High Rates of Psoriasis Clearance With Investigational TYK2 Inhibitor

NEW ORLEANS -- As many as a third of patients with moderate or severe psoriasis had complete clearance within 12 weeks with an investigational oral tyrosine kinase 2 (TYK2) inhibitor, a small randomized trial showed.

From 44% to 68% of patients met the primary endpoint of 75% improvement in the Psoriasis Area and Severity Index (PASI-75) with the three highest doses of TAK-279. Further honing of PASI results showed that 45% to 46% of patients had 90% clearance with the two highest doses, and 33% of patients achieved PASI-100 with the highest dose.

One serious adverse event (AE) occurred in a patient treated with TAK-279, and no more than two patients (<4%) in any dose group discontinued treatment because of AEs, reported April Armstrong, MD, of the Keck School of Medicine at USC in Los Angeles, at the American Academy of Dermatology meeting.

"With doses of 5 mg and above, about seven out of [every] 10 patients had a PASI-75 response at 12 weeks, and about a third of patients reached PASI-100 with 30 mg," said Armstrong. "Overall, TAK-279 was well tolerated, and the safety profile was consistent with what we know about TYK2. These efficacy and safety findings support additional larger studies of TAK-279 in patients with psoriasis."

Though no clinical studies have directly compared TAK-279 and deucravacitinib (Sotyktu), the first TYK2 inhibitor approved in the U.S., the results with TAK-279 "appeared better," observed Andrew Blauvelt, MD, of Oregon Medical Research Center in Portland. He asked whether the two drugs' TYK2 inhibitory capacity had been compared in vitro.

Laboratory studies have compared TYK2 selectivity with the same assay and TAK-279 has a "tendency" toward greater selectivity, Armstrong responded. However, she cautioned that "clinical results sometimes may not translate exactly, so I think we'll have to wait to see how other studies pan out."

TYK2 is a key component in the JAK-STAT signaling pathway, and increased activation of proinflammatory enzymes in the pathway is associated with psoriasis and other autoimmune conditions, Armstrong noted in the introduction to the study. Excluded from the JAK1 binding pocket because of a single amino acid difference, TAK-279 has approximately a 1.5-million-fold greater selectivity for TYK2 as compared with JAK1.

TAK-279 was evaluated in a dose-ranging study involving about 250 patients with moderate/severe psoriasis. The patients were randomized evenly to placebo or one of four doses of TAK-279 (2-30 mg once daily). The trial involved adults with plaque psoriasis of at least 6 months' duration and PASI ≥12, physician global assessment (PGA) ≥3, and body surface area (BSA) ≥10%. The primary endpoint was PASI-75 at week 12, and secondary endpoints included PGA 0/1, PASI-90, PASI-100, and change in quality of life (QoL) all at week 12.

The study population had a mean age of 45-50, and men accounted for 60-80% of patients in each treatment group. The patients had longstanding psoriasis of 13-18 years, associated with a baseline mean PASI score of 16-18, PGA of 3.2-3.4, BSA of 21-25%, and QoL score by Dermatology Life Quality Index of 6-8.

At 12 weeks, 5.8% of patients assigned to placebo met PASI-75 criteria as compared with 18.0%, 44.2%, 67.9%, and 67.3% in the four TAK-279 groups. Differences achieved statistical significance over placebo (P<0.001) for all but the 2-mg TAK-279 group.

No placebo-treated patients had a PASI-90 or PASI-100 response. In contrast, 21.2% to 46.2% of patients assigned to the three highest doses of TAK-279 had PASI-90 responses at 12 weeks, and 10% to 33% had complete clearance (P<0.05 to P<0.001 versus placebo). Half of patients in the two highest dose groups for TAK-279 had PGA 0/1 (clear/nearly clear) scores at week 12, and 15-33% had PGA 0 scores (clear).

Total AE count was numerically higher with the TYK2 inhibitor (53-62% vs 44% for placebo), but only one serious AE occurred during the trial (15-mg TAK-279 group). The most frequently reported AEs were COVID-19, acne, and acneiform dermatitis. Laboratory data for hematologic, renal, hepatic, and lipid parameters showed no adverse trends in any of the TAK-279 groups.

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