Desperate Times, Desperate Measures: The Case for RRx-001 in the Treatment of COVID-19

Oronsky, Bryan; Knox, Susan; Oronsky, Arnold; Reid, Tony R.

This article summarizes the likely attenuation properties of RRx-001 in COVID-19 based on its mechanism of action and the putative pathogenesis of the disease, which appears to activate inflammatory, oxidative and immune cascades with the potential to culminate in acute respiratory distress syndrome (ARDS), cytokine storm and death. An ongoing pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19 appears to present with three major patterns of clinical symptomatology: 1) mild upper respiratory tract infection, 2) non-life-threatening pneumonia and 3) severe pneumonia and ARDS that initially manifest as a mild prodrome lasting for 7-8 days before rapid clinical and radiological deterioration requiring ICU transfer. RRx-001 is a targeted nitric oxide (NO) donor. This small molecule, which has been evaluated in multiple Phase 1 – 2 clinical trials for cancer as well as a Phase 3 clinical trial for the treatment of small cell lung cancer called REPLATINUM (NCT03699956), is minimally toxic and demonstrates clear evidence of anti-tumor activity. During the course of these clinical trials it was noted that the rate of chronic obstructive pulmonary disease (COPD) exacerbation and pneumonia in actively smoking SCLC patients treated with RRx-001 is less than 1%. Due to extensive history of tobacco use, 40-70% of patients with lung cancer have COPD(1) and the expected rate of pulmonary infection in this population is 50-70%,(2) which was not observed in RRx-001 clinical trials. Moreover, in preclinical studies of pulmonary hypertension, RRx-001 was found to be comparable with or more effective than the FDA approved agent, Bosentan. The potential pulmonary protective effects of RRx-001 in patients with recurrent lung infections coupled with preclinical models demonstrating RRx-001-mediated reversal of pulmonary hypertension suggests therapeutic activity in patients with acute respiratory symptoms due to COVID 19. Clinical trials have been initiated to confirm the hypothesis that RRx-001 may be repurposed to treat SARS-CoV-2 infection.