DFV890: a new oral NLRP3 inhibitor—tested in an early phase 2a randomised clinical trial in patients with COVID-19 pneumonia and impaired respiratory function

Abstract

Background Coronavirus-associated acute respiratory distress syndrome (CARDS) has limited effective therapy to date. NLRP3 inflammasome activation induced by SARS-CoV-2 in COVID-19 contributes to cytokine storm. Methods This randomised, multinational study enrolled hospitalised patients (18–80 years) with COVID-19-associated pneumonia and impaired respiratory function. Eligible patients were randomised (1:1) via Interactive Response Technology to DFV890 + standard-of-care (SoC) or SoC alone for 14 days. Primary endpoint was APACHE II score at Day 14 or on day-of-discharge (whichever-came-first) with worst-case imputation for death. Other key assessments included clinical status, CRP levels, SARS-CoV-2 detection, other inflammatory markers, in-hospital outcomes, and safety. Findings Between May 27, 2020 and December 24, 2020, 143 patients (31 clinical sites, 12 countries) were randomly assigned to DFV890 + SoC ( n = 71) or SoC alone ( n = 72). Primary endpoint to establish clinical efficacy of DFV890 vs. SoC, based on combined APACHE II score, was not met; LSM (SE), 8·7 (1.06) vs. 8·6 (1.05); p = 0.467. More patients treated with DFV890 vs. SoC showed ≥ 1-level improvement in clinical status (84.3% vs. 73.6% at Day 14), earlier clearance of SARS-CoV-2 (76.4% vs. 57.4% at Day 7), and mechanical ventilation-free survival (85.7% vs. 80.6% through Day 28), and there were fewer fatal events in DFV890 group (8.6% vs. 11.1% through Day 28). DFV890 was well tolerated with no unexpected safety signals. Interpretation DFV890 did not meet statistical significance for superiority vs. SoC in primary endpoint of combined APACHE II score at Day 14. However, early SARS-CoV-2 clearance, improved clinical status and in-hospital outcomes, and fewer fatal events occurred with DFV890 vs. SoC, and it may be considered as a protective therapy for CARDS. Trial registration ClinicalTrials.gov, NCT04382053. Supplementary Information The online version contains supplementary material available at 10.1007/s15010-022-01904-w.

Safety and Efficacy of Disulfiram in Hospitalized Patients with Moderate COVID-19: A Randomized, Double-Blind, Placebo-Controlled Trial

“…Inhibition of inflammasome pathways and pyroptosis is being explored as potential treatments for COVID-19 [4,[31][32][33]. However, other inhibitors such as dimethyl fumarate (GSDMD inhibitor) and DFV890 (NLRP3 inhibitor) have not shown significant improvements in clinical outcomes [34,35].…”

The role of NOD-like receptors in innate immunity

“…Understanding the mechanisms of activation of NLRs is clinically significant, as the research may suggest potential therapeutic targets in several pathological conditions. In fact, NLRP3 inhibitors have already been considered in clinical trials involving diseases modulated by the NLRP3 inflammasome and IL-1β, such as in CAPS ( 125 , 126 ) and in COVID-19 ( 127 , 128 ). Future clinical trials and basic research will continue to unravel the potential to target inflammasome-associated NLRs for disease treatment and prevention.…”

Novel Sulfonylurea-Based NLRP3 Inflammasome Inhibitor for Efficient Treatment of Nonalcoholic Steatohepatitis, Endotoxic Shock, and Colitis

“…1 H NMR (400 MHz, DMSO-d 6 ) δ 8.36 (s, 1H), 8.21 (s, 1H), 7.73−7.66 (m, 2H), 7.27 (d, J = 7.7 Hz, 2H), 7.01 (s, 2H), 6.34 (s, 1H), 3.42 (s, 2H), 2.13 (s, 6H), 2.08 (s, 6H). 13 (21,42 mg, 0.12 mmol). N-((2,6-Dimethylphenyl)carbamoyl)-4-((dimethylamino)methyl)benzenesulfonamide (21, 42 mg, 0.12 mmol) was obtained from 2isocyanato-1,3-dimethylbenzene (S42b, 85 mg, 0.57 mmol), NaH (19 mg, 0.47 mmol), and 4-((dimethylamino)methyl)benzenesulfonamide (S38a, 100 mg, 0.47 mmol) as a white solid, with a yield of 25%.…”

“…5,18,19 Therefore, the reconfiguration of MCC950, in particular, the replacement of the furan moiety to improve its drug suitability, is highly necessary. As a matter of fact, there are many drugs that have been reconfigured in this way, of which ZYIL1, 20 IFM-2427, 21 Inzomelid, 22 and RG-6418 23 have entered the clinical phase, which suggests that optimizing the furan moiety could therefore be a promising strategy for obtaining a potent NLRP3 inhibitor (Figure 1). In this study, we designed and synthesized a series of NLRP3 inflammasome inhibitors, building upon the foundation of MCC950 and focusing on the optimization of its furan moiety in order to improve druggability.…”

“…Although a specific reason for drug-induced liver injury (DILI) was never disclosed, Dr. Latz and colleagues suggest that the metabolically reactive furan, along with the very high clinical dose of 1200 mg per day, could be two potential factors underlying the observed DILI. ,, Therefore, the reconfiguration of MCC950, in particular, the replacement of the furan moiety to improve its drug suitability, is highly necessary. As a matter of fact, there are many drugs that have been reconfigured in this way, of which ZYIL1, IFM-2427, Inzomelid, and RG-6418 have entered the clinical phase, which suggests that optimizing the furan moiety could therefore be a promising strategy for obtaining a potent NLRP3 inhibitor (Figure ).…”