Safety and efficacy of the selective tyrosine kinase 2/Janus kinase 1 inhibitor TLL-018 in patients with moderate-to-severe chronic spontaneous urticaria with inadequate response to H1 antihistamines: a phase Ib, randomized, double-blind, placebo-controlled pilot study.

Abstract

Chronic spontaneous urticaria (CSU) places a considerable burden on both patients and caregivers. Current treatments for CSU are inadequate for some patients. TLL-018, an oral tyrosine kinase 2/Janus kinase 1 (TYK2/JAK1) inhibitor, is currently being investigated as a potential treatment for CSU. To evaluate the efficacy and safety of TLL-018 for treating moderate-to-severe CSU in patients with an inadequate response to antihistamines. In this multicentre, double-blind, randomized, placebo-controlled, parallel-group pilot study (NCT05373355), patients with CSU who showed an inadequate response to antihistamines were given (1: 1: 1) 10 or 30 mg of TLL-018, or placebo, orally twice daily. After 4 weeks, patients on placebo were switched to TLL-018 20 mg and continued treatment for a further 8 weeks. The primary endpoint was safety, while secondary endpoints included efficacy measures, such as weekly Urticaria Activity Score (UAS7) ≤ 6, UAS7 = 0, and a Dermatology Life Quality Index score of 0 or 1, at weeks 4 and 12. Overall, 41 patients were randomly assigned to TLL-018 10 mg (n = 14), 30 mg (n = 13) or placebo (n = 14). At week 4, the placebo-adjusted change from baseline (analysed using Ancova) in UAS7, weekly Itch Severity Score and weekly Hive Severity Score was -11.5, -8.0 and -3.8, respectively, in the 10-mg TLL-018 group, and -16.0, -9.0 and -7.0, respectively, in the 30-mg group. At week 12, the proportions of patients achieving UAS7 ≤ 6 and UAS7 = 0 were 54% and 39%, respectively, in the placebo-then-20-mg group, 71% and 64% in the 10-mg group, and 62% and 54% in the 30-mg group. Common treatment-emergent adverse events included elevated serum creatine kinase and blood lipid levels, hyperglycaemia and urinary occult blood. TLL-018 was well tolerated and effective in treating moderate-to-severe CSU in patients who had an inadequate response to antihistamines.