Findings from a recent randomized phase 2a clinical trial suggest that enhancing extracellular RNase catalytic activity holds potential for effectiveness in patients diagnosed with systemic lupus erythematosus (SLE) and experiencing moderate to severe disease activity.
The role of RNA in SLE has gained increasing attention due to its well-known proinflammatory properties. RNA triggers interferon production through binding to TLR7 and is of central importance in SLE. Extracellular RNA is the primary trigger of type I interferon in SLE, and interferon plays a central role in the disease’s pathogenesis. RSLV-132 is a human RNase molecule that is catalytically active and fused with human IgG1 Fc. This innovative drug is designed to break down RNA and thereby reduce the chronic inflammation that is associated with SLE.
In the randomized clinical trial conducted by Dr. Burge et al., sixty-five patients meeting entry criteria with a baseline Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) score of 10 or higher and positivity for at least one of five autoantibodies to RNA-binding proteins (SM/RNP, SSA/Ro, SSB/La, Sm, RNP) were enrolled. Participants were randomly assigned in a 2:1 ratio to receive either 13 doses of RSLV-132 at 10 mg/kg or placebo. Results indicated that the mean change in CLASI score from baseline at day 169 was -5.7 (±7.0) in the placebo group and -6.2 (±8.5) in the RSLV-132 group. Subgroup analysis focused on participants with moderate to severe systemic disease activity and high baseline Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores (≥9), revealing that those treated with RSLV-132 demonstrated a higher percentage of British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) responses (62% vs. 44%) and SRI-4 responses (23% vs. 11%) compared to the placebo group. Additionally, a subgroup analysis of participants with high baseline CLASI scores (≥21) showed that those receiving RSLV-132 had a greater percentage of BICLA responses (28% vs. 8%) and SRI-4 responses (39% vs. 8%) compared to those on placebo.
The findings of the present study provide valuable insights into the patient population most likely to benefit from RSLV-132 in the treatment of SLE. Notably, RSLV-132 exhibited an excellent safety profile and displayed a promising trend towards efficacy in individuals with heightened systemic disease activity. However, the study’s primary limitation lies in its small cohort size. Moving forward, there is a clear need for larger-scale investigations involving patients with active systemic disease, as indicated by SLEDAI scores, to further validate these findings and ascertain the full potential of RSLV-132 as a therapeutic option for SLE management.
Reference
Burge DJ, Werth VP, Boackle SA, Posada J. Evaluation of RNase therapy in systemic lupus erythematosus: a randomised phase 2a clinical trial of RSLV-132. Lupus Sci Med. 2024 Feb 7;11(1):e001113.