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Safety of a novel oral NLRP3 inflammasome inhibitor, dapansutrile (OLT1177), in patients with stable heart failure with reduced ejection fraction

Session HFA Discoveries - ePosters

Speaker George Wohlford

Event : HFA Discoveries 2020

  • Topic : heart failure
  • Sub-topic : Chronic Heart Failure: Pharmacotherapy
  • Session type : ePoster

Authors : G Wohlford (Richmond,US), BV Van Tassell (Richmond,US), HE Billingsley (Richmond,US), D Kadariya (Richmond,US), JM Canada (Richmond,US), S Carbone (Richmond,US), V Mihalick (Richmond,US), A Vecchie (Richmond,US), JG Chiabrando (Richmond,US), E Bressi (Richmond,US), AA Marawan (Richmond,US), CR Tankle (Richmond,US), J Turlington (Richmond,US), R Markley (Richmond,US), A Abbate (Richmond,US)

Authors:
G Wohlford1 , BV Van Tassell1 , HE Billingsley1 , D Kadariya1 , JM Canada1 , S Carbone1 , V Mihalick1 , A Vecchie1 , JG Chiabrando1 , E Bressi1 , AA Marawan1 , CR Tankle1 , J Turlington1 , R Markley1 , A Abbate1 , 1Virginia Commonwealth University - Richmond - United States of America ,

Citation:

BACKGROUND. The NLRP3 (NACHT, LRR, and PYD domains-containing protein 3) inflammasome has been implicated in a wide range of inflammatory diseases. The use of anti-inflammatory drugs is limited by toxicity in patients with heart failure and reduced ejection fraction (HFrEF). The aim of this study was to determine the safety of a novel and targeted oral inhibitor of the NLRP3 inflammasome, dapansutrile (OLT1177), in patients with HFrEF.

METHODS. We conducted a phase 1B, randomized, double-blind, dose-escalation, single-center, repeat-dose safety and pharmacodynamics study of dapansutrile in stable patients with HFrEF (NYHA Class II-III). Subjects were randomized to treatment with dapansutrile for up to 14 days at a ratio of 4:1 into one of three sequential ascending dose cohorts (500 mg, 1000 mg, or 2000 mg) each comprised of 10 patients. Subjects underwent clinical assessment, biomarker determination, transthoracic echocardiogram and cardiopulmonary exercise testing at baseline, day 14, and day 28. Creatinine clearance was estimated using the Cockcroft-Gault equation. Descriptive statistics are reported as median and interquartile range. Wilcoxon signed-rank tests were performed to compare baseline and day 14 within each cohort. Placebo cases (N=2 per cohort) were used as a decoy to reduce bias and not for statistical comparisons.

RESULTS. Thirty subjects (20 males, 12 African-Americans) were treated for 13 (12-14) days. No patients experienced a serious adverse event during the study. No statistically significant within group differences were found for blood pressure, heart rate, body weight, creatinine clearance, N-terminal pro B-type natriuretic peptide or peak oxygen uptake at day 14 compared to baseline. Improvements in left ventricular ejection fraction (from 31.5% [26-39] to 36.5% [26-45.5], P=0.035) and in exercise time (from 570 [399.5-627] to 616 [446.5-688] seconds, P=0.036) were seen in the dapansutrile 2000 mg cohort.

CONCLUSIONS. Treatment with dapansutrile for 14 days was well tolerated and safe in patients with stable systolic heart failure.

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