PMID- 23083772
OWN - NLM
STAT- MEDLINE
DCOM- 20130109
LR  - 20230622
IS  - 1558-3597 (Electronic)
IS  - 0735-1097 (Linking)
VI  - 60
IP  - 19
DP  - 2012 Nov 6
TI  - 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.
PG  - 1888-98
LID - S0735-1097(12)04377-X [pii]
LID - 10.1016/j.jacc.2012.08.986 [doi]
AB  - OBJECTIVES: 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) x6, 140 or 280 mg every 2 weeks (Q2W) x3, 420 mg every 4 weeks x2, 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 x3. 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.
CI  - Copyright (c) 2012 American College of Cardiology Foundation. Published by Elsevier 
      Inc. All rights reserved.
FAU - Dias, Clapton S
AU  - Dias CS
AD  - Medical Sciences, Amgen, One Amgen Center Drive, Thousand Oaks, California 
      91320-1799, USA. claptond@amgen.com
FAU - Shaywitz, Adam J
AU  - Shaywitz AJ
FAU - Wasserman, Scott M
AU  - Wasserman SM
FAU - Smith, Brian P
AU  - Smith BP
FAU - Gao, Bing
AU  - Gao B
FAU - Stolman, Dina S
AU  - Stolman DS
FAU - Crispino, Caroline P
AU  - Crispino CP
FAU - Smirnakis, Karen V
AU  - Smirnakis KV
FAU - Emery, Maurice G
AU  - Emery MG
FAU - Colbert, Alexander
AU  - Colbert A
FAU - Gibbs, John P
AU  - Gibbs JP
FAU - Retter, Marc W
AU  - Retter MW
FAU - Cooke, Blaire P
AU  - Cooke BP
FAU - Uy, Stephen T
AU  - Uy ST
FAU - Matson, Mark
AU  - Matson M
FAU - Stein, Evan A
AU  - Stein EA
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20121017
PL  - United States
TA  - J Am Coll Cardiol
JT  - Journal of the American College of Cardiology
JID - 8301365
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Cholesterol, LDL)
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 0 (Receptors, LDL)
RN  - EC 3.4.21.- (PCSK9 protein, human)
RN  - EC 3.4.21.- (Proprotein Convertase 9)
RN  - EC 3.4.21.- (Proprotein Convertases)
RN  - EC 3.4.21.- (Serine Endopeptidases)
SB  - IM
MH  - Adult
MH  - Antibodies, Monoclonal/pharmacology/*therapeutic use
MH  - Cholesterol, LDL/*antagonists & inhibitors/*blood
MH  - Cohort Studies
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Female
MH  - Humans
MH  - Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology/*therapeutic use
MH  - Hypercholesterolemia/*blood/*drug therapy
MH  - Male
MH  - Proprotein Convertase 9
MH  - Proprotein Convertases/antagonists & inhibitors/metabolism
MH  - Receptors, LDL/antagonists & inhibitors/metabolism
MH  - Serine Endopeptidases/metabolism
MH  - Treatment Outcome
MH  - Young Adult
EDAT- 2012/10/23 06:00
MHDA- 2013/01/10 06:00
CRDT- 2012/10/23 06:00
PHST- 2012/05/22 00:00 [received]
PHST- 2012/08/08 00:00 [revised]
PHST- 2012/08/30 00:00 [accepted]
PHST- 2012/10/23 06:00 [entrez]
PHST- 2012/10/23 06:00 [pubmed]
PHST- 2013/01/10 06:00 [medline]
AID - S0735-1097(12)04377-X [pii]
AID - 10.1016/j.jacc.2012.08.986 [doi]
PST - ppublish
SO  - J Am Coll Cardiol. 2012 Nov 6;60(19):1888-98. doi: 10.1016/j.jacc.2012.08.986. 
      Epub 2012 Oct 17.