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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 log10 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. © 2022 Varona et al.


Jose F Varona, Pedro Landete, Jose A Lopez-Martin, Vicente Estrada, Roger Paredes, Pablo Guisado-Vasco, Lucia Fernandez de Orueta, Miguel Torralba, Jesus Fortun, Roberto Vates, Jose Barberan, Bonaventura Clotet, Julio Ancochea, Daniel Carnevali, Noemi Cabello, Lourdes Porras, Paloma Gijon, Alfonso Monereo, Daniel Abad, Sonia Zuñiga, Isabel Sola, Jordi Rodon, Julia Vergara-Alert, Nuria Izquierdo-Useros, Salvador Fudio, Maria Jose Pontes, Beatriz de Rivas, Patricia Giron de Velasco, Antonio Nieto, Javier Gomez, Pablo Aviles, Rubin Lubomirov, Alvaro Belgrano, Belen Sopesen, Kris M White, Romel Rosales, Soner Yildiz, Ann-Kathrin Reuschl, Lucy G Thorne, Clare Jolly, Greg J Towers, Lorena Zuliani-Alvarez, Mehdi Bouhaddou, Kirsten Obernier, Briana L McGovern, M Luis Rodriguez, Luis Enjuanes, Jose M Fernandez-Sousa, Nevan J Krogan, Jose M Jimeno, Adolfo Garcia-Sastre. Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19. Life science alliance. 2022 Apr;5(4)

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PMID: 35012962

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