TAK-279 is a highly selective, oral allosteric TYK2 inhibitor in late-stage development.

Takeda's investigational tyrosine kinase 2 (TYK2) inhibitor TAK-279 showed significant efficacy in patients with active psoriatic arthritis, according to Phase 2b data slated to be presented at the American College of Rheumatology's (ACR) annual meeting in San Diego, California.

TAK-279 is a highly selective, oral allosteric TYK2 inhibitor in late-stage development, with approximately 1.3 million–fold greater selectivity for TYK2 as compared with JAK1. Takeda plans to initiate Phase 3 studies in plaque psoriasis in 2023 and psoriatic arthritis in 2024, while exploring TAK-279 in systemic lupus erythematosus, inflammatory bowel disease, and other indications.

The study met its primary endpoint with a statistically significant proportion of patients, 53.3% (15 mg) and 54.2% (30 mg), treated with TAK-279 achieving at least an American College of Rheumatology 20 (ACR 20) response compared to 29.2% in the placebo arm at week 12. The safety and tolerability profile of TAK-279 in the trial was consistent with that observed in the Phase 2b psoriasis study. There was no statistically significant difference in ACR 20 seen in the TAK-279 5 mg arm (35.2%) compared to the placebo arm (29.2%).

"There remains a critical unmet need for psoriatic arthritis treatment options that not only improve the signs and symptoms of the condition but are well tolerated and convenient for patients," says study author Alan Kivitz, MD, a rheumatologist and President of Altoona Arthritis & Osteoporosis Center/Altoona Center for Clinical Research in Duncansville, PA, in a news release. "As psoriatic arthritis is a condition with diverse presentations of inflammation and skin involvement, the improvements seen with just 12 weeks of treatment in this Phase 2b study in patients with a low mean baseline C-reactive protein level are particularly encouraging. These results support the continued evaluation, across the psoriatic arthritis disease spectrum, of TAK-279, a once-daily oral TYK2 inhibitor with next-generation selectivity."

The study also demonstrated improvements in key secondary endpoints:

• At 15 mg and 30 mg of TAK-279, 26.7% and 26.4% of patients achieved ACR 50 response compared to 9.7% of patients on placebo.
• A numerically higher proportion of patients treated with TAK-279 15 mg (14.7%) and 30 mg (13.9%) achieved ACR 70 compared to those on placebo (5.6%).
• In patients with a body surface area (BSA) greater than or equal to 3% at baseline, Psoriasis Area and Severity Index (PASI) 75 was achieved in a greater proportion of patients treated with TAK-279 (45.7% [30 mg], 28.3% [15 mg] and 25.6% [5 mg]; and 0.186 vs placebo [15.4%]).
• In patients with Physician Global Assessment of Psoriasis (PGA-PsO) ≥2 at baseline, a greater proportion of patients treated with TAK-279 30 mg achieved a PGA-PsO score of 0 (clear) or 1 (almost clear) and at least a 2-point improvement from baseline compared to placebo (32.8% [30 mg], 20.6% [15 mg], 20.4% [5 mg] vs. 15.8% [placebo].
• Reductions were observed in mean change from baseline in the tender joint count and swollen joint count in all groups, with higher reductions with the 15 mg and 30 mg doses compared to placebo and 5 mg TAK-279.
• Minimal disease activity (MDA) response rates were higher in TAK-279 15 mg and 30 mg groups than in placebo
• The most common treatment-emergent adverse events (TEAEs) in patients who received TAK-279 5 mg, 15 mg, or 30 mg versus placebo, respectively, were nasopharyngitis (8.5%, 9.3%, 9.7%, 4.2%), upper respiratory tract infections (11.3%, 4%, 9.7%, 2.8%), headache (2.8%, 8.0%, 5.6%, 4.2%) and rash (4.2%, 8%, 5.6%, 0%). No opportunistic infections, major adverse cardiovascular events, or differences in mean laboratory parameters of interest were observed, compared with placebo. There was no clinically significant difference in adverse event rates between doses of TAK-279. Serious and grade 3 or higher TEAEs occurred infrequently and at a similar rate in the TAK-279 and placebo groups.

"Based on these promising efficacy and safety results, achieved at 12 weeks, we plan to initiate a Phase 3 study of TAK-279 in psoriatic arthritis as well as commence a Phase 3 study in plaque psoriasis," adds Andy Plump, President, Research & Development, Takeda. "We are also advancing the development of TAK-279 in Crohn's disease, ulcerative colitis, and systemic lupus erythematosus and exploring a range of other potential indications. These opportunities are being explored in parallel with the psoriasis and psoriatic arthritis programs."

The Phase 2b study is a randomized, multicenter, double-blind, placebo-controlled multiple-dosed trial designed to evaluate the efficacy, safety, and tolerability of TAK-279 in patients with active psoriatic arthritis. Eligible patients were aged ≥ 18 years, with psoriatic arthritis symptoms for ≥ 6 months before screening, met Classification criteria for Psoriatic Arthritis (CASPAR), and had ≥ 3 tender and ≥ 3 swollen joint counts (TJC/SJC) at enrollment despite prior NSAID, DMARD or biologic treatment. In total, 290 patients were randomized and treated (1:1:1:1 ratio) to receive one of three doses of TAK-279 or placebo once daily for 12 weeks with a 4-week safety follow-up period; 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). The mean baseline high-sensitivity C-reactive protein (hsCRP) was 7.0 mg/L; 45.9% had hsCRP ≥ 3 mg/L. The primary endpoint was the proportion of patients achieving at least an ACR 20 response at week 12.