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

Madurka I.; Vishnevsky A.; Soriano J.B.; Gans S.J.; Ore D.J.S.; Rendon A.; Ulrik C.S.; Bhatnagar S.; Krishnamurthy S.; Mc Harry K.; Welte T.; Fernandez A.A.; Mehes B.; Meiser K.; Gatlik E.; Sommer U.; Junge G.; Rezende E.; Bagu A.M.; Amido F.H.; Costa M.B.; Brigante J.A.; Franco G.; Ahmed N.J.; Zerega N.; Bacci M.R.; Fernandes C.C.; Ragognete H.G.; de Carvalho Rezende E.A.; Jaoude C.V.G.; de Olivera E.P.; Malacize V.Q.; Stadnik C.M.B.; Ramos E.A.; Kist G.R.; Barbosa G.R.; Filik H.; Nalin S.; Tidemandsen C.; Hakansson K.; Benfield T.; Pedersen K.B.H.; Bachman M.; Stoll M.; Olzik I.; Scharf N.; Shearman N.; Pink I.; Frey A.; Schulze P.; Sayehli C.M.; Weismann D.; Klinker H.; Goebeler M.-E.; Maier L.; Geismann F.; Hanses F.; Zeller J.; Hupf J.; Lubnow M.; Sag S.; Ripfel S.; Pabel S.; Bauernfeind S.; Leisner U.; Hitzenbichler F.; Iharos D.; Toth K.K.; Hejja M.; Esze T.; Mohan A.; Pandit A.; Kumar B.; Ratre B.K.; Tiwari P.; Singh R.; Vig S.; Bhopale S.; Bhan S.; Budhraja A.; Agrawal A.; Srikanth A.; Kaneesan K.; Unnithan M.R.J.; Srinivasan N.; Velayuthaswamy N.; Gounder S.K.M.; Vaidyanathan V.; Saha A.; Bhattacharjee A.; Datta A.; Ortiz A.C.; Moncivais B.S.; Rodriguez B.N.L.; Ramirez E.J.R.; Perez R.O.F.; Perez D.L.C.; Osornio J.S.; Ortega M.L.M.; Medina M.A.J.; VanDen Berg J.W.; Boom L.; Panhuis E.; Lancee G.; Lammens M.; Boeve-Epping N.; Bustios E.R.M.; Flores E.M.Z.; Farronay M.I.M.; Orihuela B.G.; del Pino R.M.; Morozov E.; Repnikov I.; Kiseleva M.; Kotov M.E.; Terskikh M.M.; Zykov V.A.; Smolyarchuk E.A.; Kurguzova D.; Garkavi D.A.; Messnikov O.; Kharlamova S.; Bondareva Y.A.; Sementsov K.V.; Katagarov D.N.; Belekhov G.A.; Alferov S.P.; Martynenko T.I.; Vasileva E.; Lazarenko I.V.; Gatalsky K.K.; Rudikh O.V.; Ganova O.S.; Paraeva O.S.; Pashkevich V.V.; Vishneva E.M.; Martynov A.V.; Isakova A.P.; Egorova E.A.; Gaygolnik T.V.; Pinzhina V.N.; Hinovker V.V.; Abramov V.G.; Ignatova G.L.; Blinova E.V.; Grebneva I.V.; Rodionova O.V.; Antonov V.N.; Trufanov K.V.; Krylov A.A.; Radchenko E.N.; McHarry K.; Snyman E.; Soriano J.; Serrano D.R.; Vergara A.M.; Marcos M.C.; Viladomiu A.S.; Cardozo C.; Garcia F. · Infection (2023) · DOI: 10.1007/s15010-022-01904-w

Resumen

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.