This proof-of-concept study shows that plitidepsin, a marine peptide that inhibits SARS-CoV-2 replication, has a favorable safety profile and may be an efficacious treatment for patients with COVID-19. Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log 10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19.
【저자키워드】 breath, 【초록키워드】 Treatment, Mortality, Open-label, intensive care, SARS-COV-2 infection, hospital, SARS-CoV-2 variant, peptide, lung, diarrhea, invasive ventilation, adverse events, Randomized, Viral, Viral load, adverse event, Patient, plasma, Consent, Plitidepsin, respiratory, SARS-CoV-2 replication, safety profile, Concentration, dose, Respiratory Support, hypersensitivity, elongation factor, grade 3, preclinical studies, once daily, Support, one patient, host protein, nausea, vomiting, intensive care support, Spanish, End points, viral load reduction, log, died, inhibit, required, conducted, hospitalized patient, initiated, affecting, eukaryotic translation, baseline, patients with COVID-19, 【제목키워드】 Phase I, Randomized, adults hospitalized, Preclinical, with COVID-19,