AB0515 PHARMACOKINETICS, SELECTIVITY PROFILE, AND EXPOSURE-RESPONSE RELATIONSHIP FOR EFFICACY AND SAFETY IN A PHASE 2 STUDY OF DEUCRAVACITINIB, AN ORAL, SELECTIVE, ALLOSTERIC TYK2 INHIBITOR, IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

• Published in: Annals of the rheumatic diseases Vol. 82; no. Suppl 1; pp. 1452 - 1453
• Main Authors: Ide, T, Chiney, M, Bach, H Y T, Goti, V, Murthy, B, Hobar, C, Zhao, Q, Aras, U
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group LTD 01.06.2023
• Subjects: Allosteric properties; Dose-response effects; Lupus; Pharmacokinetics; Placebos; Protein-tyrosine kinase; Psoriasis; Safety; Stockholders; Systemic lupus erythematosus; Tyk2 protein
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/annrheumdis-2023-eular.1714

BackgroundDeucravacitinib is a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor approved in multiple countries for the treatment of adults with plaque psoriasis [1,2]. Deucravacitinib binds to the unique TYK2 regulatory domain, conferring greater functional selectivity vs JAK inhibitors, which bind to the catalytic domain. Deucravacitinib showed superior efficacy vs placebo in a phase 2 trial in SLE (NCT03252587) [3].ObjectivesThis analysis assessed the pharmacokinetics (PK), selectivity profile compared to JAK inhibitors, and exposure-response (E-R) relationship for efficacy and safety of deucravacitinib in SLE.MethodsIn the phase 2 trial, patients with active SLE were randomized 1:1:1:1 to placebo or deucravacitinib (3 mg BID, 6 mg BID, 12 mg QD). PK analysis included pooled concentration data from 266 SLE patients and 328 phase 1 participants. IC50 was determined by in vitro whole blood assays and plotted against PK profiles. E-R analyses included data from 356 patients. Logistic regression analyses assessed the relationship between deucravacitinib exposure and probability of achieving efficacy endpoints and safety events at weeks 32 and 48.ResultsDeucravacitinib PK in SLE patients was not meaningfully different from that in phase 1 participants. At 12 mg QD, deucravacitinib Cmax was 8-fold lower than JAK 1/3 IC50 and 47-fold lower than JAK 2/2 IC50 (Figure 1). In the E-R analyses, the probability of achieving SRI(4) and BICLA at week 32 increased with increasing deucravacitinib CminSS, with 3 mg BID providing near-maximal response. The E-R relationship for infection and infestation was relatively flat, while skin and subcutaneous tissue disorders increased with increasing deucravacitinib CminSS. These E-R relationships were similar at week 48.ConclusionDeucravacitinib PK in SLE patients is not meaningfully different from that in phase 1 participants. At clinically relevant exposures, deucravacitinib demonstrates highly selective inhibition of TYK2 vs JAK 1/2/3. The deucravacitinib E-R relationships are well characterized for various efficacy endpoints and safety events.References[1]Armstrong A, et al. J Am Acad Dermatol. 2023;88(1):29-39.[2]Strober B, et al. J Am Acad Dermatol. 2023;88(1):40-51.[3]Morand E, et al. Arthritis Rheumatol. 2022 Nov 11 (Epub ahead of print).AcknowledgementsThis study was sponsored by Bristol Myers Squibb.Disclosure of InterestsTakafumi Ide Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Manoj Chiney Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Huynh Yen Thanh Bach Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Vineet Goti Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Bindu Murthy Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Coburn Hobar Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Qihong Zhao Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Urvi Aras Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb.