Review 1: "Opaganib in COVID-19 pneumonia: Results of a randomized, placebo-controlled Phase 2a trial"

Bin Cao; Lianhan Shang

doi:doi:10.1162/2e3983f5.2a6f9434

Opaganib in COVID-19 pneumonia: Results of a randomized, placebo-controlled Phase 2a trial

by Kevin L. Winthrop, Alan W. Skolnick, Adnan M. Rafiq, Scott H. Beegle, Julian Suszanski, Guenther Koehne, Ofra Barnett-Griness, Aida Bibliowicz, Reza Fathi, Patricia Anderson, Gilead Raday, Gina Eagle, Vered Katz Ben-Yair, Harold S. Minkowitz, Mark L. Levitt, and Michael S. Gordon

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ABSTRACTBackgroundOpaganib, an oral sphingosine kinase-2 inhibitor with antiviral and anti-inflammatory properties, was shown to inhibit SARS-CoV-2 replication in vitro. We thus considered that opaganib could be beneficial for moderate to severe COVID-19 pneumonia. The objective of the study was to evaluate the effect of opaganib on supplemental oxygen requirements, time to hospital discharge and its safety in COVID-19 pneumonia hospitalized patients requiring supplemental oxygen.MethodsThis Phase 2a, randomized, double-blind, placebo-controlled study was conducted between July and December 2020 in eight sites in the USA. Forty-two enrolled patients received opaganib (n=23) or placebo (n=19) added to standard of care for up to 14 days and were followed up for 28 days after their last dose of opaganib/placebo.ResultsThe relative decrease in total supplemental oxygen requirement from baseline to Day 14 was 61.6% in the opaganib versus 46.7% in the placebo arms. By Day 14, 50.0% of patients in the opaganib and 22.2% in the placebo group no longer required supplemental oxygen for at least 24 hours, while 86.4% and 55.6%, respectively, were discharged from hospital. The incidence of ≥ Grade 3 treatment-emergent adverse events was 17.4% and 33.3% in the opaganib and placebo groups, respectively. Three deaths occurred in each group.ConclusionsIn this proof-of-concept study, hypoxic, hospitalized patients receiving oral opaganib required less supplementary oxygen and had earlier hospital discharge, with no safety concerns arising. These findings support further evaluation of opaganib in this population.SummaryUpon receiving opaganib, patients with COVID-19 pneumonia who were hospitalized and required supplemental oxygen showed symptomatic clinical improvement compared to placebo, with less supplemental oxygen requirement, resulting in earlier hospital discharge, and no safety concerns arising.

RR:C19 Evidence Scale rating by reviewer:

Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.

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Review:

Opaganib is a selective sphingosine kinase-2 (SK-2) inhibitor previously mainly investigated for cancer indications. However, due to potential anti-inflammatory effects, Opaganib is considered a repurposed drug for COVID-19. This proof-of-concept study is a Phase 2a randomized controlled trial investigating the efficacy and safety of Opaganib for the treatment of COVID-19 patients requiring supplementary oxygen. The study recruited 42 patients (23 patients in the Opaganib group, 19 patients in the placebo group). It used a modified intention-to-treat population for efficacy analysis (22 patients in the Opaganib group, 18 patients in the placebo group).

Numerically, a higher portion of patients in the Opaganib group required no oxygen by day 14, which provides some numerical signal for the potential efficacy of opaganib. Here are several concerns with this study:

1. Due to the limitation of data and sample size, the predefined primary outcome and several secondary outcomes were not analyzed according to what was planned. Besides, the statistical analyses of the results were descriptive. Also, there seems to be an imbalance in baseline characteristics, such as lower median age (52 vs. 61 years) a higher proportion of never-smokers (87.0% vs. 73.7%) in the Opaganib group. The contribution of the baseline imbalance to the observed difference in outcomes was uncertain. Therefore, the study results can only be hypothesis-generating and cannot be used to draw reliable conclusions for the efficacy of Opaganib. The drug's actual efficacy remains to be proved by a large-scale Phase 3 trial.

2. For COVID-19 patients requiring oxygen therapy (severe patients), the most important clinical outcomes are death and disease progression (requiring a higher level of oxygen therapy, e.g., mechanical ventilation). However, the numerical difference in intubation/mechanical ventilation (9.6% in the Opaganib group vs 11.1% in the placebo group) was very small. And the mortality benefits were largely unclear (15.0% vs. 11.9% by day 30, 15.0% vs. 19.2% by the end of safety follow-up). The reasons for the results might be a small sample size and potential baseline imbalance. Further study is needed to evaluate Opaganib‘s mortality and disease progression benefits.

3. The study used “high dose” corticosteroids as co-therapy for the patients. Currently, corticosteroids were recommended for severe COVID-19 patients with low but not high doses.¹ As there is no specific description of the actual dose of the corticosteroids in the article, it is uncertain whether the use of corticosteroids may impact the study results.

4. The authors highlight the advantage of Opaganib as having both antiviral and anti-inflammatory effects in the discussion part. However, as mentioned in the article, the anti-SARS-CoV-2 effects of Opaganib were suggested by in vitro model, but not clinical data. Besides, the study did not set virological endpoints, such as nasopharyngeal viral load. Therefore, it may not be appropriate to highlight the antiviral effects of Opaganib without further evidence.

Overall, the study provides preliminary evidence for potential clinical benefits of Opaganib for COVID-19 patients requiring supplementary oxygen. However, due to limitations such as sample size, baseline imbalance, and descriptive statistical analysis, the benefits were still uncertain and await further investigation in large-scale trials.

References:

1. Rochwerg B, Agarwal A, Siemieniuk RA, et al. A living WHO guideline on drugs for covid-19. BMJ 2020;370:m3379.