Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19
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Abstract
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 10 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.
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SciScore for 10.1101/2021.05.25.21257505: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Nevertheless, our study has several limitations, including the small number of patients evaluated, the large variability, and the lack of a control group. These characteristics are likely limiting the observation of evident dose-response effects. An …
SciScore for 10.1101/2021.05.25.21257505: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Nevertheless, our study has several limitations, including the small number of patients evaluated, the large variability, and the lack of a control group. These characteristics are likely limiting the observation of evident dose-response effects. An international controlled phase 3 trial exploring the efficacy and safety of plitidepsin in hospitalized patients with moderate COVID-19 (NEPTUNO; NCT04784559) has already received initial regulatory authorization in UK and several other European countries, the latter through a Voluntary Harmonisation Procedure [VHP1842 (VHP2021019)]. In summary, we have integrated preclinical and clinical studies on the use of plitidepsin to treat SARS-CoV-2 and other coronavirus infections, and generated promising patient data supporting the launching of phase 3 clinical studies to demonstrate the efficacy of treatment with plitidepsin in moderate COVID-19 patients.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04784559 Not yet recruiting Trial to Determine the Efficacy/Safety of Plitidepsin vs Con… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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