Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19
Varona, Jose F. (Universidad San Pablo-CEU. Facultad de Medicina, Madrid)
Landete, Pedro (Universidad Autónoma de Madrid)
Lopez-Martin, Jose A. (Virology and Inflammation Unit, PharmaMar, SA, Madrid)
Estrada, Vicente (Universidad Complutense de Madrid)
Paredes, Roger (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Guisado-Vasco, Pablo (Universidad Europea de Madrid)
Fernandez de Orueta, Lucia (Hospital Universitario de Getafe (Madrid))
Torralba, Miguel (Hospital Universitario de Guadalajara)
Fortún, Jesús (Hospital Universitario Ramón y Cajal (Madrid))
Vates, Roberto (Hospital Universitario de Getafe (Madrid))
Barberán, José (Facultad de Medicina, Universidad San Pablo-CEU, Madrid)
Clotet Sala, Bonaventura (Universitat Autònoma de Barcelona. Departament de Medicina)
Ancochea, Julio (Centro de Investigación Biomédica en Red de Enfermedades Respiratorias)
Carnevali, Daniel (Universidad Europea de Madrid)
Cabello, Noemi (Hospital Clínico San Carlos (Madrid))
Porras, Lourdes (Hospital General Universitario de Ciudad Real)
Gijon, Paloma (Hospital General Universitario Gregorio Marañón. Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM))
Monereo, Alfonso (Hospital Universitario de Getafe (Madrid))
Abad, Daniel (Hospital Universitario de Getafe (Madrid))
Zuñiga, Sonia (Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid)
Sola, Isabel (Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid)
Rodon, Jordi (Institut de Recerca i Tecnologia Agroalimentàries. Centre de Recerca en Sanitat Animal)
Vergara-Alert, Júlia (Institut de Recerca i Tecnologia Agroalimentàries. Centre de Recerca en Sanitat Animal)
Izquierdo Useros, Nuria (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Fudio, Salvador (Clinical Pharmacology Unit, PharmaMar, Madrid)
Pontes, Maria Jose (Medical Affairs, PharmaMar, Madrid)
de Rivas, Beatriz (Medical Affairs, PharmaMar, Madrid)
Giron de Velasco, Patricia (Virology and Inflammation Unit, PharmaMar, Madrid)
Nieto, Antonio (Bio Statistics Unit, PharmaMar, Madrid)
Gomez, Javier (Bio Statistics Unit, PharmaMar, Madrid)
Avilés, Pablo (Preclinical Unit, Pharmamar, Madrid)
Lubomirov, Rubin (Clinical Pharmacology Unit, PharmaMar, Madrid)
Belgrano, Alvaro (Bio Statistics Unit, PharmaMar, Madrid)
Sopesen, Belen (Biocross, SL, Valladolid)
White, Kris M. (Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York)
Rosales, Romel (Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York)
Yildiz, Soner (Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York)
Reuschl, Ann-Kathrin (Division of Infection and Immunity, University College London)
Thorne, Lucy G. (Division of Infection and Immunity, University College London, London, UK)
Jolly, Clare (Division of Infection and Immunity, University College London)
Towers, Greg J. (Division of Infection and Immunity, University College London)
Zuliani-Alvarez, Lorena (Department of Cellular and Molecular Pharmacology, University of California, San Francisco)
Bouhaddou, Mehdi (Department of Cellular and Molecular Pharmacology, University of California, San Francisco)
Obernier, Kirsten (Department of Cellular and Molecular Pharmacology, University of California, San Francisco)
McGovern, Briana L. (Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York)
Rodriguez, M. Luis (Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York)
Enjuanes, Luis (Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid)
Fernandez-Sousa, Jose M. (Pharmamar, Madrid)
Krogan, Nevan J. (Department of Cellular and Molecular Pharmacology, University of California, San Francisco)
Jimeno, Jose M. (Virology and Inflammation Unit, PharmaMar, SA, Madrid)
Garcia-Sastre, Adolfo (Icahn School of Medicine at Mount Sinai, New York)

Data:	2022
Resum:	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 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.
Nota:	Altres ajuts: Govern d'Espanya: PIE_INTRAMURAL_LINEA 1-202020E079, PIE_INTRAMURAL_CSIC-202020E043; PharmaMar; National Institutes of Health: P50AI150476, U19AI135990, U19AI135972, R01AI143292, R01AI120694, P01AI063302; Excellence in Research Award; GlaxoSmithKline 133122P; Roddenberry Foundation; DARPA HR0011-19-2-0020; NIAID: U19AI142733, U19AI135972; DoD W81XWH-20-1-0270; Open Philanthropy Project 2020-215611 (5384)
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Life Science Alliance, Vol. 5 (january 2022) , ISSN 2575-1077

DOI: 10.26508/lsa.202101200
PMID: 35012962

22 p, 3.1 MB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
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