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

  • Infection. 2023 Jun;51(3):641-654. doi: 10.1007/s15010-022-01904-w.
Ildiko Madurka  1 ,  Alexander Vishnevsky  2 ,  Joan B Soriano  3 ,  Stephanus J Gans  4 ,  Danilo Joel Salazar Ore  5 ,  Adrian Rendon  6 ,  Charlotte S Ulrik  7 ,  Sushma Bhatnagar  8 ,  Srikanth Krishnamurthy  9 ,  Kirsten Mc Harry  10  11 ,  Tobias Welte  12 ,  Alberto A Fernandez  13 ,  Beata Mehes  14 ,  Karin Meiser  14 ,  Ewa Gatlik  14 ,  Ulrike Sommer  14 ,  Guido Junge  14 ,  Ederlon Rezende  15 ,  Study group
Affiliations
  • 1. Orszagos Koranyi TBC es Pulmonologiai Intezet, Budapest, Hungary. [email protected].
  • 2. St Petersburg State Institution of Healthcare, Pokrovskaya City Hospital, St Petersburg, Russia.
  • 3. Hospital Universitario de la Princesa-UAM, Madrid, Spain.
  • 4. Ziekenhuis St. Jansdal, Harderwijk, Netherlands.
  • 5. Hospital Nacional Cayetano Heredia, San Martin de Porres, Peru.
  • 6. Hospital Universitario Dr José Eleuterio Gonzalez, CIPTIR, Monterrey, Mexico.
  • 7. Copenhagen University Hospital-Hvidovre, Hvidovre, Denmark.
  • 8. Department of Neurology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India.
  • 9. Hindusthan Hospital, Coimbatore, India.
  • 10. Eden Task, George, South Africa.
  • 11. TASK Eden, George Regional Hospital, George, South Africa.
  • 12. Medizinische Hochschule Hannover, Hannover, Germany.
  • 13. Sanatorio Modelo de Quilmes, Buenos Aires, Argentina.
  • 14. Novartis Pharma AG, Basel, Switzerland.
  • 15. Intensive Care Unit, Hospital do Servidor Público Estadual Francisco Morato de Oliveira, São Paulo, Brazil.
PMID: 36104613 DOI: 10.1007/s15010-022-01904-w
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.

Keywords
Coronavirus-associated acute respiratory distress syndrome; DFV890; NLRP3 inhibitors; Randomised controlled trial; SARS-CoV-2.
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