Efficacy, safety, and tolerability of a monoclonal antibody to proprotein
convertase subtilisin/kexin type 9 as monotherapy in patients with
hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled,
phase 2 study.
Author(s): Koren MJ, Scott R, Kim JB, Knusel B, Liu T, Lei L, Bolognese M, Wasserman SM.
Affiliation(s): Jacksonville Center for Clinical Research, FL, USA. mkoren@encoredocs.com
Publication date & source: 2012, Lancet. , 380(9858):1995-2006
BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases serum
LDL-cholesterol (LDL-C) concentrations. We assessed the effects of AMG 145, a
human monoclonal antibody against PCSK9, in patients with hypercholesterolaemia
in the absence of concurrent lipid-lowering treatment.
METHODS: In a phase 2 trial done at 52 centres in Europe, the USA, Canada, and
Australia, patients (aged 18-75 years) with serum LDL-C concentrations of 2·6
mmol/L or greater but less than 4·9 mmol/L were randomly assigned equally through
an interactive voice response system to subcutaneous injections of AMG 145 70 mg,
105 mg, or 140 mg, or placebo every 2 weeks; subcutaneous AMG 145 280 mg, 350 mg,
or 420 mg or placebo every 4 weeks; or oral ezetimibe 10 mg/day. The primary
endpoint was percentage change from baseline in LDL-C concentration at week 12.
Analysis was by modified intention to treat. Study personnel and patients were
masked to treatment assignment of AMG 145 or placebo. Ezetimibe assignment was
open label. This trial is registered with ClinicalTrials.gov, number NCT01375777.
FINDINGS: 406 patients were assigned to AMG 145 70 mg (n=45), 105 mg (n=46), or
140 mg (n=45) every 2 weeks; AMG 145 280 mg (n=45), 350 mg (n=45), or 420 mg
(n=45) every 4 weeks; placebo every 2 weeks (n=45) or every 4 weeks (n=45); or
ezetimibe (n=45). AMG 145 significantly reduced LDL-C concentrations in all dose
groups (mean baseline LDL-C concentration 3·7 mmol/L [SD 0·6]; changes from
baseline with every 2 weeks AMG 145 70 mg -41·0% [95% CI -46·2 to -35·8]; 105 mg
-43·9% [-49·0 to -38·7]; 140 mg -50·9% [-56·2 to -45·7]; every 4 weeks AMG 145
280 mg -39·0% [-44·1 to -34·0]; 350 mg -43·2% [-48·3 to -38·1]; 420 mg -48·0%
[-53·1 to -42·9]; placebo every 2 weeks -3·7% [-9·0 to 1·6]; placebo every 4
weeks 4·5% [-0·7 to 9·8]; and ezetimibe -14·7% [-18·6 to -10·8]; p<0·0001 for all
doses vs placebo or ezetimibe). Treatment-emergent adverse events occurred in 136
(50%) of 271 patients in the AMG 145 groups, 41 (46%) of 90 patients in the
placebo groups, and 26 (58%) of 45 patients in the ezetimibe group; no deaths or
serious treatment-related adverse events were reported.
INTERPRETATION: The results of our study support the further assessment of AMG
145 in long-term studies with larger and more diverse populations including
patients with documented statin intolerance.
FUNDING: Amgen.
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