RLF-100™ is a synthetic form of Vasoactive Intestinal Peptide (VIP) consisting of 28 amino acids which was first discovered in 1970. Although initially identified in the intestinal tract, human VIP is now known to be produced throughout the body and to be primarily concentrated in the lungs. Here VIP has shown a multimodal mechanism of action: inhibition of viral replication, deterrence of inflammatory cytokines, prevention of cell death and upregulation of surfactant production. 70% of the VIP in the body is bound to a rare cell in the lung, the alveolar type 2 cell, which is critical to the transmission of oxygen to the body.
RLF-100™ has a 20-year history of safe use in humans in multiple human trials for sarcoidosis, pulmonary fibrosis, asthma/allergy, and pulmonary hypertension. It 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.
RLF-100™ is currently in clinical testing for acute lung injury (ALI) associated with the SARS-CoV-2 virus (COVID-19).
Relief devised a swift plan of action to respond to one of the largest healthcare disasters our time by rapidly advancing RLF-100™ towards approval in COVID-19-induced lung injury. Through its multimodal mechanism of action, RLF-100™ may uniquely target the pathways attacked by the SARS-CoV-2 virus (COVID-19), preventing acute lung injury (ALI).
COVID-19-related death is primarily caused by respiratory failure. 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. Coronaviruses are 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. (Mason 2020). 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. Other than RLF-100™, no currently proposed treatments for COVID-19 specifically target these vulnerable type 2 cells.
RLF-100™ specifically targets alveolar type 2 (AT2) cells in the lung.
Pulmonary alveolar type 2 (AT2) cells
Pulmonary alveolar type 2 (AT2) cells
Because of its safety profile and more cost-effective manufacturing process compared to proprietary biologics, RLF-100™ may be uniquely attractive to those focused on global countermeasures against COVID-19.
RLF-100™ is being investigated in two U.S. Phase 2b/3 clinical trials in respiratory deficiency due to COVID-19. These two trials will evaluate the curative and protective effect of RLF-100™ on COVID-19-induced ALI in both critical and moderate to severe patients.
Topline data from the intravenous study is expected Q4 2020, with topline data from the inhaled study anticipated in H1 2021. Relief is currently preparing a European phase 2b/3 study with RLF-100™ in COVD-19 patients.
(IV and Inhaled)and
Since July 2020, severe COVID-19 patients have been treated with intravenous RLF-100™ under FDA Emergency Use Investigational New Drug (IND) authorization and Expanded Access Protocol (NCT04453839)*** authorization for the treatment of respiratory failure in COVID-19. By granting RLF-100™ Expanded Access Protocol, the FDA has made a potentially lifesaving drug immediately available to critically ill patients who have no other available treatment option. The Expanded Access Protocol is designed to treat patients whose co-morbidities exclude them from enrollment in the ongoing phase 2b/3 trial of intravenous RLF-100™ in severe COVID-19 patients. Data from the first 21 patients in the Expanded Access Protocol showed promising results that warrant further study. The data demonstrated that some critically ill patients with COVID-19 experienced substantial clinical improvement when treated with RLF-100™.
In September, the Company, via its U.S. Partner, NeuroRx, submitted a request for an Emergency Use Authorization (EUA) with the U.S. FDA for the use of intravenous RLF-100™ in patients who are receiving intensive care and who have exhausted all approved treatments. The submission is based on a case-control study that compared patients who were treated with RLF-100™ (n=21) to those receiving maximal standard of care treatment (n=30) in the same ICU by the same medical staff. Patients treated with RLF-100™ demonstrated a 3-fold advantage in survival, recovery from respiratory failure, and other parameters indicative of meaningful clinical improvement.
Beyond COVID-19, Relief’s objective is to establish RLF-100™ as the standard of care for Intensive Care Units (ICUs) in acute as well as chronic contexts to prevent and cure respiratory failure and its complications.
Standard of Care in ICU to prevent / cure respiratory failure:
Since RLF-100™’s mechanism of action (MoA) is not restricted to the protection of AT2 cells, beneficial effects could extend to other types of ALI where involvement of AT2 cells is not the leading cause. Preclinical and pilot clinical data in sepsis-induced ALI support this view. Other forms of ALI where treatment with RLF-100™ may hold promise include ALI due to trauma, transfusion and cardio surgery. These other programs are likely to be viewed as risk-mitigated, should RLF-100™ be shown to be safe and effective in treating COVID-19-induced ALI.
Development of lung fibrosis is a direct consequence of COVID-19 infection. Recent studies support the anti-fibrotic effect of RLF-100™. Therefore, RLF-100™ treatment of COVID-19 patients should extend beyond the initial ALI episode. Positive data from current studies could support treatment continuation utilizing the inhaled formulation to prevent/reduce lung fibrosis. RLF-100™ could be applied long-term in fibrotic diseases of the lung.
An open label phase 2 trial (Avisarco II) in 20 patients withdemonstrated clinically significant suppression of inflammatory processes in the lung, as well as amelioration of dry cough and of exertional dyspnea (shortness of breath). It was found that RLF-100™ significantly restored immune tolerance by promoting regulatory T-lymphocytes, improved CD4/CD8 ration and normalized TNF-a production. Improvements could also be seen in sarcoidosis relevant biomarkers. RLF-100™ showed very good safety and compliance indicating that the drug could potentially suppress sarcoidosis-associated cough with almost no side effects. A multicenter, placebo-controlled, double-blind, randomized phase 3 study involving 200 sarcoidosis patients indicated for active treatment originally planned for 2019 has been postponed in favor of the development of RLF-100™ in the two COVID-19 studies.
In September 2020, Relief announced its partnership with NeuroRx for the global commercialization of RLF-100™ and the selection of commercial partners. This partnership is designed to rapidly advance RLF-100™ through clinical development so that it reaches COVID-19 patients worldwide as soon as possible. NeuroRx will lead commercialization in the United States, Canada, and Israel, while Relief will lead commercialization in Europe and the rest of the world.
The two companies have now taken steps to increase manufacturing of RLF-100™ and are in the final stages of contracting with a fill/finish manufacturer, along with potential distribution partners. Manufacturing, distribution and logistics capacities are expected to be in place by January 2021 to deliver sufficient drug quantities to treat 150,000 patients per month worldwide.
General partnering strategy
To bring new therapeutic options to the market as quickly as possible, Relief seeks partnerships with companies who have late-stage clinical assets that can be rapidly advanced.
Criteria to evaluating new assets include: