Efficacy and Safety of TLL-018 in Moderate to Severe Chronic Spontaneous Urticaria Patients with Inadequate Response to H1 Antihistamine: Results from a Phase Ⅰb Study

To evaluate the efficacy and safety of TLL-018, a potent and selective small molecule TYK2/JAK1 inhibitor, in chronic spontaneous urticaria (CSU) adults with inadequate response to antihistamine. This is a randomized double-blind, placebo-controlled, pilot study of TLL-018 in adults with moderate-to-severe CSU who had inadequate response to antihistamine (NCT05373355). Patients with uncontrolled urticaria under a high dose or combination of antihistamine treatment for at least 28 days before randomization were assigned 1:1:1 to receive 10mg, 30mg TLL-018, or placebo orally twice daily (BID). After four weeks of treatment, patients treated with placebo were transferred to TLL-018 20mg BID, and all patients continued the treatment for another eight weeks. A total of 41 patients were enrolled. Mean Urticaria Activity Score (UAS7) /Itch Severity Score (ISS7) at baseline were 29.4/14.3, 28.2/13.6 and 26.2/14.1 in placebo, 10mg and 30mg groups, respectively. At week 4, Least squares (LS) mean change from baseline in UAS7/ISS7 was -7.5/-2.3 with placebo, -19.1/-10.3 with 10mg (P<0.01 vs. placebo), and -23.6/-11.3 with 30mg (P<0.0001 vs. placebo). At week 12, change from baseline in UAS7/ISS7 was -23.3/-11.5, -24.8/-12.9 and -26.5/-12.5, and the percent of UAS7≤6/UAS7=0 was 53.8%/38.5%, 71.4%/64.3% and 61.5%/53.8% in placebo-to-20mg, 10mg and 30mg groups, respectively. Adverse events were mild to moderate, and the frequency was similar across treatment groups. TLL-018 was well tolerated and showed high efficacy in moderate-to-severe CSU patients with inadequate response to high doses or a combination of antihistamine treatment.