Preclinical and randomized phase I studies of plitidepsin in adults hospitalized 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 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

Plitidepsin has a positive therapeutic index in adult patients with COVID-19 requiring hospitalization

Plitidepsin is a marine-derived cyclic-peptide that inhibits SARS-CoV-2 replication at low nanomolar concentrations by the targeting of host protein eEF1A (eukaryotic translation-elongation-factor-1A). We evaluated a model of intervention with plitidepsin in hospitalized COVID-19 adult patients where three doses were assessed (1.5, 2 and 2.5 mg/day for 3 days, as a 90-minute intravenous infusion) in 45 patients (15 per dose-cohort). Treatment was well tolerated, with only two Grade 3 treatment-related adverse events observed (hypersensitivity and diarrhea). The discharge rates by Days 8 and 15 were 56.8% and 81.8%, respectively, with data sustaining dose-effect. A mean 4.2 log10 viral load reduction was attained by Day 15. Improvement in inflammation markers was also noted in a seemingly dose-dependent manner. These results suggest that plitidepsin impacts the outcome of patients with COVID-19.This study has been funded by Pharmamar, S.A. (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.I.U. has non-restrictive funding from PharmaMar to study the antiviral effect of Plitidepsin. N.J.K. 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 UCSF, UCB, and 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 CRIP (Center for Research for Influenza Pathogenesis), a NIAID supported Center of Excellence for Influenza Research and Surveillance (CEIRS, contract # HHSN272201400008C), 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 AG-S. S.Y. received funding from a Swiss National Foundation (SNF) Early Postdoc Mobility fellowship (P2GEP3_184202).N

Preclinical and randomized phase I studies of plitidepsin in adults hospitalized 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 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.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).Peer reviewe

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Risk stratification for splenic marginal zone lymphoma based on hemoglobin, platelet count, high LDH level and extrahilar lymphadenopathy: development and validation on 593 cases

We report an international retrospective study of 593 Splenic Marginal Zone Lymphoma (SMZL) patients aiming to identify factors conditioning the starting of treatment and the factors influencing lymphoma-specific survival (LSS). Logistic regression was used to identify the factors associated with treatment. A Cox regression was used to analyze LSS in a training set of 366 patients. This produced a prognostic index (PI) and enabled to identify three risk groups. The resulting stratification was validated in another set of 227 patients. The present stratification was compared with the Interguppo Italiano Linfomi (IIL) score in the set of 450 patients for whom all the required data were available using an extension of the net reclassification improvement. Hemoglobin, extrahilar lymphadenopathy and HCV status were associated with the initiation of treatment. Hemoglobin, platelet count, high LDH and extrahilar lymphadenopathy were independently associated with LSS. Three risk groups with significantly different five-year LSS (94%, 78% and 69%, respectively) were identified. This stratification (named HPLL on the basis of determinant factors) had a better discriminative power than the IIL score. This system is useful to stratify SMZL patients into risk groups and may help selecting risk-tailored treatment approaches

Quantitative assessment of interstitial lung disease in Sjögren’s syndrome

Interstitial lung disease (ILD) is a frequent manifestation of Sjögren's syndrome (SS), an autoimmune disease of salivary and lacrimal glands, and affects approximately 20% of patients. No clinical or serological features appear to be useful to predict its presence, severity or progression, and chest high-resolution computed tomography (CT) remains the gold standard for diagnosis. Semiquantitative CT (SQCT) based on visual assessment (Goh and Taouli scoring) can estimate ILD extent, although it is burdened by relevant intra- and interobserver variability. Quantitative chest CT (QCT) is a promising alternative modality to assess ILD severity