LAUSR

BACKGROUND & AIMS Current therapies for ulcerative colitis (UC) fail to achieve satisfactory disease control. Selective inhibition of Janus kinase (JAK) type 1 may improve clinical outcomes in patients with UC while avoiding side effects associated with pan-JAK inhibition. The safety and efficacy of the selective JAK1 inhibitor ivarmacitinib (formerly SHR0302) were evaluated in patients with moderate-to-severe, active UC. METHODS AMBER2 was a double-blind, placebo-controlled, phase II trial conducted at 63 clinical centers in China, the USA, and Europe. Patients (N=164) were randomized 1:1:1:1 to receive oral ivarmacitinib 8 mg once daily (QD), 4 mg twice daily (BID), or 4 mg QD, or placebo for 8 weeks, followed by an 8-week extension period. The primary endpoint was clinical response rate at week 8. Hochberg's procedure was used to control the study-wise type 1 error at alpha=0.1. RESULTS 146 (89.0%) patients completed 8 weeks of treatment. Week 8 clinical response rates were significantly higher in the 8 mg QD (46.3%; P=.066), 4 mg BID (46.3%; P=.059), and 4 mg QD (43.9%; P=.095) groups versus placebo (26.8%). Week 8 rates of clinical remission were 22.0% (P=.020), 24.4% (P=.013), and 24.4% (P=.011) in three ivarmacitinib treatment groups, respectively, versus 4.9% for placebo. During the initial 8-week period, treatment-emergent adverse events occurred in 43.9%-48.8% of ivarmacitinib-treated patients and in 39.0% of the placebo group, and were predominantly mild. There were no deaths, or major adverse cardiovascular or thromboembolic events. CONCLUSION Ivarmacitinib demonstrated clinical efficacy and was well tolerated in patients with moderate-to-severe, active, UC. Ivarmacitinib represents a promising new treatment for moderate-to-severe UC.