ODYSSEY HIGH FH - ODYSSEY HIGH FH

Nov 19, 2014
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Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Sanofi and Regeneron Pharmaceuticals, Inc.
Date Presented:
01/01/2014
Date Updated:
11/19/2014
Original Posted Date:
11/19/2014
References

Description:

The current trial sought to study the safety and efficacy of alirocumab, a PCSK9 inhibitor, compared with placebo in heterozygous familial hypercholesterolemia (HeFH) patients who were on maximal tolerated doses of a statin, but had low-density lipoprotein cholesterol (LDL-C) levels ≥160 mg/dl.

Hypothesis:

Alirocumab would be superior to placebo in reducing LDL-C levels in HeFH patients with suboptimal LDL-C control despite being on maximal tolerated doses of a statin with or without other lipid-lowering therapy.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • HeFH patients on maximally tolerated statin ± other lipid-lowering agent
  • LDL-C ≥160 mg/dl

    Number of enrollees: 107
    Duration of follow-up: 24 weeks
    Mean patient age: 51 years
    Percentage female: 45%

Primary Endpoints:

  • Percent LDL-C change from baseline at 24 weeks

Secondary Endpoints:

  • Percent LDL-C change from baseline at 52 weeks

Drug/Procedures Used:

Patients were randomized in a 2:1 fashion to either self-administered alirocumab 150 mg subcutaneous Q2W or matching placebo.

Principal Findings:

A total of 107 patients were randomized, 72 to alirocumab and 35 to placebo. Baseline characteristics were fairly similar between the two arms. A genotypic diagnosis of HeFH was present in 17%, and the rest met clinical criteria. About 15% had diabetes, and 50% had a history of coronary heart disease. Nearly 80% of patients were on a high-dose statin at enrollment, and 27% were on ezetimibe. The mean baseline LDL-C was ~200 mg/dl, non–HDL-C was 227 mg/dl, and Lp(a) was 26 mg/dl.

Alirocumab significantly reduced LDL-C at 24 weeks compared with placebo at 24 weeks; percent decrease from baseline was 45.7% vs. 6.6%, difference 39.1, p < 0.0001. The absolute values of LDL-C at 24 weeks were also significantly lower (107 vs. 182 mg/dl). LDL-C lowering with alirocumab reached peak efficacy around 4 weeks, and was sustained thereafter. Patients in the alirocumab arm were more likely to achieve a target LDL-C <100 mg/dl (57% vs. 11%, p < 0.0001).

Injection-site reactions were higher in the alirocumab arm (8.3% vs. 2.9). On safety analysis, adjudicated cardiovascular (CV) events were similar (8.3% vs. 0%). Transaminitis (4.2% vs. 2.9%) and creatine kinase >3 x upper limit of normal (2.8% vs. 0%) were similar.

Interpretation:

The results of this trial indicate that alirocumab is superior to placebo in lowering LDL-C levels and achieving target levels in HeFH patients already on maximal tolerated doses of statins (with or without other lipid-lowering therapy). These results are smaller than those of the smaller phase 2 ODYSSEY LONG TERM trial, and add to the growing body of literature with PCSK9 inhibitors. Other large outcomes-based trials are ongoing. The higher CV event rate in this trial with alirocumab has also been observed in a few other phase 2/3 trials (none individually significant), and needs careful attention in the outcomes trials.

References:

Presented by Dr. Henry N. Ginsberg at the American Heart Association Scientific Sessions, Chicago, IL, November 19, 2014.

Keywords: Lipoproteins, LDL, Creatine Kinase, Cholesterol, LDL, Azetidines, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Coronary Disease, Maximum Tolerated Dose, Diabetes Mellitus, AHA Annual Scientific Sessions


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