Background:Tyrosine kinase 2 (TYK2) is an intracellular kinase that mediates signaling by key cytokines involved in psoriatic arthritis (PsA) and plaque psoriasis (PsO) pathogenesis. Deucravacitinib is a novel oral agent that selectively inhibits TYK2 via an allosteric mechanism by binding to the nonconserved regulatory domain of the kinase. A previous Phase 2 trial in PsO had demonstrated that deucravacitinib was efficacious and well tolerated, with no laboratory abnormalities observed.Objectives:To evaluate the efficacy and safety of deucravacitinib in active PsA.Methods:This is an ongoing, 1-year, randomized, double-blind, placebo (PBO)-controlled (initial 16 weeks), multiregional, Phase 2 trial (NCT03881059). Eligible patients had a PsA diagnosis for ≥6 months, met CASPAR criteria, and had active disease with ≥3 tender and ≥3 swollen joints, C-reactive protein ≥3 mg/L (ULN, 5 mg/L), and ≥1 psoriatic lesion (≥2 cm). Patients had failed or were intolerant to ≥1 nonsteroidal anti-inflammatory drug, corticosteroid, conventional synthetic disease-modifying antirheumatic drug (csDMARD), and/or 1 TNF inhibitor (TNFi; ≤30%). Patients were randomized 1:1:1 to deucravacitinib 6 mg once daily (QD) or 12 mg QD, or PBO. The primary endpoint was achievement of ACR 20 response at Week 16. Additional endpoints included the proportion of patients achieving ACR 50/70 response, Health Assessment Questionnaire-Disability Index (HAQ-DI) response (≥0.35 improvement from baseline), enthesitis resolution (Leeds Index score of 0), minimal disease activity, change from baseline in SF-36 physical component score (SF-36 PCS) and mental component score (SF-36 MCS), Psoriasis Area and Severity Index (PASI) 75 response, adverse events (AEs), and laboratory parameters.Results:Of 203 patients randomized, 180 (89%) completed 16 weeks of treatment (deucravacitinib 6 mg QD, 63/70 [90%]; deucravacitinib 12 mg QD, 59/67 [88%]; PBO, 58/66 [88%]). Demographic and baseline disease characteristics were similar across groups. Mean age was 49.8 years, 51% of patients were female, median PsA duration was 4.5 years, 66% of patients used csDMARDs at baseline and throughout the study, and 15% had used a TNFi. This study met its primary endpoint, with deucravacitinib 6 mg and 12 mg QD demonstrating significantly higher ACR 20 responses versus PBO at Week 16 (Figure 1). Additional endpoints were also met with deucravacitinib versus PBO (Figure 1). Adjusted mean changes from baseline in SF-36 PCS and SF-36 MCS at Week 16, respectively, were significantly higher in the deucravacitinib 6 mg QD group (5.6 vs 2.3, P=0.0062; 3.6 vs 0.7, P=0.0211) and 12 mg QD group (5.8 vs 2.3, P=0.0042; 3.5 vs 0.7, P=0.0263) compared with PBO. PASI 75 responses were also significantly higher in the deucravacitinib groups (P≤0.0136 vs PBO). The most common AEs in the deucravacitinib 6 mg/12 mg/PBO groups, respectively, during the 16-week treatment period were nasopharyngitis (5.7%/17.9%/7.6%), sinusitis (0%/7.5%/0%), headache (7.1%/1.5%/4.5%), and rash (4.3%/6.0%/0%). No serious AEs, herpes zoster infections, opportunistic infections, or thrombotic events were reported in deucravacitinib-treated patients during this period. Additionally, no significant changes from baseline in hematologic parameters (lymphocytes, neutrophils, platelets, and hemoglobin) or serum lipids were observed with deucravacitinib treatment.Conclusion:Deucravacitinib was efficacious versus PBO over 16 weeks in patients with active PsA. Treatment was generally well tolerated and the safety and laboratory parameter profile of deucravacitinib was consistent with that observed in an earlier Phase 2 PsO trial.Acknowledgements:This study was sponsored by Bristol Myers Squibb. Professional medical writing assistance was provided by Peloton Advantage, LLC, an OPEN Health company, and funded by Bristol Myers Squibb.Disclosure of Interests:Philip J Mease Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, SUN Pharma, UCB, Grant/research support from: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, SUN Pharma, UCB, Atul Deodhar Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Galapagos, Glaxo Smith & Kline, Janssen, Novartis, Pfizer, UCB, Grant/research support from: AbbVie, Eli Lilly, Glaxo Smith & Kline, Novartis, Pfizer, UCB, Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma, Frank Behrens Consultant of: Pfizer, AbbVie, Sanofi, Lilly, Novartis, Genzyme, Boehringer, Janssen, MSD, Celgene, Roche, Chugai, Bristol Myers Squibb, UCB Pharma, Grant/research support from: Pfizer, Janssen, Chugai, Celgene, Roche, Alan Kivitz Shareholder of: Pfizer, Sanofi, GlaxoSmithKline, Gilead Sciences, Inc., Novartis, Paid Consultant: AbbVie, Boehringer Ingelheim, Flexion, Janssen, Pfizer, Sanofi, Regeneron, SUN Pharma Advanced Research, Gilead Sciences, Inc., Speakers bureau: Celgene, Merck, Lilly, Novartis, Pfizer, Sanofi, Genzyme, Flexion, AbbVie, Jonghyeon Kim Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Shalabh Singhal Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Miroslawa Nowak Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Subhashis Banerjee Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb
Proline-Rich Tyrosine Kinase 2 and Rac Activation by Chemokine and Integrin Receptors Controls NK Cell Transendothelial Migration
