Background/Purpose: Tyrosine kinase 2 (TYK2) is an intracellular kinase that mediates signaling by key cytokines involved in psoriatic arthritis (PsA) pathophysiology. Deucravacitinib (BMS-986165) is a novel oral agent that selectively inhibits TYK2 through an allosteric mechanism by binding to the regulatory domain of TYK2 in contrast to inhibitors of the closely related Janus kinases (JAK1–3) that bind to the active site in the kinase domain.¹ In a previous Phase 2 trial in plaque psoriasis (PsO), 67%–75% of patients who received deucravacitinib ≥3 mg twice daily achieved PASI 75 at 12 weeks versus 7% for placebo (PBO; P< 0.001).² No deucravacitinib-related serious adverse events (AEs) were observed.² The current trial evaluated the efficacy and safety of deucravacitinib in PsA.

Methods: This is an ongoing, 1-year, randomized, double-blind, PBO-controlled (initial 16 weeks), multicenter, Phase 2 trial (NCT03881059). Eligible patients had a PsA diagnosis for ≥6 months, met CASPAR criteria, and had active disease (≥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 (IR) to ≥1 nonsteroidal anti-inflammatory drug, corticosteroid, and/or conventional synthetic disease-modifying antirheumatic drug (csDMARD), 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 ACR 20 response at Week 16. Key secondary endpoints included improvement from baseline in the Health Assessment Questionnaire–Disability Index (HAQ-DI) and Short Form-36 Physical Component Score (SF-36 PCS). Additional endpoints included the proportion of patients achieving ACR 50/70, HAQ-DI response (≥0.35 improvement from baseline), minimal disease activity, enthesitis resolution (Leeds Index), and AEs.

Results: Of 203 patients randomized, 180 (89%) completed 16 weeks of treatment. Demographic and baseline disease characteristics were similar across the 3 groups. Mean age was 49.8 years, median PsA duration was 4.5 years, 66% of patients were using csDMARDs at baseline, and 15% were TNFi-IR. The study met its primary objective of showing a dose-response relationship (P< 0.001), with both deucravacitinib 6 mg (n=70) and 12 mg QD (n=67) demonstrating significantly greater ACR 20 responses versus PBO (n=66) at Week 16 (52.9% and 62.7% versus 31.8%, respectively; Figure 1). Key secondary objectives were achieved with significant and generally similar improvements in secondary endpoints for both deucravacitinib doses versus PBO (Figure 2). Nasopharyngitis, sinusitis, headache, and rash were the most common AEs in deucravacitinib-treated patients (Table). Most AEs were mild or moderate. No serious AEs were reported in deucravacitinib-treated patients, including no serious infections, herpes zoster, opportunistic infections, or thrombotic events.

Conclusion: Deucravacitinib was efficacious versus PBO over 16 weeks of treatment in patients with active PsA. Treatment was well tolerated and the safety profile was consistent with that observed in the Phase 2 PsO trial.²

References

1. Burke JR et al. Sci Transl Med. 2019;11:1-16.
2. Papp K et al. N Engl J Med. 2018;379:1313-21.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/efficacy-and-safety-of-deucravacitinib-bms-986165-an-oral-selective-tyrosine-kinase-2-inhibitor-in-patients-with-active-psoriatic-arthritis-results-from-a-phase-2-randomized-double-blind-plac/