Date: 14-May-2020

Relief Therapeutics Partner NeuroRx Seeks US FDA Approval To Begin Phase 2/3 Trial Of Inhaled RLF-100 To Treat Non-acute Lung Injury

Relief Therapeutics announced that its US partner, NeuroRx, has filed an investigational protocol with the US Food and Drug Administration under the Coronavirus Treatment Acceleration Program (CTAP) to conduct a phase 2/3 clinical trial assessing inhaled RLF-100 as a treatment for patients with non-acute lung injury caused by the SARS-CoV-2 virus (COVID-19). RLF-100 is a patented formulation of Aviptadil, a synthetic human vasoactive intestinal polypeptide (VIP). VIP is known from numerous animal models of lung injury and lung disease to inhibit inflammatory cytokines and to protect pulmonary epithelial cells that line the air sacs (alveolae) of the lung.

Recent findings suggest that the type-2 alveolar cells are particularly vulnerable to coronavirus because of cell surface receptors that allow the virus to enter the cell. The type-2 cells are essential to replenishing the pulmonary epithelium and to manufacturing surfactant, which coats the inside of the lung and allows oxygen exchange to occur. Without surfactant, the alveolae do not stay open and blood oxygen drops quickly, as is seen in patients with COVID-19.

RLF-100 is already in clinical trials for the treatment of Acute Respiratory Distress Syndrome (ARDS) in COVID-19 patients on mechanical ventilation. Currently, four out of five patients who progress to this acute, severe, stage of COVID-19 disease are reported to die despite maximum intensive care.

“The early stage of COVID-19 is different from more familiar viral pneumonia in its characteristic hypoxia (low blood oxygen) in advance of the devastating cytokine storm that too frequently leads to death,” said Jonathan Javitt, M.D., MPH, founder and CEO of NeuroRx. “Our clinical trial partners have asked us to develop a treatment approach for patients presenting with early lung injury in the hopes of preventing progression to ICU care and mechanical ventilation. VIP is heavily concentrated in the lung and plays a critical role in the body’s natural defense against many lung injuries, ranging from infectious to chemical substances to smoke inhalation. VIP is known to preferentially bind the precious type 2 cells in the lung that are directly attacked by the coronavirus. While there are many drugs being tested in the clinic today against specific cytokines (such as IL-6), we believe RLF-100 is the only drug candidate that specifically targets the pulmonary cells attacked in COVID-19 lung injury and the only experimental drug that targets the broad array of inflammatory cytokines produced during SARS-CoV-2 infection.”

The multicenter randomized placebo-controlled trial aims to enroll 144 patients with COVID-19 with shortness of breath and early pulmonary symptoms in an effort to slow COVID-19 progression. Because these patients can still breathe on their own, RLF-100 will be inhaled, rather than injected, a dosage form that is suitable both for home and hospital use. Inhaled dosing allows delivery of RLF-100 directly to the lung tissue most at risk from the coronavirus.

The trial will be conducted in at least 20 sites. Patients will be randomized to receive inhaled RLF-100 plus standard of care or placebo plus standard of care. The primary endpoints will be progression to ARDS over 28 days and improvement in blood oxygenation. Secondary endpoints will include blood oxygenation as measured by pulse oximetry, dyspnea, exercise tolerance, and levels of TNFa, IL-6 and other cytokines.

Vasoactive Intestinal Polypeptide (VIP) is now known to be manufactured throughout the body and to be heavily 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 to 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 on their cell membranes, which are bound by the SARS-CoV-2 virus and serve as the route of entry for the virus 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 theory that VIP specifically protects 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 is 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.

RLF-100 is a patented formulation of Vasoactive Intestinal Polypeptide (VIP) that was originally developed and is currently marketed in Europe for the treatment of erectile dysfunction. VIP is known to be highly concentrated in the lung and to inhibit a variety of inflammatory cytokines.