Background. APL-1401, a first-in-class dopamine β-hydroxylase inhibitor, has demonstrated anti-inflammatory and mucosal-protective effects in multiple preclinical models of ulcerative colitis (UC). This phase 1b study evaluated its safety, tolerability, and preliminary efficacy in patients with moderately to severely active UC. Methods. This phase 1b multi-regional clinical trial (MRCT; NCT05743010) enrolled adults aged 18–65 years with Mayo score 6–12, who were randomized (5:1) to receive oral APL-1401 or placebo once daily for 4 weeks. Sequential dose-escalation (120 mg, 160 mg, 200 mg) was guided by tolerability. Primary endpoints included incidence of adverse events (AEs), serious AEs (SAEs), and AEs of special interest (AESIs). Secondary endpoints comprised clinical response (≥30% and ≥2-point reduction in the modified Mayo score [stool frequency, rectal bleeding, and endoscopy subscores], plus ≥1-point decrease in rectal bleeding subscore or subscore of 0/1) and histologic improvement (Geboes score ≤3.1), adjudicated by central laboratory dual readers. Results. Between January 2023 and June 2025, 18 out of 43 screened participants (41.9%) were randomized to APL-1401 (120 mg, n=5; 160 mg, n=10) or placebo (n=3). Baseline characteristics included 12 Asian (80%) and 3 Caucasian (20%) participants, with males predominating (76.7%, 10/15). No SAEs occurred. AEs were reported in 2/5 (40.0%) and 8/10 (80.0%) participants in the 120 mg and 160 mg cohort, respectively (Table 1). Reported AEs included rash, dizziness, herpes zoster, hot flush, hypertension, chest discomfort, tachycardia, elevated liver enzymes, decreased white blood cell count, and others. Rash was the most frequent AE (20.0% at 120 mg; 40.0% at 160 mg). One patient per cohort discontinued due to rash; all cases resolved with management and strict citrus avoidance. Histologic improvement was observed in 41.7% (5/12) of evaluable patients. The 120 mg cohort showed numerically higher clinical response (33.3% vs 12.5%) and histologic improvement (66.7% vs 33.3%) compared with the 160 mg cohort. No histologic improvement or clinical response was observed in placebo group. Early signals of endoscopic improvement were detected in the 120 mg cohort, with 33.3% achieving a 1-point reduction in the Mayo Endoscopic Subscore (MES) and 100% exhibiting a 1-point reduction in rectal bleeding subscores. Conclusion. The 120 mg dose of APL-1401 demonstrated a favorable safety profile and early signals of efficacy in patients with moderate-to-severe active UC during this 4-week MRCT. These findings support further evaluation of the 120 mg dose of APL-1401 in an extended 12-week study.