Study in Participants With Homozygous Familial Hypercholesterolemia - ODYSSEY HoFH

Jul 20, 2020
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Sanofi and Regeneron Pharmaceuticals, Inc.
Date Published:
07/06/2020
Original Posted Date:
07/20/2020
References

Contribution To Literature:

The ODYSSEY HoFH trial showed that alirocumab taken every other week significantly reduces LDL-C among patients with diagnosed HoFH without obvious safety signals. 

Description:

The goal of the trial was to compare the safety and efficacy of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in reducing low-density lipoprotein cholesterol (LDL-C) among patients with homozygous familial hypercholesterolemia (HoFH).

Study Design

Eligible patients were randomized in a 2:1 fashion to either alirocumab (n = 45) or placebo (n = 24). Alirocumab was administered as 150 mg subcutaneously every 2 weeks, for a total of 12 weeks. All participants subsequently entered a 12-week open-label treatment period and received alirocumab 150 mg every 2 weeks.

  • Total number of enrollees: 69
  • Duration of follow-up: 24 weeks
  • Mean patient age: 44 years
  • Percentage female: 50%
  • Percentage white: 78%

Inclusion criteria:

  • Clinical or genetic diagnosis of HoFH
  • LDL-C ≥70 mg/dl
  • Stable dose of statin at the screening visit or have documented lack of efficacy with statins/statin intolerance
  • If patients were undergoing apheresis, they must have received treatment for ≥3 months and have been on a stable schedule for ≥8 weeks

Exclusion criteria:

  • Documented evidence of a null mutation in both LDL receptor (LDLR) alleles
  • Use of a PCSK9 inhibitor within 10 weeks of the screening visit
  • Background medical lipid-lowering therapy that had not been stable for ≥4 weeks (6 weeks for fibrates, 24 weeks for mipomersen, 12 weeks for maximum tolerated dose of lomitapide) before the screening visit
  • Presence of any clinically significant uncontrolled endocrine disease known to influence serum lipids or lipoproteins
  • Chronic use of systemic corticosteroids

Other salient features/characteristics:

  • Genotype confirmed HoFH: 62% (homozygous LDLR: 41%)
  • Prior myocardial infarction: 11%
  • High-intensity statin: 86%
  • Baseline LDL-C: 275 mg/dl

Principal Findings:

The primary efficacy endpoint, least squares mean percent change in LDL-C from baseline at week 12, for alirocumab vs. placebo, is -26.9% vs. 8.6% (p < 0.0001).

  • LDL-C at 12 weeks: 219.9 vs. 291.6 mg/dl

Secondary endpoints for alirocumab vs. placebo:

  • Change in apolipoprotein B from baseline at 12 weeks: -22.5 vs. 7.2% (p < 0.0001)
  • ≥30% reduction in LDL-C: 57.1% vs. 4.2% (p < 0.0001)
  • Any treatment-related adverse events: 44.4% vs. 50%
  • General allergic events: 2.2% vs. 0%

Interpretation:

The results of this trial indicate that the use of alirocumab taken every other week significantly reduces LDL-C among patients with diagnosed HoFH. There were no obvious safety signals.

The LDL-C reduction in this cohort is lower than reported from other populations (usually approximately 60%), likely related to genetic deficiencies in the LDLR pathway; these agents block PCSK9 and increase LDLR on the liver surface, thereby increasing LDL-C clearance from the circulation. The median LDL-C levels at the end of the study period were still >200 mg/dl in the alirocumab arm (who were also on high-dose statins for the most part), suggesting that other additional therapies may be warranted in this high-risk patient population.

References:

Blom DJ, Harada-Shiba M, Rubba P, et al. Efficacy and Safety of Alirocumab in Adults With Homozygous Familial Hypercholesterolemia: The ODYSSEY HoFH Trial. J Am Coll Cardiol 2020;76:131-42.

Editorial Comment: PCSK9 Inhibitors for Homozygous Familial Hypercholesterolemia: Useful But Seldom Sufficient. J Am Coll Cardiol 2020;76:143-5.

Clinical Topics: Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

Keywords: Apolipoproteins B, Atherosclerosis, Antibodies, Monoclonal, Apolipoproteins B, Cholesterol, LDL, Dyslipidemias, Genotype, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Myocardial Infarction, PCSK9 protein, human, Primary Prevention, Proprotein Convertase 9


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