Efficacy, safety, and tolerability of a monoclonal antibody to proprotein
convertase subtilisin/kexin type 9 in combination with a statin in patients with
hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled,
dose-ranging, phase 2 study.
Author(s): Giugliano RP, Desai NR, Kohli P, Rogers WJ, Somaratne R, Huang F, Liu T,
Mohanavelu S, Hoffman EB, McDonald ST, Abrahamsen TE, Wasserman SM, Scott R,
Sabatine MS; LAPLACE-TIMI 57 Investigators.
Affiliation(s): TIMI Study Group, Brigham and Women's Hospital, Boston, MA, USA.
rgiugliano@partners.org
Publication date & source: 2012, Lancet. , 380(9858):2007-17
BACKGROUND: LDL cholesterol (LDL-C) is a well established risk factor for
cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9)
binds LDL receptors, targeting them for degradation. We therefore assessed the
efficacy, safety, and tolerability of AMG 145, a human monoclonal IgG2 antibody
against PCSK9, in stable patients with hypercholesterolemia on a statin.
METHODS: In a phase 2, dose-ranging study done in 78 centres in the USA, Canada,
Denmark, Hungary, and Czech Republic, patients (aged 18-80 years) with LDL-C
greater than 2·2 mmol/L on a stable dose of statin (with or without ezetimibe),
were randomly assigned equally, through an interactive voice response system, to
subcutaneous injections of AMG 145 70 mg, 105 mg, or 140 mg, or matching placebo
every 2 weeks; or subcutaneous injections of AMG 145 280 mg, 350 mg, or 420 mg,
or matching placebo every 4 weeks. Everyone was masked to treatment assignment
within the every 2 weeks and every 4 weeks schedules. The primary endpoint was
the percentage change in LDL-C concentration from baseline after 12 weeks.
Analysis was by modified intention to treat. This study is registered with
ClinicalTrials.gov, number NCT01380730.
FINDINGS: 631 patients with hypercholesterolaemia were randomly assigned to AMG
145 70 mg (n=79), 105 mg (n=79), or 140 mg (n=78), or matching placebo (n=78)
every 2 weeks; or AMG 145 280 mg (n=79), 350 mg (n=79), and 420 mg (n=80), and
matching placebo (n=79) every 4 weeks. At the end of the dosing interval at week
12, the mean LDL-C concentrations were reduced generally dose dependently by AMG
145 every 2 weeks (ranging from 41·8% to 66·1%; p<0·0001 for each dose vs
placebo) and AMG 145 every 4 weeks (ranging from 41·8% to 50·3%; p<0·0001). No
treatment-related serious adverse events occurred. The frequencies of
treatment-related adverse events were similar in the AMG 145 and placebo groups
(39 [8%] of 474 vs 11 [7%] of 155); none of these events were severe or
life-threatening.
INTERPRETATION: The results suggest that PCSK9 inhibition could be a new model in
lipid management. Inhibition of PCSK9 warrants assessment in phase 3 clinical
trials.
FUNDING: Amgen.
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