Assessment of the Impact of RNase in Patients With Severe Fatigue Related to Post-Acute Sequelae of SARS-CoV-2 Infection (PASC): A Randomized Phase 2 Trial of RSLV-132.

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and RNA debris persist in viral reservoirs for weeks to months following infection, potentially triggering interferon production and chronic inflammation. RSLV-132 is a biologic drug composed of catalytically active human RNase1 fused to human IgG1 Fc and is designed to remain in circulation and digest extracellular RNA. We hypothesized that removal of SARS-CoV-2 viral RNA from latent reservoirs may improve inflammation, neuroinflammation, and fatigue associated with post-acute sequelae of SARS-CoV-2 infection (PASC). METHODS: This was a phase 2, double-blind, placebo-controlled randomized clinical trial in participants with a 24-week history of PASC and severe fatigue. The primary endpoint of the trial assessed the impact of 6 intravenous doses of RSLV-132 on the mean change from baseline at day 71 in the Patient-Reported Outcomes Measurement Information System Fatigue Short Form 7a (PROMIS Fatigue SF 7a). RESULTS: A statistically significant difference on day 71 was not observed with respect to the primary or secondary endpoints. This was likely due to a placebo response that increased during the trial. Statistically significant improvement in fatigue as measured by the PROMIS Fatigue SF 7a, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), and Physicians Global Assessment (PGA) instruments were observed earlier in the trial, with women demonstrating greater responses to RSLV-132 than men. CONCLUSION: While fatigue was not statistically significantly improved at Day 71, earlier timepoints revealed statistically significant improvement in fatigue and physician global assessment. The data suggest eliminating latent viral RNA by increasing serum RNase activity may improve fatigue in PASC patients. Women may respond better to this approach than men. Future studies will aim to confirm these findings.