Brief Report
Myeloperoxidase Inhibition in Heart Failure With Preserved or Mildly Reduced Ejection Fraction: SATELLITE Trial Results

https://doi.org/10.1016/j.cardfail.2023.04.003Get rights and content
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Highlights

  • Does treatment for 90 days with 5 mg oral doses of the myeloperoxidase inhibitor AZD4831 decrease myeloperoxidase specific activity in patients with heart failure and a left ventricular ejection fraction of at least 40%, with acceptable safety and tolerability?

  • AZD4831 reduced normalized ex vivo myeloperoxidase specific activity by more than 50% from baseline and by 75% vs placebo in this randomized, double-blind, phase 2a trial in 41 patients, with few treatment-related adverse events and no safety signals of concern.

  • The level of myeloperoxidase inhibition and the safety profile observed with AZD4831 warrant further clinical investigation of the efficacy and safety of this first-in-class myeloperoxidase inhibitor in patients with heart failure and preserved or mildly reduced left ventricular ejection fraction.

Abstract

Background

Inflammation is a key driver of heart failure with preserved left ventricular ejection fraction. AZD4831 inhibits extracellular myeloperoxidase, decreases inflammation, and improves microvascular function in preclinical disease models.

Methods and Results

In this double-blind phase 2a study (Safety and Tolerability Study of AZD4831 in Patients With Heart Failure [SATELLITE]; NCT03756285), patients with symptomatic heart failure, left ventricular ejection fraction of ≥40%, and elevated B-type natriuretic peptides were randomized 2:1 to once-daily oral AZD4831 5 mg or placebo for 90 days. We aimed to assess target engagement (primary end point: myeloperoxidase specific activity) and safety of AZD4831. Owing to coronavirus disease 2019, the study was terminated early after randomizing 41 patients (median age 74.0 years, 53.7% male). Myeloperoxidase activity was decreased by more than 50% from baseline to day 30 and day 90 in the AZD4831 group, with a placebo-adjusted decreased of 75% (95% confidence interval, 48, 88, nominal P < .001). No improvements were noted in secondary or exploratory end points, apart from a trend in Kansas City Cardiomyopathy Questionnaire overall summary score. No deaths or treatment-related serious adverse events occurred. AZD4831 treatment-related adverse events were generalized maculopapular rash, pruritus, and diarrhea (all n = 1).

Conclusions

AZD4831 inhibited myeloperoxidase and was well tolerated in patients with heart failure and left ventricular ejection fraction of 40% or greater. Efficacy findings were exploratory owing to early termination, but warrant further clinical investigation of AZD4831.

Lay Summary

Few treatments are available for patients with the forms of heart failure known as heart failure with preserved or mildly reduced ejection fraction. Current treatments do not target inflammation, which may play an important role in this condition. We tested a new drug called AZD4831 (mitiperstat), which decreases inflammation by inhibiting the enzyme myeloperoxidase. Among the 41 patients in our clinical trial, AZD4831 had a good safety profile and inhibited myeloperoxidase by the expected amount. Results mean we can conduct further trials to see whether AZD4831 decreases the symptoms of heart failure and improves patients’ ability to participate in physical exercise.

Key Words

Heart failure
preserved ejection fraction
mildly reduced ejection fraction
myeloperoxidase
inflammation
pharmacokinetics
pharmacodynamics
randomized controlled trial

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Affiliation at the time the work was conducted: Research and Early Clinical Development, Cardiovascular, Renal and Metabolic, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.