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

BACKGROUND: Chronic spontaneous urticaria (CSU) poses a significant burden on both patient and caregiver. Currently treatments for CSU are inadequate for some patients. TLL-018, an oral TYK2/JAK1 inhibitor, is under investigation for CSU treatment. OBJECTIVES: To evaluate the efficacy and safety of TLL-018 for treating moderate-to-severe CSU in patients who had an inadequate response to antihistamines. METHODS: In this multicenter, double-blind, randomized, placebo-controlled, parallel-group pilot study (NCT05373355), patients with CSU who showed an inadequate response to antihistamines received either 10 mg or 30 mg of TLL-018, or placebo orally twice daily. After 4 weeks, patients on placebo were switched to 20 mg of TLL-018, and continuing treatment for an additional 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 of 0 or 1 at weeks 4 and 12. RESULTS: The study involved of 41 patients. At week 4, the ANCOVA versus change from placebo of UAS7/weekly Itch Severity Score/weekly Hive Severity Score were -11.5/-8.0/-3.8 in the 10-mg groups and -16.0/-9.0/-7.0 in the 30-mg groups. At week 12, the percentages achieving UAS7 ≤ 6 and UAS7 = 0 were 53.8%/38.5%, 71.4%/64.3%, and 61.5%/53.8% in the placebo-to-20 mg, the 10-mg, and the 30-mg TLL-018 groups, respectively. Common treatment-emergent adverse events included elevated serum creatine kinase and blood lipid levels, hyperglycemia, and urinary occult blood. CONCLUSIONS: TLL-018 was well-tolerated and effective in treating moderate-to-severe CSU in patients who had an inadequate response to antihistamines.