LB0004 EFFICACY AND SAFETY OF DEUCRAVACITINIB, AN ORAL, SELECTIVE, ALLOSTERIC TYK2 INHIBITOR, IN PATIENTS WITH ACTIVE SYSTEMIC LUPUS ERYTHEMATOSUS: A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY

Abstract

Background: Tyrosine kinase 2 (TYK2) mediates signaling of Type I interferons, IL-23, and IL-12, key cytokines involved in lupus pathogenesis. Deucravacitinib (DEUC) is an oral, selective, allosteric TYK2 inhibitor with a unique mechanism of action, distinct from Janus kinase (JAK) 1/2/3 inhibitors, and has shown effi- cacy in psoriasis and psoriatic arthritis. Objectives: Assess efficacy and safety of DEUC in patients with active systemic lupus erythematosus (SLE). Methods: This was a 48-week (wk), randomized, double-blind, placebo (PBO)-controlled, phase 2 trial (NCT03252587). Eligible patients met SLICC cri- teria, were seropositive (ANA/anti-dsDNA/anti-Sm), and had a SLEDAI-2K score ≥6 and ≥1 BILAG index A or >2 BILAG B manifestations from the musculoskel- etal or mucocutaneous domain. Patients on standard background medications were randomized 1:1:1:1 to PBO or DEUC (3 mg BID, 6 mg BID, 12 mg QD). Oral corticosteroid tapering to 7.5 mg/day was required from wks 8-20; further taper- ing was optional from wks 32-40. The primary endpoint was the proportion of patients achieving SRI(4) at wk 32. Key secondary endpoints at wk 48 included SRI(4), BICLA, LLDAS, CLASI-50, and change from baseline in active (tender and swollen) joint count. Results: A total of 363 patients were randomized, with baseline demographic and disease characteristics similar across treatment groups. Of randomized patients, 275 (76%) completed 48 wks of treatment. The primary endpoint at wk 32 was met, with significantly greater proportion of patients in DEUC 3 mg BID and 6 mg BID groups vs PBO achieving SRI(4) responses (PBO: 34.4%; DEUC 3 mg BID: 58.2%, P=0.0006; DEUC 6 mg BID: 49.5%, P=0.021; DEUC 12 mg QD: 44.9%, P=0.078). SRI(4) response was sustained across all DEUC groups up to 48 wks (Figure 1). At wk 48, the DEUC 3 mg BID group demonstrated statistical significance in BICLA, LLDAS, CLASI-50, and active joint count, and the two other DEUC groups demonstrated clinically meaningful differences vs PBO (Figure 1). Rates of adverse events (AEs), serious AEs, and AEs of inter- est were similar between DEUC and PBO groups (Table 1). Most common AEs (≥10%) with DEUC were upper respiratory tract infection, nasopharyngitis, headache, and urinary tract infection. No deaths, major cardiac events, throm- botic events, systemic opportunistic infections, or active tuberculosis occurred. Malignancies were rare with similar rates across all groups. No meaningful abnormalities in mean levels of hematology and chemistry laboratory param- eters were observed. Conclusion: In patients with active SLE, DEUC showed statistically significant and sustained clinical efficacy in SRI(4), improvement across multiple composite and organ-specific measures up to 48 wks, and was well tolerated. DEUC shows prom- ise as a novel therapy for SLE and warrants further investigation in phase 3 trials.