisin/kexin type 9 (PCSK9) downregulates low-density lipoprotein (LDL) receptors, thereby leading to a rise in circulating LDL cholesterol (LDL-C). RG7652 is a fully human monoclonal antibody against PCSK9. This placebo-controlled, phase 1 ascending-dose study in healthy subjects evaluated the safety of RG7652 and its efficacy as a potential LDL-C-lowering drug.


OBJECTIVE
Anti-PCSK9 antibody therapy safely and effectively reduces LDL-C.


METHODS
Subjects (N = 80) were randomized into 10 cohorts. Six sequential single-dose cohorts received 10, 40, 150, 300, 600, or 800 mg of RG7652 via subcutaneous injection. Four multiple-dose cohorts received 40 or 150 mg of RG7652 once weekly for 4 weeks, either with or without statin therapy (atorvastatin).


RESULTS
Adverse events (AEs) were generally mild; the most common AEs were temporary injection-site reactions. No serious AEs, severe AEs, AEs leading to study-drug discontinuation, or dose-limiting toxicities were reported. RG7652 monotherapy reduced mean LDL-C levels by up to 64% and as much as 100 mg/dL at week 2; the effect magnitude and duration increased with dose (≥57 days following a single RG7652 dose ≥300 mg). Exploratory analyses showed reduced oxidized LDL, lipoprotein(a), and lipoprotein-associated phospholipase A2 with RG7652. Antidrug antibody against RG7652 tested positive in 2 of 60 (3.3%) RG7652-treated and in 4 of 20 (20.0%) placebo-treated subjects. Simultaneous atorvastatin administration did not appear to impact the pharmacokinetic profile or lipid-lowering effects of RG7652.


CONCLUSIONS
Overall, RG7652 elicited substantial and sustained dose-related LDL-C reductions with an acceptable safety profile and minimal immunogenicity.
Genentech Inc., South San Francisco, California.
Amos
http://orcid.org/0000-0002-7940-8150
A
Baruch
Genentech Inc., South San Francisco, California.
Diana
D
Luca
Genentech Inc., South San Francisco, California.
Robert S
RS
Kahn
Genentech Inc., South San Francisco, California.
Kyra J
KJ
Cowan
Genentech Inc., South San Francisco, California.
Maya
M
Leabman
Genentech Inc., South San Francisco, California.
Nageshwar R
NR
Budha
Genentech Inc., South San Francisco, California.
Cecilia P C
CPC
Chiu
Genentech Inc., South San Francisco, California.
Yan
Y
Wu
Genentech Inc., South San Francisco, California.
Daniel
D
Kirchhofer
Genentech Inc., South San Francisco, California.
Andrew
A
Peterson
Genentech Inc., South San Francisco, California.
John C
JC
Davis
Genentech Inc., South San Francisco, California.
Whittemore G
WG
Tingley
D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000187:drug effects / Q000276:immunology / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents / Q000008:administration & dosage; D000069059:Atorvastatin / Q000008:administration & dosage; D015415:Biomarkers / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood* / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D000091362:PCSK9 Inhibitors; D000071449:Proprotein Convertase 9 / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents; D015415:Biomarkers; D008078:Cholesterol, LDL; D000091362:PCSK9 Inhibitors; C000600650:RG7652; D000069059:Atorvastatin; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
Clinical trial; LDL receptor; PCSK9 inhibitors; RG7652; antibody drug; cholesterol; phase 1