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.

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

Fig. 1

CONSORT flowchart of trial participation. N number of patients, SoC standard-of-care. *One patient randomised to the DFV890 arm did not receive any study treatment

Fig. 2

APACHE II scores up to 2 weeks (safety analysis set). APACHE II scores were modelled using a mixed-effects model with treatment, visit, stratification factors, visit*treatment, and visit*stratification factors as fixed effects and baseline score and visit*baseline as continuous covariates. Stratification factors were age group (≤ 65 years, > 65 years), administration of any antiviral therapy (yes/no), and presence of comorbidities ≥ 1 (yes/no). The one-sided p value for the overall treatment factor was p = 0.225. The safety analysis set included all randomised patients who attended at least one post-baseline visit. APACHE Acute Physiology and Chronic Health Evaluation, SE standard error, SoC standard-of-care

Fig. 3

a Sankey plot of change from baseline in clinical status and summary of at least one-level improvement in clinical status (WHO 9-point ordinal scale; safety analysis set); b Kaplan–Meier plot for mechanical ventilation-free survival. The safety analysis set included all randomised patients who attended at least one post-baseline visit. a Responders were defined as patients with a reduction of ≥ 1 on a 9-point ordinal scale score from screening to Day 14/28. 90% CI was based on Fisher’s exact test. The two-sided p value for the treatment effect on Day 14 and Day 28 was 0.1509 and 0.6380, respectively; b Mechanical ventilation-free survival was defined as a 9-point ordinal scale score of < 6 points. CI confidence interval, SoC standard-of-care, WHO World Health Organization

Fig. 4

Subgroup analysis of inflammatory markers in patients with more severe inflammation (CRP↑) who received lower corticosteroid doses in the first week (compliant analysis set). Only patients with baseline CRP greater than median baseline CRP (> 78.8 mg/L) and an average daily dose of corticosteroids ≤ 10 mg during the first week after randomisation were included. The analysis was based on the compliant analysis set (patients with confirmed SARS-COV-2 infection were included and patients with APACHE II score < 10 at baseline and ≥ 6 missed doses of study drug were excluded). The model adjusted the results to the average markers and clinical status at baseline. Dotted line represents APACHE II score < 10 at baseline. APACHE Acute Physiology and Chronic Health Evaluation, IL interleukin, IP-10 interferon-γ-inducible protein-10, CRP C-reactive protein, SoC standard-of-care