Background/Purpose: TYK2 mediates signaling by key cytokines involved in the pathogenesis of immune-mediated inflammatory diseases such as psoriatic arthritis (PsA) and psoriasis (PsO). TAK-279 is a highly selective, oral, allosteric TYK2 inhibitor shown to be clinically effective with an acceptable safety profile in a phase 2b trial in patients with moderate-to-severe PsO (Armstrong et al. AAD 2023).The current study evaluated efficacy and safety of TAK-279 in patients with active PsA treated over 12 weeks.

Methods: This phase 2b randomized, multicenter, double-blind, placebo (PBO)-controlled, dose-ranging study (NCT05153148) was conducted at 45 sites in North America and Europe. Eligible patients were aged ≥ 18 years, with PsA symptoms for ≥ 6 months prior to screening, met CASPAR criteria, and had ≥ 3 tender and ≥ 3 swollen joint counts (TJC/SJC) at enrollment despite prior NSAID, DMARD or biologic treatment. Patients were randomized 1:1:1:1 to receive oral TAK-279 5 mg, 15 mg, 30 mg, or PBO, once daily for 12 weeks. Primary endpoint: ACR 20 response at Week 12. Secondary endpoints at Week 12 included: ACR 50, ACR 70, PASI 75 responses (in patients with ≥ 3% BSA), change from baseline in TJC/SJC, physician global assessment (PhGA) of PsA, and safety.

Results: In total, 290 patients were randomized and treated; 245 completed 12 weeks’ treatment. Baseline characteristics were generally comparable across groups (except for a lower mean TJC in the 30 mg group); 58.6% had BSA ≥ 3% (of which mean baseline PASI score was 6.2), and 32.1% had prior biologic use (20.7% TNFis). Mean baseline hsCRP was 7.0 mg/L; 45.9% had hsCRP ≥ 3 mg/L. The primary endpoint was met with a significantly greater proportion of patients achieving ACR 20 with TAK-279 15 mg and 30 mg vs PBO (53.3% and 54.2% vs 29.2%, both p = 0.002; Figure 1). ACR 50 response rates were also higher in the TAK-279 15 mg and 30 mg groups vs PBO (p = 0.005 and p = 0.009, respectively; Figure 2). PASI 75 response was highest in the 30 mg group vs other doses and PBO (45.7% [30 mg] and 28.3% [15 mg] vs 15.4% [PBO]; p = 0.002 and p = 0.101, respectively).A numerically higher proportion of patients treated with TAK-279 15 mg and 30 mg achieved ACR 70 than with PBO (Figure 2). Numerical reductions were observed in mean change from baseline in the TJC/SJC in all groups, with higher reductions with the 15 mg and 30 mg doses vs PBO and 5 mg TAK-279. Improvements from baseline were seen in PhGA of PsA in all TAK-279 groups vs PBO (5 mg [p = 0.016]; 15 mg [p = 0.004]; 30 mg [p = 0.003]). Safety outcomes are summarized in Table 1. Nasopharyngitis, upper respiratory tract infections, headache and rash were the most common treatment-emergent adverse events (TEAEs) in TAK-279-treated patients. No opportunistic infections, major adverse cardiovascular events or differences in mean laboratory parameters of interest were observed, compared with PBO. Serious and grade 3 or higher TEAEs occurred infrequently and at a similar rate in the TAK-279 and PBO groups.

Conclusion: TAK-279 was well tolerated and demonstrated superior dose-dependent efficacy to PBO over 12 weeks of treatment in patients with active PsA. Its safety profile was consistent with that observed in the phase 2b PsO study.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/efficacy-and-safety-outcomes-of-tak-279-a-selective-oral-tyrosine-kinase-2-tyk2-inhibitor-from-a-randomized-double-blind-placebo-controlled-phase-2b-trial-in-patients-with-active-psoriatic-arthr/