Background RNA-associated with immune complexes (ICs) is recognized to play a central role in driving interferon production and systemic inflammation in systemic lupus erythematosus (SLE). To date, therapeutic strategies which have sought to block interferon directly or to target various B-cell regulatory proteins have met with mixed success. Given the proximal point of nucleic acid-containing ICs in the inflammatory cascade, reduction in associated RNA is expected to render the ICs less pathogenic. RSLV-132 is a fully-human Fc fusion protein consisting of the Fc domain of IgG1 fused to human RNase 1 that is designed to enzymatically digest RNA-containing ICs.
Objectives This multiple ascending dose study of RSLV-132 in SLE patients was carried out to assess the safety, pharmacokinetics (PK), serum enzyme activity, and immunogenicity of this novel biologic in SLE.
Methods A phase 1b, multicenter, randomized, double-blind, placebo-controlled study evaluated 4 dose cohorts (0.3 – 10.0 mg/kg) administered by intravenous infusion. Each cohort consisted of 8 subjects (6 received RSLV-132 and 2 received placebo). Three to five doses were given over 29 days. Serum samples were collected and analyzed for PK analysis, anti-drug antibody (ADA) assessment, autoantibody profiles, and RNase catalytic activity assessment.
Results A total of 61 adverse events (AEs) were recorded in the 32 subjects during the study. One grade 3 event (cholecystitis; unrelated) occurred in a subject in the 0.3 mg/kg group There were no deaths in the study. The PK analysis demonstrated a linear increase in serum RSLV-132 concentration with a terminal half-life of approximately 19 days. None of the subjects in the study were positive for ADA. RNase catalytic activity increased in a proportional manner up to approximately 100 ug/ml at Cmax in the 10 mg/kg dose cohort, and very closely paralleled the drug concentration curve detected by ELISA. SLEDAI scores were recorded during the study and of the evaluable subjects (SLEDAI >0) a greater proportion of RSLV-132-treated subjects (44%) saw a reduction in SLEDAI scores than in the placebo group (33%). Given the small size of the study this trend will need to be confirmed in larger studies.
Conclusions RSLV-132 is a promising, novel biologic for the treatment of SLE. An excellent safety profile was observed in the current study. The PK profile showed good dose-proportionality and the observed half-life will support bi-weekly dosing going forward. High serum RNase activities were achieved and sustained over the entire course of the study with no evidence of an ADA response. The results of this study support continued development of RSLV-132 in SLE.
Disclosure of Interest None declared