Background Both IL-12 and IL-23 have been implicated in the pathogenesis of human and experimental lupus,^1–6 and in a drug repositioning analysis, the anti-IL-12/23 monoclonal antibody ustekinumab (UST) was identified as a high-priority candidate for the treatment of patients with SLE.⁷ We evaluated the efficacy, safety, and molecular effects of UST in a Ph2 trial.⁸

Methods A Ph2, placebo (PBO)-controlled study was conducted in 102 adults with seropositive (ANA, anti-dsDNA, and/or anti-Smith autoantibodies) SLE by SLICC criteria and active (SLEDAI 6 and 1 BILAG A and/or 2 BILAG B) disease. Patients were randomized (3:2) to receive UST IV~6 mg/kg or PBO at wk0, followed by SC injections of UST 90 mg q8w or PBO, both added to standard care. PBO patients crossed over to SC UST at wk24. The primary endpoint was proportion of patients achieving SLE Responder Index (SRI)−4 response at wk24. Circulating levels of type I (IFN-I) and type II interferon (IFN-) were assessed by microarray of whole blood RNA samples and serum protein ELISA analyses.

Results SRI-4 response at wk24 was significantly greater (p=0.0057) in the UST group (62%) vs PBO (33%). UST also demonstrated greater improvement in musculoskeletal and mucocutaneous disease features vs PBO at wk24. The risk of a new BILAG flare (1 new BILAG A or 2 new BILAG B) was significantly lower in the UST group vs. PBO (HR 0.11 [95% CI 0.01–0.94]; p=0.0078; wk12 to wk24 prespecified analysis). Between wk24 and wk48, response rates across disease measures were either sustained (e.g. SRI-4, 62% at wk24 vs 63% at wk48; joint response 87% at wk24 vs 87% at wk48) or increased (CLASI response, 53% at wk24 vs 69% at wk48) in those randomized to UST. Following crossover at wk 24, an additional 10%–20% of PBO patients responded to UST (n=33) in the outcomes studied. Clinical response to UST was associated with decreases in IFN- protein and gene signature. In contrast, IFN-I levels were stable over time and were not associated with UST response. Safety events were consistent with the known UST safety profile.

Conclusions UST provided sustained clinical benefit in global and organ (mucocutaneous and joint disease)-specific SLE activity measures with a safety profile consistent with approved indications. Thus, UST may be an effective biologic therapy for SLE by blocking IL-12 and IL-23-driven pathogenic mechanisms which are independent of the IFN-I pathway.

Funding Source(s): Janssen Research and Development, LLC supported this study.

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