Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19
José F. Varona, Pedro Landete, José A. López-Martín, Vicente Estrada, Roger Paredes, Pablo Guisado‐Vasco, Lucía Fernández de Orueta, Miguel Torralba, Jesús Fortün, Roberto Vates, José Barberán, Bonaventura Clotet, Julio Ancochea, Daniel Carnevali, Noemí Cabello, Lourdes Porras, Paloma Gijón, A Monereo, Daniel Abad, Sonia Zúñiga, Isabel Sola, Jordi Rodon, Júlia Vergara‐Alert, Nuria Izquierdo‐Useros, Salvador Fudio, María José Pontes, Beatriz de Rivas, Patricia Girón de Velasco, Antonio Martínez Nieto, Javier Gómez, Pablo Avilés, Rubin Lubomirov, Alvaro Belgrano, Belén Sopesén, Kris M. White, Romel Rosales, Soner Yildiz, Ann‐Kathrin Reuschl, Lucy Thorne, Clare Jolly, Greg J. Towers, Lorena Zuliani‐Alvarez, Mehdi Bouhaddou, Kirsten Obernier, Briana L McGovern, Myosotys Rodriguez, Luis Enjuanes, Jose M Fernandez-Sousa, Nevan J. Krogan, José Jimeno, Adolfo García‐Sastre
Abstract
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.