Phase 1B, Randomized, Double-Blinded, Dose Escalation, Single-Center, Repeat Dose Safety and Pharmacodynamics Study of the Oral NLRP3 Inhibitor Dapansutrile in Subjects With NYHA II-III Systolic Heart Failure

Abstract

The NLRP3 inflammasome has been implicated in the development and progression of heart failure. The aim of this study was to determine the safety of an oral inhibitor of the NLRP3 inflammasome, dapansutrile (OLT1177), in patients with heart failure and reduced ejection fraction (HFrEF). This was a phase 1B, randomized, double-blind, dose escalation, single-center, repeat dose safety and pharmacodynamics study of dapansutrile in stable patients with HFrEF (New York Heart Association Class II-III). Subjects were randomized to treatment with dapansutrile for up to 14 days at a ratio of 4:1 into 1 of 3 sequential ascending dose cohorts (500, 1000, or 2000 mg) each including 10 patients. Subjects underwent clinical assessment, biomarker determination, transthoracic echocardiogram, and maximal cardiopulmonary exercise testing at baseline, day 14, and day 28 to ascertain changes in clinical status. Placebo cases (N = 2 per cohort) were used as a decoy to reduce bias and not for statistical comparisons. Thirty participants (20 men) were treated for 13 (12-14) days. No serious adverse events during the study were recorded. All clinical or laboratory parameters at day 14 compared with baseline suggested clinical stability without significant within-group differences in the dapansutrile-pooled group or the 3 dapansutrile cohorts. Improvements in left ventricular EF [from 31.5% (27.5-39) to 36.5% (27.5-45), P = 0.039] and in exercise time [from 570 (399.5-627) to 616 (446.5-688) seconds, P = 0.039] were seen in the dapansutrile 2000 mg cohort. Treatment with dapansutrile for 14 days was safe and well tolerated in patients with stable HFrEF.

Trial registration: ClinicalTrials.gov NCT03534297.

Conflict of interest statement

B. W. Van Tassell has served as a consultant for Novartis and Serpin Pharma. A. Abbate has served as a consultant for AstraZeneca, Janssen, Kiniksa Pharmaceuticals Ltd, Merck, Novartis, Olatec, and Serpin Pharma. A. Bonaventura and A. Vecchié received a travel grant from Kiniksa Pharmaceuticals Ltd to attend the 2019 American Heart Association Scientific Sessions. S. Carbone is supported by a Career Development Award 19CDA34660318 from the American Heart Association. The remaining authors report no conflicts of interest.

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.

Figures

FIGURE 1.

CONSORT diagram of the flow of study participants.

FIGURE 2.

Dapansutrile levels during the study period. A dose-dependent increase in the dapansutrile level was observed across the 3 cohorts, whereas no detectable levels were recorded in the placebo cohort.

FIGURE 3.

LVEF modifications across the study period. LVEF significantly increased from baseline at day 12 ± 2 in the dapansutrile-pooled cohort. This was mainly because of an improvement in LVEF in the dapansutrile 2000 mg daily cohort, whereas no significant changes in the 500 mg daily cohort, 1000 mg daily cohort, or in the placebo-pooled group were observed. *P < 0.05 for Wilcoxon signed-rank.

FIGURE 4.

Exercise time changes across the study period. A significant increase in the exercise time was found in the dapansutrile 2000 mg daily cohort, but not in the dapansutrile-pooled, the 500 mg daily, the 1000 mg daily, or the placebo-pooled groups. *P < 0.05 for Wilcoxon signed-rank.