Effect of MN-166 (ibudilast) on acute respiratory failure prevention in hospitalized participants with COVID-19: a randomized, double-blind, placebo-controlled phase 2 study

Abstract

Background: MN-166 (ibudilast) is an orally available small molecule drug candidate that inhibits macrophage migration inhibitory factor and phosphodiesterase 4 and 10. The rationale for using MN-166 to prevent Acute Respiratory Failure (ARF) is based upon its cellular and molecular target actions and recent research in LPS-induced ARF animal model. Methods: In this double-blind, randomized (1:1), placebo-controlled study conducted at two centers in the United States, we evaluated MN-166 (100 mg/day: 50 mg twice daily for 7 days) compared to placebo in hospitalized participants with COVID-19 at risk for ARF. The study’s co-primary endpoints were the proportion of participants free of respiratory failure at Day 7 and the proportion of participants with at least a one-point clinical status improvement in the National Institute of Allergy and Infectious Diseases 8-point ordinal scale at Day 7. All randomized participants received a study drug and were evaluated for efficacy and safety. Results: A total of 34 participants were randomly assigned to either MN-166 or placebo (17 in each treatment group). The study achieved one of the co-primary endpoints, a statistically significant difference (P < 0.02) between groups related to the proportion of participants free from respiratory failure. Two-fold of participants in the MN-166 treatment group were free from respiratory failure on Day 7 versus the placebo group (70.6% vs. 35.3%; percentage difference: 35.3% [95% CI: 1.98 to 59.46]; P < 0.02). Sensitivity analysis showed similar differences among participants receiving interleukin-6 antibody therapy, with a statistically significant percentage difference from the placebo group (71.4% vs. 25%; 46.4%, 95% CI: 1.48 to 91.38, P < 0.05). MN 166 treatment was better tolerated than placebo. Two deaths were reported in the placebo group and none in the MN-166 treatment group. Conclusions: MN-166 treatment was associated with faster recovery from respiratory failure in participants with COVID-19, independent of interleukin-6 antibody therapy. MN-166 was well-tolerated with fewer adverse events compared to placebo. Trial registration: ClinicalTrials.gov NCT04429555, Registered 11 June 2020,