Relief Therapeutics and its U.S. partner, NeuroRx, announced treatment of the first patients with RLF-100 at the University of Miami Miller School of Medicine, FL. This is part of a Phase 2b/3 clinical trial to assess RLF-100 as a treatment for Acute Respiratory Distress Syndrome (ARDS) in COVID-19 patients on mechanical ventilation. RLF-100 is a patented formulation of Aviptadil, a synthetic human vasoactive intestinal polypeptide (VIP) that targets alveolar type 2 cells in the lungs that could be the major target of the SARS-CoV-2 virus.

“ARDS is the primary cause of COVID-19 related deaths triggered by acute inflammation in the air sacs (alveolae) of the lungs. As a result, they fill with fluid rendering them unable to deliver oxygen to the body. There is an urgent need for a treatment that can specifically protect type 2 alveolar cells and suppress excessive inflammation,” said Dushyantha T Jayaweera M.D., principal study investigator at the University of Miami. “We are pleased to be the first site to treat patients with RLF-100, it reflects our commitment to advancing clinical research on COVID-19 to provide critically ill patients the best care and improve their chances of survival.”

“RLF-100 previously showed promising phase 1 results in ARDS related to sepsis and promising phase 2 results in the treatment of other inflammatory lung conditions.  Aviptadil specifically binds to the cells in the lung that are essential to transmitting oxygen to the body and to making surfactant that is essential to oxygen exchange (the Alveolar Type II cells). These are the same cells that are targeted and killed by the SARS-CoV-2 virus. Fifty years of research into the biology of VIP suggests that it  may protect the vulnerable cells in the lungs while inhibiting the inflammatory cytokines that contribute to disease progression, without impairing the immune response necessary to clear the infection,” Jonathan Javitt, M.D., MPH, CEO of NeuroRx, said.

The multicenter randomized placebo-controlled trial aims to enroll 120 patients with COVID-19 who have Acute Respiratory Distress and require intensive care with mechanical ventilation. Patients will be randomized to intravenous (IV) RLF-100 plus maximal intensive care or placebo plus maximal intensive care. The primary endpoints will be mortality and index of respiratory distress. The secondary endpoint will include levels of TNFα and multi-system organ failure free days.

Relief Therapeutics and NeuroRx are engaging clinical trials authorities in the European Union, the United Kingdom, Russia, and Australia in order to broaden the clinical study and increase access to RLF-100.

Vasoactive Intestinal Polypeptide (VIP) was first discovered by the late Dr. Sami Said in 1970. 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 100 peer-reviewed studies to have potent anti-inflammatory/anti-cytokine activity in animal models of respiratory distress, acute lung injury, and inflammation. VIP has a 20-year history of safe use in humans in multiple human trials for sarcoidosis, pulmonary fibrosis, asthma/allergy, and pulmonary hypertension.

COVID-19-related death is primarily caused by Acute Respiratory Distress Syndrome (ARDS). The trigger for ARDS is widely attributed to a cytokine storm in the lungs, in which the virus causes release of inflammatory molecules called cytokines. As a result, the air sacs (alveolae) of the lungs fill with water and become impermeable to oxygen, even in the setting of mechanical ventilation. Before this acute phase, however, there is evidence of early viral infection of the alveolar type 2 cells. These cells are known to have angiotensin converting enzyme 2 (ACE2) receptors at high levels, which serve as the route of entry for the SARS-CoV-2 into the cells. Although not yet shown for COVID-19, the coronavirus that causes SARS (SARS-CoV) is shown to replicate in alveolar type 2 cells, but not in the more numerous type 1 cells. These same type 2 alveolar cells have high concentrations of VIP receptors on their cell surfaces giving rise to the hypothesis that VIP could specifically protect these cells from injury.

Injury to the type 2 alveolar cells is an increasingly plausible mechanism of COVID-19 disease progression. These specialized cells replenish the more common type 1 cells that line the lungs. More importantly, type 2 cells manufacture surfactant that coats the lung and are essential for oxygen exchange. Patients with early COVID-19 lung injury commonly describe “crackling sounds” in their lungs, combined with extreme shortness of breath. No currently proposed treatments for COVID-19 specifically target these vulnerable type 2 cells.