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

BackgroundTyrosine 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 efficacy in psoriasis and psoriatic arthritis.ObjectivesAssess efficacy and safety of DEUC in patients with active systemic lupus erythematosus (SLE).MethodsThis was a 48-week (wk), randomized, double-blind, placebo (PBO)-controlled, phase 2 trial (NCT03252587). Eligible patients met SLICC criteria, 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 musculoskeletal 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 tapering 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.ResultsA 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 interest 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, 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.Table 1.Summary of Adverse Events Through Week 48AE, na(%)Placebo n = 90DEUC 3 mg BID n = 91DEUC 6 mg BID n = 93DEUC 12 mg QD n = 89AE79 (87.8)85 (93.4)81 (87.1)75 (84.3)SAE11 (12.2)7 (7.7)8 (8.6)7 (7.9)AEs leading to treatment discontinuation3 (3.3)8 (8.8)6 (6.5)11 (12.4)Skin-related AEsb12 (13.3)15 (16.5)32 (34.4)30 (33.7)Overall infections/infestations48 (53.3)60 (65.9)60 (64.5)45 (50.6)Serious infections/infestations1 (1.1)1 (1.1)2 (2.2)1 (1.1)Infections of interest Tuberculosis0000 Herpes zosterc4 (4.4)3 (3.3)3 (3.2)2 (2.2) Influenza1 (1.1)3 (3.3)1 (1.1)3 (3.4) COVID-193 (3.3)3 (3.3)5 (5.4)3 (3.4)Malignancy events1 (1.1)d1 (1.1)e01 (1.1)fMACE0000Thrombotic events0000an is the number of patients who experienced an event. bIncludes (≤8.6% in any arm) acne, rash, dermatitis acneiform, pruritus, skin lesion, urticaria. cIncludes herpes zoster, herpes ophthalmic, genital herpes zoster. dBasal cell carcinoma. eBreast carcinoma. fVaginal squamous cell carcinoma.AE, adverse event; COVID-19, coronavirus disease 2019; DEUC, deucravacitinib; MACE, major adverse cardiac events; SAE, serious adverse event.ConclusionIn 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 promise as a novel therapy for SLE and warrants further investigation in phase 3 trials.AcknowledgementsThis study was sponsored by Bristol Myers Squibb. Professional medical writing assistance was provided by Julianne Hatfield, PhD at Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, USA, and funded by Bristol Myers Squibb. The authors acknowledge Christina Crater, MD, who was employed by Bristol Myers Squibb at the time the study was conducted, for contributions to study conduct.Disclosure of InterestsEric Morand Consultant of: AstraZeneca, Bristol Myers Squibb, Biogen, Eli Lilly, EMD Serono, Genentech, Servier, and Novartis , Grant/research support from: AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Biogen, Eli Lilly, EMD Serono, Genentech, Janssen, and UCB , Marilyn Pike Consultant of: AstraZeneca, Bristol Myers Squibb, and Pfizer, Joan T. Merrill Consultant of: UCB, GlaxoSmithKline, AbbVie, EMD Serono, Remegen, Celgene/Bristol Myers Squibb, AstraZeneca, Amgen, Janssen, Lilly, Genentech, Aurinia, Astellas, Alexion, Sanofi, Zenas, and Provention , Grant/research support from: GlaxoSmithKline and AstraZeneca , Ronald van Vollenhoven Consultant of: UCB, Pfizer, AbbVie, AstraZeneca, Biogen, Biotest, Celgene, Galapagos, Gilead, Janssen, Servier, Paid instructor for: Roche, Pfizer, Speakers bureau: UCB, Pfizer, AbbVie, Galapagos, Janssen, Grant/research support from: Bristol Myers Squibb, GlaxoSmithKline, Eli Lilly, UCB, , Victoria P. Werth Consultant of: Celgene, Medimmune, Resolve, Genentech, Idera, Janssen, Lilly, Biogen, Bristol Myers Squibb, Gilead, Amgen, Medscape, Nektar, Incyte, EMD Serono, CSL Behring, Principia, Crisalis, Viela Bio, Argenx, Kirin, AstraZeneca, AbbVie, GSK, AstraZeneca, Cugene, UCB, Corcept, Beacon Bioscience , Grant/research support from: Celgene, Janssen, Biogen, Gilead, AstraZeneca, Viela, Amgen, Lupus Research Alliance/BMS , Coburn Hobar Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Nikolay Delev Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Vaishali Shah Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Brian Sharkey Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Thomas Wegman Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Ian Catlett Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Subhashis Banerjee Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Shalabh Singhal Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb