Effect of Opaganib on Supplemental Oxygen and Mortality in Patients with Severe SARS-CoV-2 Pneumonia

Rationale There are few treatment options for severe COVID-19 pneumonia. Opaganib is an oral treatment under investigation. Objective Evaluate opaganib treatment in hospitalized patients with severe COVID-19 pneumonia. Methods A randomized, placebo-controlled, double-blind phase 2/3 trial was conducted in 60 sites worldwide from August 2020 to July 2021. Patients received either opaganib (n=230; 500mg twice daily) or matching placebo (n=233) for 14 days. Main Outcome Measurements Primary outcome was the proportion of patients no longer requiring supplemental oxygen by day 14. Secondary outcomes included changes in the World Health Organization Ordinal Scale for Clinical Improvement, viral clearance, intubation, and mortality at 28- and 42-days. Main Results Pre-specified primary and secondary outcome analyses did not demonstrate statistically significant benefit (except for time to viral clearance). Post-hoc analysis revealed the fraction of inspired oxygen (FiO2) at baseline was prognostic for opaganib treatment responsiveness and corresponded to disease severity markers. Patients with FiO2 levels at or below the median value (≤60%) had better outcomes after opaganib treatment (n=117) compared to placebo (n=134). The proportion of patients with ≤60% FIO2 at baseline that no longer required supplemental oxygen (≥24 hours) by day 14 of opaganib treatment increased (76.9% vs 63.4%: p-value =0.033). There was a 62.6% reduction in intubation/mechanical ventilation (6.84% vs 17.91%; p-value=0.012) and a clinically meaningful 62% reduction in mortality (5.98% vs 16.7%; p-value=0.019) by day 42. No new safety concerns observed. Conclusions Post-hoc analysis supports opaganib benefit in COVID-19 severe pneumonia patients that require lower supplemental oxygen (≤60% FiO2). Further studies are warranted. Trial registration number NCT04467840 ### Competing Interest Statement Eagle, Gerlach, Campbell, Bibliowicz, Fathi, Anderson, Raday, Fehrmann, Katz Ben-Yair, and Levitt are employees or consultants to RedHill Biopharma. ### Clinical Trial NCT04467840 ### Funding Statement The study was funded by RedHill Biopharma Ltd. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The following Ethics Committees in Brazil, Mexico, Poland, Colombia, Italy, Israel and Russia have approved the conduct of the study: Santa Casa De Misericordia De Sao Faculdade De Medicina Do ABC/Fundacao Do ABC-FMABC USP-Hospital Das Clinicas Da Faculdade De Medicina Da Universidade De Sao Paulo-HCFMUSP Centro Universitario De Maringa - UNICESUMAR Hospital Regional Hans Dieter Schmidt/SES/SC (CEP) Universidade Do Sul De Santa Catarina - UNISUL (CEP) Hospital Ver Cruz - HVC/MG (HVC) Hospital De Clinicas De Porto Alegre Da Universidade Federal Do Rio Grande Do Sul - HCPA UFRGS Universidade De Passo Fundo/Vice-Reitoria De Pesquisa E Pos-Graduacao-VRPPG/UPF Hospital Felicio Rocho/MG Biosafety Research Committee of the American British Cowdray Medical Center IAP Biosafety Research Committee of the American British Cowdray Medical Center IAP Hospital La Mision - Research Ethics Committee The independent Ethics Committee at the Warmia and Mazury Chamber of Physicians in Olsztyn Research Ethics Committee: Centro Medico Imbanao Universidad Pontificia Bolivariana Comite de Etica en Investigacion en seres Humanos Ceish Comite de Etica de la Investigacion National Clinics/en Alianza Con/Hospital Universitario Clinica San Rafael-Research Ethics Committee Comitato Etico Brianza Ospedale Luigi Sacco-Regionale Lombardia Comitato Etico Interaziendale, Azienda Ospedaliera Nazionale Comitato Etico Interaziendale, A.O.U. Citta della Salute e della Scienza di Torino Shaare Zedek Medical Center Helsinki Committee Assuta Samsom Hospital Helsinki Committee Ziv Medical Center Helsinki Committee Wolfson Medical Center Helsinki Committee Galilee Medical Center, Helsinki Committee EMMS Nazareth Hospital, Helsinki Committee Biomedical Ethics Committee of the State Budgetary Healthcare Institution of the City of Moscow N.V. Sklifosovsky Clinica The Independent Ethics Committee at RSBHI-Clinical Hospital No 1 I.P. Pavlov Ryazan State Med University-Local Ethics Committee Ministry of Health for the Tver Region-State Budgetary Healthcare Institution for the Tver Region-Ethics Committee Ministry of Health of the Russian Federation-IV Razumovsky Saratov State Medical University of the Ministry of Health of Russia St Petersburg State Budgetary Institution Elizavetinskaya Hospital-Bioethics Ethics Committee Ministry of Health for Altai Krai -Local Ethics Committee St Petersburg State healthcare Institution Municipal Hospital No 15 Yaroslavl Regional Clinical Hospital of War Veterans Ethics Committee St Petersburg State University-Bioethics Ethics Committee St Petersburg State Budgetary Institution Elizavetinskaya Hospital Ethics Committee Murmansk Regiona Clinical Hospital Named After PA Bayandin Ethics Committee St Petersburg State Budgetary Institution Elizavetinskaya Hospital Ethics Committee Local Ethics Committee of the Saint Petersburg State Budgetary Healthcare Institution City Pokrovskaya Hospital Federal State Budgetary Institution Central Clinical Hospital -Ethics Committee I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. 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