Safety and efficacy of the selective tyrosine kinase 2/Janus kinase 1 inhibitor TLL-018 in moderate-to-severe plaque psoriasis: a phase Ib, randomized, double-blind, placebo-controlled study

BACKGROUND: Psoriasis treatments that provide rapid and extensive itch relief as well as lesion clearance are currently inadequate. OBJECTIVES: To evaluate the efficacy and safety of the tyrosine kinase 2/Janus kinase 1 inhibitor TLL-018 in patients with moderate-to-severe psoriasis. METHODS: This phase Ib, double-blind, placebo-controlled study (NCT05342428) randomized participants to receive TLL-018 10 mg, 20 mg, 30 mg or placebo 2 : 2 : 2 : 1 orally twice daily for 12 weeks. The study included 73 patients with moderate-to-severe psoriasis. Eligible patients were aged 18-75 years and were diagnosed with moderate-to-severe psoriasis at least 6 months prior to screening, as defined by a Psoriasis Area and Severity Index (PASI) of ≥ 12, a body surface area ≥ 10% and a Physician's Global Assessment (PGA) of ≥ 3. The primary endpoint was safety of TLL-018. The efficacy endpoints were proportions of patients at week 12 achieving a ≥ 75% improvement from baseline in PASI (PASI 75), PGA of 0 or 1 (PGA 0/1) and Dermatology Life Quality Index of 0 or 1. RESULTS: A total of 73 participants were treated. TLL-018 was well tolerated, and most treatment-emergent adverse events were mild/moderate. At week 12, 40% of patients (8 of 20) achieved PASI 75 with TLL-018 10 mg, 48% (10 of 21) with 20 mg, 62% (13 of 21) with 30 mg and 9% (1 of 11) with placebo. The proportions of patients with PGA 0/1 were 35%, 43%, 71% and 0%, respectively. Of the 21 patients in the TLL-018 30-mg group, 10 (48%) achieved a ≥ 90% improvement from baseline in PASI. CONCLUSIONS: TLL-018 was well tolerated and showed promising efficacy at week 12 compared with placebo in patients with moderate-to-severe plaque psoriasis.