TAK-279 is a highly potent and selective oral, allosteric TYK2 inhibitor that was shown to be clinically effective with an acceptable safety profile in a Phase IIb trial in patients with moderate-to-severe psoriasis.

In total, 290 patients were enrolled and received treatment, with 245 completing the 12-week treatment period (Phase IIb; NCT05153148). The baseline characteristics were generally similar across the groups, except for a slightly lower mean TJC (tender joint counts) in the 30 mg group. Around 58.6% of patients had a BSA (Body Surface Area) of 3% or higher, with a mean baseline PASI score of 6.2. About 32.1% had prior biological treatment, with 20.7% having used TNF inhibitors. The average baseline hsCRP (high-sensitivity C-reactive protein) level was 7.0 mg/L, and 45.9% of patients had hsCRP levels of 3 mg/L or higher.

The primary endpoint of the study was achieved, showing a significantly higher proportion of patients achieving ACR 20 with TAK-279 at 15 mg and 30 mg compared to placebo (53.3% and 54.2% vs. 29.2%, respectively). ACR 50 response rates were also higher in the 15 mg and 30 mg groups compared to placebo (26.4% and 26.7% vs. 15.5%, respectively). The PASI 75 response rate was highest in the 30 mg group compared to other doses and placebo (45.7% for 30 mg, 28.3% for 15 mg, and 15.4% for placebo). Similarly, ACR 70 rates were also higher in the 15 mg and 30 mg groups compared to placebo (14.7% and 13.9% vs. 5.6%, respectively). There were numerical reductions in mean change from baseline in TJC/SJC (swollen joint counts) in all groups, with greater reductions in the 15 mg and 30 mg doses compared to placebo and 5 mg TAK-279. Improvements were also observed in the physician global assessment (PhGA) of Psoriatic Arthritis in all TAK-279 groups compared to placebo.

Regarding safety, common treatment-emergent adverse events (TEAEs) in TAK-279-treated patients included nasopharyngitis, upper respiratory tract infections, headache, and rash. There were no notable differences in serious adverse events or major cardiovascular events between TAK-279 and placebo groups, and laboratory parameters remained stable across all groups.

KOL Insight

“No significant difference in malignancy risk in patients with rheumatic disease and a prior history of malignancy who started bDMARDs or tsDMARDs. Interestingly, IL-17i had 0 malignancy events and CD-20i were next lowest.”- Rheumatologist, US

Conclusion: TYK2 inhibitors are attracting significant interest, particularly due to their distinct safety profile compared to JAK inhibitors, even though TYK2 is classified as the fourth JAK. These inhibitors are oral molecules that have demonstrated no serious safety concerns in clinical trials. However, the trials did reveal mucocutaneous manifestations, such as skin rashes and mouth ulcers. Although these issues did not lead to patient discontinuation, they are notable findings that warrant attention. This differentiation in safety could make TYK2 inhibitors a promising option in the therapeutic landscape.

TAK-279 showed good tolerability and exhibited better efficacy compared to placebo in a dose-dependent manner during the 12-week treatment period for patients with active PsA. The safety profile of TAK-279 was similar to what was observed in the Phase IIb study for psoriasis. The 15 mg and 30 mg groups were shown to be slightly more similar regarding arthritis outcomes; the psoriasis outcomes were clearly differentiated with a higher dose. 

TAK-279 may be an attractive targeted oral medication for patients with PsA, as there are presently few approved medicines for active PSA.