NeuroRx announced the Phase 2b/3 trial of ZYESAMI™ (aviptadil, previously RLF-100™) for the treatment of Respiratory Failure in critically ill patients with COVID-19 has demonstrated multidimensional benefit around its prespecified primary endpoint of Recovery from Respiratory Failure with discharge from hospital and ICU (without relapse) by day 28 in patients with critical COVID-19 who were treated with High Flow Nasal Oxygen. Although not envisioned at the start of the clinical trial, High Flow Nasal Oxygen has become the predominant form of treatment in Covid-19 respiratory failure, with mechanical ventilation reserved for those whose blood oxygen levels cannot be maintained on this less invasive modality. The trial was conducted at 10 U.S. hospitals under the direction of NeuroRx in collaboration with RELIEF THERAPEUTICS. NeuroRx has signed an agreement to complete a business combination with Big Rock Partners Acquisition.
The clinical trial was originally approved as a 28-day study at FDA's direction. In December, NeuroRx added a 60-day endpoint based on the recognition that the traditional 28-day endpoint adopted in the 1990s for trials in Acute Respiratory Distress Syndrome is not appropriate for critically ill patients with COVID-19, who are frequently maintained in the ICU with advanced technologies well beyond this time point. NeuroRx and other clinical trial sponsors alerted FDA to this trend and yesterday the FDA published formal guidance† changing the required time for measuring the prespecified endpoint of "alive and free of respiratory failure" in critically ill patients to 60 days. Interim data are being reported because they were unblinded as per the original protocol and the last patient in the trial reached day 60 yesterday. Therefore, study conduct cannot be adversely influenced by release of these interim findings.
At 28 days, patients treated with ZYESAMI™ demonstrate 35% higher likelihood of recovery from respiratory failure with continued survival compared to patients treated with placebo (Hazard Ratio 1.53; P=.08). In tertiary care hospitals, ZYESAMI-treated patients were 46% more likely to recover and return home before day 28 (Hazard Ratio controlling for age and severity 1.84; P=.058). Should these trends continue through day 60, they have the potential to reach statistical significance. At day 28, a highly significant 10-day difference in median time to recovery and hospital discharge has emerged in ZYESAMI-treated patients compared to those treated with placebo (P<.006).
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Should the above trends continue through day 60, NeuroRx anticipates filing a request for Emergency Use Authorization in this population of critically ill patients (i.e. those on High Flow Nasal Oxygen) who have exhausted all currently approved treatments. FDA decisions implement a benefit/risk framework. NeuroRx previously announced the high degree of safety observed with use of ZYESAMI. This safety has continued to be documented in the more than 300 additional patients treated under the Expanded Access Protocol and in patients who have filed requests under the federal Right to Try act.
Vasoactive Intestinal Polypeptide (VIP) was first discovered by the late Dr. Sami Said in 1970, for whom ZYESAMI™ is named. Although first identified in the intestinal tract, VIP is now known to be produced throughout the body and to be primarily concentrated in the lungs. VIP has been shown in more than 500 peer-reviewed studies to have potent anti-inflammatory/anti-cytokine activity in animal models of respiratory distress, acute lung injury, and inflammation. Most importantly, 70% of the VIP in the body is bound to a rare cell in the lung, the alveolar type II cell (ATII), that is critical in the production of lung surfactant that is essential to transmission of oxygen from the air to the blood by the pulmonary epithelial cells that line the air sacs (alveoli) of the lung. Initial radiographic changes in COVID-19 are suggestive of collapse of these alveoli.
COVID-19-related respiratory failure is caused by selective infection of the ATII cell by the SARS-CoV-2 virus. The ATII cells are vulnerable because of their (ACE2) surface receptors, which serve as the route of entry for the virus. These specialized cells manufacture surfactant that coats the lung and is essential for oxygen exchange. Loss of surfactant causes collapse of the air sacs (alveolae) in the lung and results in respiratory failure.
VIP is shown to block Coronavirus replication in the ATII cell, block cytokine synthesis, block viral-induced cell death (cytopathy), and upregulate surfactant production. To our knowledge, other than ZYESAMI™, no currently proposed treatments for Covid-19 specifically target these vulnerable Type II cells. Recent laboratory findings suggest that VIP directly interferes with the spike protein complex of the SARS-CoV-2 virus.