ODYSSEY FH I and FH II - ODYSSEY FH I and FH II

Sep 01, 2015
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Presenter/Author:
John J.P. Kastelein, MD
Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Kim A. Eagle, MD, MACC
Trial Sponsor:
Sanofi, Regeneron
Date Presented:
09/01/2015
Date Published:
09/01/2015
Date Updated:
09/01/2015
Original Posted Date:
08/31/2014
References

Description:

The goal of the trial was to evaluate treatment with alirocumab, a monoclonal antibody targeting PCSK9, compared with placebo among participants with heterozygous familial hypercholesterolemia.

Contribution to the Literature: The ODYSSEY FH I and FH II trials showed that alirocumab markedly reduced LDL-C among patients on maximum tolerated statin therapy.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Participants with heterozygous familial hypercholesterolemia
  • On maximum tolerated statin therapy
  • LDL-C >70 mg/dl and history of cardiovascular disease, or
  • LDL-C >100 mg/dl and no history of cardiovascular disease

    Number of enrollees: 735
    Duration of follow-up: 52 weeks
    Mean patient age: 52 years
    Percentage female: 44%

Primary Endpoints:

  • From baseline to 24 weeks, the change in LDL-C

Drug/Procedures Used:

Participants with heterozygous familial hypercholesterolemia on maximum tolerated statin therapy were randomized to self-administered alirocumab 75 mg subcutaneous injection (up-titration possible to 150 mg) every 2 weeks (n = 490) versus placebo subcutaneous injection every 2 weeks (n = 245).

Concomitant Medications:

Statin: 100% (approximately 80% was high-intensity statin)

Principal Findings:

Overall, 735 patients were randomized. The median age was 52 years, 44% were women, mean body mass index was 29 kg/m2, and 9.6% had diabetes. The mean LDL-C was 145 mg/dl.

In FH I: From baseline to 24 weeks, the change in LDL-C was -48.8% for alirocumab compared with 9.1% for placebo (p < 0.0001). The dose of alirocumab was up-titrated in 43.4% of participants. This reduction was maintained to 52 weeks.

In FH II: From baseline to 24 weeks, the change in LDL-C was -48.7% for alirocumab compared with 2.8% for placebo (p < 0.0001). The dose of alirocumab was up-titrated in 38.6% of participants. This reduction was maintained to 52 weeks.

Treatment-emergent adverse events leading to drug discontinuation occurred in 3.1% of the alirocumab group vs. 3.7% of the placebo group.

Cardiovascular events occurred in 1.6% of the alirocumab group vs. 1.2% of the placebo group.

In a pooled analysis of four alirocumab vs. placebo trials (n = 1,257), alirocumab resulted in a 58% reduction in LDL-C at 52 weeks and a 56% reduction in LDL-C at 78 weeks. Target LDL-C <70 mg/dl was achieved in 63% of subjects. Treatment emergent adverse events leading to death occurred in 0.8%, and to study drug discontinuation in 3.9%.

Interpretation:

Among patients with heterozygous familial hypercholesterolemia, alirocumab resulted in a large reduction in LDL-C compared with placebo, which was maintained to 52 weeks. Approximately 50% of participants were able to achieve their LDL-C target on the lower dose of alirocumab. Alirocumab appeared to be generally well-tolerated and was associated with low cardiovascular events. Future studies will examine the impact of this agent on clinical outcomes.

References:

Kastelein JJ, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J 2015;Sep 1:[Epub ahead of print].

Editorial: Laufs U, Parhofer KG. Simplified algorithm to facilitate communication of familial hypercholesterolaemia. Eur Heart J 2015;Sep 1:[Epub ahead of print].

Presented by Dr. John Kastelein at the European Society of Cardiology Congress, London, September 1, 2015.

Presented by Dr. John Kastelein at the European Society of Cardiology Congress, Barcelona, Spain, August 31, 2014.

Keywords: Lipoproteins, LDL, Body Mass Index, Hyperaldosteronism, Cholesterol, LDL, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Injections, Subcutaneous, Hyperlipoproteinemia Type II, Diabetes Mellitus, ESC Congress


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