Efficacy, Safety, and Tolerability of a Monoclonal Antibody to PCSK9 in Combination With a Statin in Patients With Hypercholesterolemia - LAPLACE-TIMI 57

Description:

The goal of the trial was to evaluate treatment with AMG 145, a monoclonal antibody, against proprotein convertase subtilisin/kexin type 9 (PCSK9) compared with placebo among stable patients with hypercholesterolemia treated with a statin.

PCSK9 binds low-density lipoprotein cholesterol (LDL-C) receptors and targets them for degradation.

Hypothesis:

AMG 145 will safely lower LDL-C.

Study Design

  • Randomized
  • Blinded
  • Parallel
  • Placebo Controlled

Patient Populations:

  • Stable patients ≥18 years of age with hypercholesterolemia treated with a statin

    Number of screened applicants: 934
    Number of enrollees: 631
    Duration of follow-up: 12 weeks

Exclusions:

  • Severe comorbidities
  • Use of a lipid-lowering drug other than a statin or ezetimibe

Primary Endpoints:

  • Percent change in LDL-C level from baseline to 12 weeks

Secondary Endpoints:

  • Absolute change in LDL-C level from baseline to 12 weeks
  • Percent change in non–HDL-C and apolipoprotein B, and ratios of total cholesterol to HDL-C and apolipoprotein B to apoliprotein A1 concentrations
  • Serious adverse events

Drug/Procedures Used:

Stable patients with hypercholesterolemia treated with a statin were randomized to AMG 145 versus placebo.

In this phase 2 dose-ranging study, AMG was administered as a subcutaneous injection in the following doses: 70 mg (n = 79), 105 mg (n = 79), 140 mg (n = 78), or matching placebo (n = 78) every 2 weeks, or 280 mg (n = 79), 350 mg (n = 79), 420 mg (n = 80), or matching placebo (n = 79) every 4 weeks.

Principal Findings:

Overall, 631 patients were randomized. The mean age was 62 years, 51% were women, mean body mass index was 29 kg/m2, 16% had diabetes, 30% had coronary artery disease, and 99% were taking a statin medication.

At 12 weeks, the mean change in LDL-C with AMG 145 given every 2 weeks versus placebo is provided for the following doses (p < 0.0001 for all comparisons):
- 70 mg: -41.8%
- 105 mg: -60.2%
- 140 mg: -66.1%

At 12 weeks, the mean change in LDL-C with AMG 145 given every 4 weeks versus placebo is provided for the following doses (p < 0.0001 for all comparisons):
- 280 mg: -41.8%
- 350 mg: -50.0%
- 420 mg: -50.3%

At 12 weeks, the achieved LDL-C with AMG 145 given every 2 weeks versus placebo is provided for the following doses:
- 70 mg: 73 mg/dl
- 105 mg: 54 mg/dl
- 140 mg: 45 mg/dl

At 12 weeks, the achieved LDL-C with AMG 145 given every 4 weeks versus placebo is provided for the following doses (p < 0.0001 for all comparisons):
- 280 mg: 69 mg/dl
- 350 mg: 60 mg/dl
- 420 mg: 59 mg/dl

At 12 weeks, the mean change in non-HDL-C with AMG 145 given every 2 weeks versus placebo is provided for the following doses (p < 0.0001 for all comparisons):
- 70 mg: -38.4%
- 105 mg: -55.4%
- 140 mg: -61.4%

At 12 weeks, the mean change in non-HDL-C with AMG 145 given every 4 weeks versus placebo is provided for the following doses (p < 0.0001 for all comparisons):
- 280 mg: -37.8%
- 350 mg: -45.8%
- 420 mg: -47.6%

At 12 weeks, the mean change in apolipoprotein-B with AMG 145 given every 2 weeks versus placebo is provided for the following doses (p < 0.0001 for all comparisons):
- 70 mg: -34.7%
- 105 mg: -50.1%
- 140 mg: -56.4%

At 12 weeks, the mean change in apolipoprotein-B with AMG 145 given every 4 weeks versus placebo is provided for the following doses (p < 0.0001 for all comparisons):
- 280 mg: -34.4%
- 350 mg: -40.8%
- 420 mg: -42.0%

Serious adverse events were low and ranged from 0 to 5%. There were no treatment-related adverse events that led to study drug discontinuation.

Interpretation:

Among stable patients with hypercholesterolemia, PCSK9 inhibition by AMG 145 reduced LDL-C, non-HDL-C, and apolipoprotein-B in a dose-dependent fashion without serious adverse events. Further study in phase 3 trials is warranted.

References:

Giugliano RP, Desai NR, Kohli P, et al., on behalf of the LAPLACE-TIMI 57 Investigators. 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. Lancet 2012;380:2007-17.

Presented by Dr. Robert Giugliano at the American Heart Association Scientific Sessions, Los Angeles, CA, November 6, 2012.

Clinical Topics: Dyslipidemia, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Coronary Artery Disease, Follow-Up Studies, Hypercholesterolemia, Proprotein Convertases, Lipoproteins, LDL, Body Mass Index, Azetidines, Injections, Subcutaneous, Subtilisins, Diabetes Mellitus


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