TY - JOUR
T1 - Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19
AU - Varona, Jose F.
AU - Landete, Pedro
AU - Lopez-Martin, Jose A.
AU - Estrada, Vicente
AU - Paredes, Roger
AU - Guisado-Vasco, Pablo
AU - de Orueta, Lucia Fernandez
AU - Torralba, Miguel
AU - Fortun, Jesus
AU - Vates, Roberto
AU - Barberan, Jose
AU - Clotet, Bonaventura
AU - Ancochea, Julio
AU - Carnevali, Daniel
AU - Cabello, Noemi
AU - Porras, Lourdes
AU - Gijon, Paloma
AU - Monereo, Alfonso
AU - Abad, Daniel
AU - Zuñiga, Sonia
AU - Sola, Isabel
AU - Rodon, Jordi
AU - Vergara-Alert, Julia
AU - Izquierdo-Useros, Nuria
AU - Fudio, Salvador
AU - Pontes, Maria Jose
AU - de Rivas, Beatriz
AU - de Velasco, Patricia Giron
AU - Nieto, Antonio
AU - Gomez, Javier
AU - Aviles, Pablo
AU - Lubomirov, Rubin
AU - Belgrano, Alvaro
AU - Sopesen, Belen
AU - White, Kris M.
AU - Rosales, Romel
AU - Yildiz, Soner
AU - Reuschl, Ann Kathrin
AU - Thorne, Lucy G.
AU - Jolly, Clare
AU - Towers, Greg J.
AU - Zuliani-Alvarez, Lorena
AU - Bouhaddou, Mehdi
AU - Obernier, Kirsten
AU - McGovern, Briana L.
AU - Rodriguez, M. Luis
AU - Enjuanes, Luis
AU - Fernandez-Sousa, Jose M.
AU - Krogan, Nevan J.
AU - Jimeno, Jose M.
AU - Garcia-Sastre, Adolfo
N1 - Funding Information:
We are indebted to the women and men that gave their consent to participate in this study, and to their relatives, for understanding their decision in these exceptional circumstances. We would like to thank Pascal Besman for his input, Timothy Silverstein for providing editorial support, and Lorena Martin Peña for technical and secretarial assistance. The full clinical research teams at each one of the participating sites have played an instrumental role. We recognize hard work and commitment done by Paz Cañadas, Daniel Sánchez-Brualla, and Carlota Costa from Synlab Diag-nósticos Globales, SAU as central laboratory in charge of viral RT-PCR assessments. We appreciate the collaboration with Boryung Pharmaceuticals in the first in vitro study on the activity of plitidepsin in SARS-CoV-2 infection models. We thank R Albrecht for support with the BSL-3 facility and procedures at the Icahn School of Medicine at Mount Sinai, New York. We thank Ana Tercero, Angelines Barroso, Barbara Garcia, Cora Loste, Daniel Perez-Zsolt, Ester Ballana, Gemma Lladós, Hervé Dhellot, Ivette Casafont, Joaquim Segalés, Jon Cendoya, Jordana Muñoz-Basagoiti, José Ramón Santos, Laura Soldevila, Lola Castro, Lourdes Mateu, Lucía Gutiérrez-Chamorro, María Luisa Ramírez, Miriam Ramírez, Rafael Fernández Alonso, and Sonia Extremera for their dedication and commitment. Funding: This study has been funded by Pharmamar, SA (Madrid, Spain). This work was supported by grants from the Government of Spain (PIE_INTRAMURAL_ LINEA 1 - 202020E079; PIE_INTRAMURAL_CSIC-202020E043). The research of CBIG consortium (constituted by IRTA-CReSA, BSC, & IrsiCaixa) is supported by Grifols pharmaceutical. We also acknowledge the crowdfunding initiative #Yomecorono (https://www.yomecorono.com). N Izquierdo-Useros has nonrestrictive funding from PharmaMar to study the antiviral effect of Plitidepsin. NJ Krogan was funded by grants from the National Institutes of Health (P50AI150476, U19AI135990, U19AI135972, R01AI143292, R01AI120694, and P01AI063302); by the Excellence in Research Award (ERA) from the Laboratory for Genomics Research (LGR), a collaboration between the University of California, San Francisco (UCSF), University of California, Berkley (UCB), and GlaxoSmithKline (GSK) (#133122P); by the Roddenberry Foundation, and gifts from QCRG philanthropic donors. This work was supported by the Defense Advanced Research Projects Agency (DARPA) under Cooperative Agreement #HR0011-19-2-0020. The views, opinions, and/or findings contained in this material are those of the authors and should not be interpreted as representing the official views or policies of the Department of Defense or the U.S. Government. This research was partly funded by Center for Research for Influenza Pathogenesis and Transmission (CRIPT), a National Institute of Allergy and Infectious Diseases (NIAID) supported Center of Excellence for Influenza Research and Response (CEIRS, contract # 75N93021C00014), by DARPA grant HR0011-19-2-0020, by supplements to NIAID grants U19AI142733, U19AI135972, and DoD grant W81XWH-20-1-0270, and by the generous support of the JPB Foundation, the Open Philanthropy Project (research grant 2020-215611 (5384)), and anonymous donors to A García-Sastre. S Yildiz received funding from a Swiss National Foundation Early Postdoc Mobility fellowship (P2GEP3_184202).
Funding Information:
V Estrada has received personal fees from Janssen, Gilead, and ViiV and grants from MSD. R Paredes has participated in Advisory Boards from Gilead, MSD, ViiV Healthcare, and Theratechnologies. M Torralba has received consulting fees as a member of Advisory Committee and honoraria and speaking fees from Gilead, Janssen, MSD, and ViiV Companies. J Fortún has participated in scientific events and received consulting or speaking fees or oral presentations from Pfizer, Gilead, MSD, Astellas, Novartis, and Roche.
Publisher Copyright:
© 2022 Rockefeller University Press. All rights reserved.
PY - 2022/4
Y1 - 2022/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85123459591&partnerID=8YFLogxK
U2 - 10.26508/lsa.202101200
DO - 10.26508/lsa.202101200
M3 - Article
C2 - 35012962
AN - SCOPUS:85123459591
SN - 2575-1077
VL - 5
JO - Life Science Alliance
JF - Life Science Alliance
IS - 4
M1 - 202101200
ER -