Outcomes and Clinical Characteristics of the Compassionate Use of Plitidepsin for Immunocompromised Adult Patients with COVID-19

Background: Immunocompromised patients are more vulnerable to SARS-CoV-2 infection and to develop respiratory insufficiency. In a phase I clinical trial, treatment with plitidepsin, resulted in viral load reductions and improvement on inflammatory biomarkers. Previously published case reports of immunocompromised patients with COVID-19 treated with plitidepsin reinforce the safety of the drug.Methods: This study aimed to evaluate the compassionate use of plitidepsin as an antiviral treatment in hospitalized immunocompromised adult patients with moderate-to-severe COVID-19. The primary outcome measures were time to respiratory recovery (saturation/fraction of inspired oxygen [SpFi] ≥ 315); COVID-19-related cumulative mortality 30 days after first plitidepsin infusion; and time to undetectable levels of viral RNA in nasopharyngeal swab samples.Findings: Thirty-three patients receiving a full course of plitidepsin (2·5 mg [n= 29] or 1·5 mg [n= 4]) were included. Most (69·7%) had a malignant hematological disease, 27·3% had solid tumors, and 3% had antineutrophil cytoplasmic antibody-associated vasculitis syndrome. A total of 111 infusions were administered with lack of relevant safety events. The median time from plitidepsin initiation to SpFi ≥315 was 8 days (95% confidence interval [CI], 7; 19). The median time to first negative RT-PCR for SARS-CoV-2 (Ct > 36) was 17 days (95% CI 13; 25). The mortality rate was 16% (95% CI 3; 37·3).Interpretation: These data support plitidepsin as a well-tolerated treatment that might have potential clinical and antiviral efficacy in immunocompromised patients with COVID-19.Funding: Study costs have been supported by Pharma Mar S.A. and Hospital Universitario QuironSalud Madrid.Funding Information: Study costs have been supported by Pharma Mar S.A. and Hospital Universitario QuironSalud Madrid.Declaration of Interests: JMM holds stocks of Pangaea Oncology, has a non-remunerated role in the Scientific Advisory Board, and holds stocks of Promontory Therapeutics; and is a full-time employee and share-holder of PharmaMar, S.A. (Madrid, Spain), and a co-inventor of two patents for Plitidepsin (WO99-42125). JAL is a full-time employee and share-holder of PharmaMar, S.A (Madrid, Spain), and a co-inventor of a patent for Plitidepsin (WO2008135793A1). XELE is a full-time employee of Pharma Mar, S.A. (Madrid, Spain). RL is a full-time employee and share-holder of PharmaMar, S.A (Madrid, Spain). PGV received speaker fees from FLS Science, PharmaMar SA (Madrid, Spain) and GlaxoSmithKline (Spain); consulting fees from Angelini Pharma and PharmaMar SA; served as an advisory board member for Berlin Cures GmbH and Pharma Mar SA; and meeting grants from GlaxoSmithKline and PharmaMar SA. DCR received speaking fees from GlaxoSmithKline and Gilead Sciences. JAG received meeting grant from PharmaMar SA. PVF received speaking fee from GlaxoSmithKline (Spain) and served as an advisory board member for PharmaMar SA. MGC received meeting grant from Biomerieux. VPF received speaking fees from Janssen, Jazz 23 Pharmaceuticals, Roche; and also, consultant fee from Italfarmaco S.A. CF (Heorfy Consulting) has received fees from Hospital Universitario Quirónsalud Madrid as a payment for statistical analysis. All remaining authors have declared no conflicts of interest.Ethics Approval Statement: Patient data were pseudonymized using a study code that could only be linked to the clinical history by the medical team. The study was conducted in accordance with ethical principles of the Declaration of Helsinki and the International Conference on Harmonisation-Good Clinical Practice guidelines and approved by the Jimenez Diaz Foundation Ethics Committee (EO065-22).