Efficacy and safety of zapnometinib in hospitalised adult patients with COVID-19 (RESPIRE): a randomised, double-blind, placebo-controlled, multicentre, proof-of-concept, phase 2 trial.

Background: Zapnometinib is an oral, non-ATP-competitive, small-molecule inhibitor of MEK1/MEK2 with immunomodulatory and antiviral properties. We aimed to investigate the safety and efficacy of zapnometinib in patients with COVID-19.
Methods: In this randomised, double-blind, placebo-controlled, multicentre, proof-of-concept, phase 2 trial, we recruited hospitalised adults with moderate or severe COVID-19 from 18 hospitals in Germany, India, Romania, South Africa, and Spain. Those requiring ICU admission or ventilator support at screening or randomisation were excluded. Patients were randomly assigned (1:1) to receive oral zapnometinib (900 mg on Day 1; 600 mg on Days 2-6) or matching placebo, on top of standard of care. Randomisation, stratified by baseline clinical severity status (CSS 3 or 4, measured on a 7-point ordinal scale), was done using Interactive Response Technology. Patients, investigators, and the sponsor were masked to treatment allocation. The primary endpoint was CSS at Day 15 and was conducted on the full analysis set (FAS: all patients who were randomised to the study, received at least one dose of study medication and had at least one post-dose assessment of CSS, as randomised). Safety analyses were conducted on the safety analysis set (all study participants who received at least one dose of study medication, as treated). This study is registered at ClinicalTrials.gov (NCT04776044) and EudraCT (2020-004206-59).
Findings: The trial was terminated early as the emergence of the Omicron variant impacted recruitment. Between 12th April 2021 and 9th August 2022, 104 of the planned 220 patients were enrolled and randomly assigned, 103 were treated, and 101 were included in the FAS (zapnometinib: n = 50; placebo: n = 51). The primary outcome was not significantly different between the two groups, but patients on zapnometinib had higher odds of improved CSS versus placebo (odds ratio [OR] 1.54 [95% CI 0.72-3.33]; p = 0.26). Predefined subgroup analyses identified trends for improved CSS in patients with severe disease at baseline (OR 2.57 [0.76-8.88]; p = 0.13) and non-Omicron variants (OR 2.36 [0.85-6.71]; p = 0.10); the p value of the CSS subgroup by Treatment interaction term in the model was p = 0.28. The frequency and intensity of adverse events was low and similar between arms. Twenty (39.2%) patients treated with zapnometinib experienced adverse events compared with eighteen (34.6%) patients treated with placebo. One patient receiving zapnometinib and two patients receiving placebo died during the study. None of the deaths were considered related to study medication.
Interpretation: These results provide proof-of-concept for the innovative approach of targeting the Raf/MEK/ERK pathway in patients with hospitalised moderate/severe COVID-19. Further clinical studies will be required to evaluate the clinical benefit of zapnometinib in this and other indications.
Funding: Atriva Therapeutics GmbH and the Federal Ministry of Education and Research, Germany.
Competing Interests: G.R. reports personal fees from Astra Zeneca, Atriva Therapeutics, Boehringer Ingelheim, GSK, Insmed, MSD, Sanofi, Novartis, and Pfizer for consultancy during advisory board meetings, and personal fees from Astra Zeneca, Berlin Chemie, BMS, Boehringer Ingelheim, Chiesi, Essex Pharma, Grifols, GSK, Insmed, MSD, Roche, Sanofi, Solvay, Takeda, Novartis, Pfizer and Vertex for lectures including service on speakers’ bureaux. S.S., M.B., and T.O. are employees of Atriva Therapeutics. H.P. and G.M. have nothing to declare. O.S. reports investigator fees from Atriva Therapeutics, Algernon Pharmaceuticals, Atea Pharmaceuticals, Diffusion Pharmaceuticals, Regeneron Pharmaceuticals, PureTech, Celltrion Inc., and Adagio Therapeutics. W.K. reports payment from Atriva Therapeutics to provide statistical support during the RESPIRE study. D.N. reports payment, funded by Atriva Therapeutics, as an employee of the contract research organisation that supported the RESPIRE study. O.P. reports grants to his institution from the Federal Ministry of Education and Research, Germany (Bundesministerium für Bildung und Forschung; BMBF), personal fees for consulting from Atriva Therapeutics, receipt of equipment and materials to his institution from Atriva Therapeutics and is a shareholder of Atriva Therapeutics. A.T. reports consulting fees from Pfizer and Janssen, and payment/honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events, and participation in a Data Safety Monitoring Board or Advisory Board, from Pfizer, Janssen, and Biomerieux. M.W. reports grants from the Deutsche Forschungsgemeinschaft, BMBF, Deutsche Gesellschaft für Pneumologie, European Respiratory Society, Marie Curie Foundation, Else Kröner Fresenius Stiftung, Capnetz Stiftung, Bayer Health Care, Biotest, and Pantherna, consulting fees from Insmed, Pantherna, Pherecydes, Aptarion, Glaxo Smith Kline, Inflarx, and Biotest, and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Astra Zeneca, Insmed, Chiesi, Novartis, Teva, Actelion, Boehringer Ingelheim, Glaxo Smith Kline, Biotest, Bayer Health Care. M.W. also holds relevant patents: EPO 12181535.1: IL-27 for modulation of immune response in acute lung injury (2012), WO/2010/094491: Means for inhibiting the expression of Ang-2 (2010), DE 102020116249.9: Camostat/Niclosamide cotreatment in SARS-CoV-2 infected human lung cells (2020/21), and PCT/EP2021/075627: New medical use of cystic fibrosis transmembrane conductance regulator (CFTR) modulators (2021).
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