Abstract

Abstract Background Plitidepsin has shown potent preclinical activity against SARS-CoV-2 and was generally well tolerated in a Phase I trial of hospitalized patients with COVID-19. NEPTUNO, a Phase III, multicenter, randomized, controlled trial, was designed to evaluate the efficacy and safety of plitidepsin in the management of moderate COVID-19 in hospitalized adult patients. Methods Included patients had documented SARS-CoV-2 infection, required oxygen therapy, and had adequate organ function. The planned sample size was 609 patients. Patients were randomized 1:1:1 to at least 3 days of dexamethasone plus either plitidepsin (1.5 mg/day or 2.5 mg/day, for 3 days) or standard of care (control). The primary endpoint was the time to sustained withdrawal of supplemental oxygen. Secondary endpoints included time to sustained hospital discharge, clinical status, duration of oxygen support, percentage of patients requiring admission to the intensive care unit, and safety. Findings After randomizing 205 patients, NEPTUNO was discontinued due to a notable drop in COVID-19-related hospitalizations. Available data suggest a 2-day improvement in the median time to sustained oxygen therapy discontinuation (5 vs 7 days) favoring both plitidepsin arms (hazard ratio [HR] 1.37, 95% confidence interval [CI] 0.96–1.96, p=0.08 for plitidepsin 1.5 mg vs control; HR 1.06, 95% CI 0.73–1.53, p=0.78 for plitidepsin 2.5 mg vs control). Plitidepsin was generally well tolerated. Interpretation Despite the trial limitations, these results suggest that plitidepsin may have a positive benefit-risk ratio in the management of patients requiring oxygen therapy. Further studies with plitidepsin, including those in immunosuppressed patients, are warranted. Funding This trial has been funded by Pharmamar, S.A. (Madrid, Spain).