Key data from the phase 2b/3 trial of ZYESAMI vs. Placebo (COVID-AIV) for treating patients with Respiratory Failure in Critical COVID-19 were presented at the February 2022 Congress on Retroviruses and Opportunistic Infections (CROI). The virtual meeting was limited to registered attendees only and the data may now be shared with the public. The data were presented by Prof. Dushyantha Jayaweera MD, FACP, of the University of Miami, National Study CoChair.
In summary, 196 participants were randomized (2:1) to receive aviptadil vs. placebo. An overall favorable trend was seen for the primary endpoint at 60 days (OR 1.6: confidence limit 0.95- 2.2; P=.08). Patients treated with aviptadil experienced 2-fold increased odds of survival (95% CL 1.05-3.88; P=.035) at Day 60 compared to placebo controlling for baseline NIAID score.
In contrast to the overall results, those patients randomized and treated at tertiary care centers had significantly higher odds of meeting the primary and secondary endpoint with 2.5 fold increased odds of being alive and free of respiratory failure and 4-fold increased odds of day 60 survival. The subgroup of patients who were progressing despite treatment with remdesivir demonstrated a significant 3-fold increased odds of meeting the primary endpoint (P=.03) and 4-fold increased odds of day 60 survival (P=.006).
Aviptadil was associated with statistically significant (P=.02) improvement in PaO2/FiO2)(P/F ratio) and with a 5-fold reduction in Cytokine IL-6 increase from baseline through Day 7 compared with placebo (P=.02), suggesting that improving oxygenation and attenuation of cytokine storm are two plausible mechanisms of action. Both, PF ratio improvement and prevention of Cytokine IL-6 release were highly correlated with attaining the primary endpoint and with day 60 survival (P<.001).
These data have been included in NRx’s submissions for Emergency Use Authorization (EUA) and Breakthrough Therapy Designation (BTD) and are now under review at a peer-reviewed journal. The EUA and BTD applications are currently being updated with safety data provided to NRx by the National Institutes of Health based on the first 451 patients randomized in the ongoing ACTIV-3b trial. As noted in the Press Release issued at the time of the Data Safety Monitoring Board meeting, no treatment-related Serious Adverse Events have been noted.
NRx views this additional safety and survival information from the ACTIV-3b trial as relevant to the review given FDA’s prior request for additional safety data in order to facilitate the determination that the known and anticipated benefits of treatment with aviptadil outweigh the known and anticipated risks. While the survival rates on ZYESAMI seen in the ACTIV-3b trial will not be known until the study is unblinded, the safety reports received to date are consistent with experiences recently reported from the ongoing use under Federal Right to Try laws and other clinical trials data. Although the review of the EUA is ongoing, submission of new data to a BTD application requires restarting of the review clock. NRx does not view this as disadvantageous because the benefits of BTD – if granted – may result in more rapid review of a future New Drug Application and are not relevant to the EUA process.