Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins.
OBJECTIVE
The aim of this study was to evaluate the safety, tolerability, and effects of AMG 145 on low-density lipoprotein cholesterol (LDL-C) in healthy and hypercholesterolemic subjects on statin therapy.


BACKGROUND
Proprotein convertase subtilisin/kexin type 9 (PCSK9) down-regulates surface expression of the low-density lipoprotein receptor (LDL-R), increasing serum LDL-C. AMG 145, a fully human monoclonal antibody to PCSK9, prevents PCSK9/LDL-R interaction, restoring LDL-R recycling.


METHODS
Healthy adults (phase 1a) were randomized to 1 dose of AMG 145: 7, 21, 70, 210, or 420 mg SC; 21 or 420 mg IV; or matching placebo. Hypercholesterolemic adults (phase 1b) receiving low- to moderate-dose statins were randomized to multiple SC doses of AMG 145: 14 or 35 mg once weekly (QW) ×6, 140 or 280 mg every 2 weeks (Q2W) ×3, 420 mg every 4 weeks ×2, or matching placebo. Eleven subjects receiving high-dose statins and 6 subjects with heterozygous familial hypercholesterolemia were randomized to SC AMG 145 140 mg or placebo Q2W ×3.


RESULTS
In the trials (AMG 145 n = 85, placebo n = 28), AMG 145 reduced LDL-C up to 64% (p < 0.0001) versus placebo after 1 dose ≥21 mg and up to 81% (p < 0.001) with repeated doses ≥35 mg QW. No serious adverse events (AEs) occurred. Overall incidence of treatment-emergent AEs was similar in AMG 145 versus placebo groups: 69% versus 71% (phase 1a); 65% versus 64% (phase 1b).


CONCLUSIONS
In phase 1 studies, AMG 145 significantly reduced serum LDL-C in healthy and hypercholesterolemic statin-treated subjects, including those with heterozygous familial hypercholesterolemia or taking the highest doses of atorvastatin or rosuvastatin, with an overall AE profile similar to placebo.
Medical Sciences, Amgen, One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA. claptond@amgen.com
Clapton S
CS
Dias
Adam J
AJ
Shaywitz
Scott M
SM
Wasserman
Brian P
BP
Smith
Bing
B
Gao
Dina S
DS
Stolman
Caroline P
CP
Crispino
Karen V
KV
Smirnakis
Maurice G
MG
Emery
Alexander
A
Colbert
John P
JP
Gibbs
Marc W
MW
Retter
Blaire P
BP
Cooke
Stephen T
ST
Uy
Mark
M
Matson
Evan A
EA
Stein
D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D008078:Cholesterol, LDL / Q000037:antagonists & inhibitors* / Q000097:blood*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood* / Q000188:drug therapy*; D008297:Male; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011973:Receptors, LDL / Q000037:antagonists & inhibitors / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
D000911:Antibodies, Monoclonal; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases