Efficacy and safety of deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, in patients with active systemic lupus erythematosus: results from a Phase 2, randomized, doubleblind, placebo-controlled study

BACKGROUND: Tyrosine kinase 2 (TYK2) mediates signaling of Type I interferons and IL‐23, key cytokines involved in systemic lupus erythematosus (SLE) pathogenesis. Deucravacitinib is an oral, selective, allosteric TYK2 inhibitor with a unique mechanism of action, distinct from Janus kinase (JAK) 1/2/3 inhibitors. Deucravacitinib is approved in multiple countries for the treatment of adults with plaque psoriasis. This analysis assessed the efficacy and safety of deucravacitinib in patients with active SLE. METHODS: This was a 48‐week, double‐blind, placebo‐controlled, Phase 2 trial (NCT03252587).1 Eligible patients met the Systemic Lupus International Collaborating Clinics (SLICC) criteria, were seropositive, and had a Systemic Lupus Erythematosus Disease Activity Index 2000 score ≥6 and ≥1 British Isles Lupus Assessment Group (BILAG) index A or ≥2 BILAG B manifestations from the musculoskeletal or mucocutaneous domain. Patients on standard background medications were randomized 1:1:1:1 to deucravacitinib (3mg BID, 6 mg BID, 12mg QD) or placebo. Oral corticosteroid tapering was required from Weeks 8‐20; further tapering was optional from Weeks 32‐40. The primary endpoint was the proportion of patients achieving SLE Responder Index (SRI[4]) at Week 32. Key secondary endpoints at Week 48 included the proportion of patients achieving SRI(4) and decrease of 50 percent or more from baseline Cutaneous Lupus Erythematosus Disease 2 Area and Severity Index (CLASI‐50) in patients with baseline CLASI ≥10. Change from baseline in CLASI Activity Score (CLASI‐A) over time was also assessed. RESULTS: Of 363 randomized patients, 275 (76%) completed 48 weeks of treatment. Baseline demographic and disease characteristics were balanced across treatment groups, with baseline mean CLASI‐A scores ranging from 8.0‐8.6 across groups. The primary endpoint at Week 32 was met, with significantly greater proportions of patients in the deucravacitinib 3mg BID and 6mg BID groups vs placebo achieving SRI4 responses (placebo: 34.4%; deucravacitinib 3 mg BID 58.2%, P=0.0006; 6 mg BID 49.5%, P=0.021; 12mg QD 44.9%, P=0.078). SRI4 response was sustained across all deucravacitinib groups up to 48 weeks. At Week 48, patients treated with deucravacitinib demonstrated improvement across all secondary endpoints compared with placebo. In patients with CLASI ≥10 at baseline, greater mean changes from baseline in CLASI‐A were observed in deucravacitinib vs placebo at Week 48 (placebo: 16.7%; deucravacitinib 3mg BID 69.6%, P=0.0006; 6 mg BID 56.0%, P=0.0058; 12mg QD 62.1%, P=0.0009). Rates of adverse events (AEs), serious AEs, and AEs of interest were similar between deucravacitinib and placebo groups. Most common AEs (≥10%) with deucravacitinib were upper respiratory tract infection, nasopharyngitis, headache, and urinary tract infection. No deaths, major adverse cardiac events, thrombotic 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 parameters were observed. CONCLUSION: Deucravacitinib demonstrated sustained, meaningful clinical efficacy in SRI,4 improvement in mucocutaneous activity as measured by CLASI‐A responses, and was well tolerated in patients with active SLE up to 48 weeks. Deucravacitinib shows promise as a novel therapy for SLE and warrants further investigation in Phase 3 trials.