Effect of Opaganib on Supplemental Oxygen and Mortality in Patients with Severe SARS-CoV-2 Based upon FIO2 Requirements

Abstract

Once a patient has been diagnosed with severe COVID-19 pneumonia, treatment options have limited effectiveness. Opaganib is an oral treatment under investigation being evaluated for treatment of hospitalized patients with severe COVID-19 pneumonia. A randomized, placebo-controlled, double-blind phase 2/3 trial was conducted in 57 sites worldwide from August 2020 to July 2021. Patients received either opaganib (n = 230; 500 mg twice daily) or matching placebo (n = 233) for 14 days. The 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. Pre-specified primary and secondary outcome analyses did not demonstrate statistically significant benefit (except nominally 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 h) by day 14 of opaganib treatment increased (76.9% vs. 63.4%; nominal p-value = 0.033). There was a 62.6% reduction in intubation/mechanical ventilation (6.84% vs. 17.91%; nominal p-value = 0.012) and a clinically meaningful 62% reduction in mortality (5.98% vs. 16.7%; nominal p-value = 0.019) by day 42. No new safety concerns were observed. While the primary analyses were not statistically significant, post-hoc analysis suggests opaganib benefit for patients with severe COVID-19 requiring supplemental oxygen with an FIO₂ of ≤60%. Further studies are warranted to prospectively confirm opaganib benefit in this subpopulation.

Keywords: ABC294640; COVID-19; SARS-CoV-2 pneumonia; opaganib; sphingosine kinase 2; trial registration number: NCT04467840.

Figure 1

Consort flow diagram. mITT = modified intention to treat, all subjects who were randomized and treated with at least one dose (even partial) of the study drug.

Figure 2

Kaplan–Meier curves of cumulative incidence for time to two consecutive negative swabs for SARS-CoV-2 by RT-PCR, at least 24 h apart, in the mITT population that was RT-PCR positive for SARS-CoV-2 at screening. Twenty-six (26) patients that were excluded from this analysis had an eligibility RT-PCR up to 7 days prior to screening, but not at screening.

Figure 3

Kaplan–Meier curve of cumulative incidence for time to recovery as defined by improvement to a score of 1 or less on the WHO Ordinal Scale of Clinical Improvement (mITT). Subjects who were lost to follow-up, withdrew consent, or died before day 14 were censored to day 14. Remaining subjects without the event were censored to day 14 or end of study day if it occurred earlier.

Figure 4

Kaplan–Meier curves of time to death by day 42 (FIO₂ ≤ 60% population). Kaplan–Meier curve of time to death through the end of day 42 from the mITT population with FIO₂ ≤ 60% at baseline. Patients were censored at day 42 or at study termination if it occurred before day 42.