Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19.
Клиническое исследование I фазыСтатьяМногоцентровое исследованиеРандомизированное исследованиеПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПоддержка службы здравоохранения СШАНазвание и аннотация: Перевод пока не подготовлен
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Varona Jose F, Landete Pedro, Lopez-Martin Jose A, Estrada Vicente, Paredes Roger, Guisado-Vasco Pablo, Fernandez de Orueta Lucia, Torralba Miguel, Fortun Jesus, Vates Roberto, Barberan Jose, Clotet Bonaventura, Ancochea Julio, Carnevali Daniel, Cabello Noemi, Porras Lourdes, Gijon Paloma, Monereo Alfonso, Abad Daniel, Zuñiga Sonia, Sola Isabel, Rodon Jordi, Vergara-Alert Julia, Izquierdo-Useros Nuria, Fudio Salvador, Pontes Maria Jose, de Rivas Beatriz, Giron de Velasco Patricia, Nieto Antonio, Gomez Javier, Aviles Pablo, Lubomirov Rubin, Belgrano Alvaro, Sopesen Belen, White Kris M, Rosales Romel, Yildiz Soner, Reuschl Ann-Kathrin, Thorne Lucy G, Jolly Clare, Towers Greg J, Zuliani-Alvarez Lorena, Bouhaddou Mehdi, Obernier Kirsten, McGovern Briana L, Rodriguez M Luis, Enjuanes Luis, Fernandez-Sousa Jose M, Krogan Nevan J, Jimeno Jose M, Garcia-Sastre Adolfo
Аннотация
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.