P0725 First-in-human Phase 1b Study of the Dopamine β-Hydroxylase Inhibitor APL-1401 in Patients with Moderate-to-Severe ULCERATIVE COLITIS: Pharmacokinetics and Preliminary Results

Abstract 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, pharmacokinetics (PK), and preliminary efficacy in patients with moderately to severely active UC. Methods In this multi-regional trial (NCT05743010), adults aged 18–65 years with a total Mayo score of 6–12 were randomized (5:1) to receive oral APL-1401 or placebo once daily (QD) for 4 weeks. Doses were escalated sequentially (120 mg, 160 mg, 200 mg) based on tolerability. Primary endpoints included the incidence of adverse events (AEs), serious AEs (SAEs), and AEs of special interest (AESIs). Secondary endpoints included PK parameters, 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 review. Results Between January 2023 and June 2025, 18 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 a predominance of males (76.7%, 10/15). No SAEs occurred. Rash was the most frequent AESI (20.0% at 120 mg; 40.0% at 160 mg), leading to one discontinuation per cohort; all cases resolved with appropriate management and strict citrus avoidance. APL-1401 was rapidly absorbed (Tmax 1–3 h) with a half-life of approximately 10 hours, supporting QD dosing. At steady state, AUC0–τ,ss values were 2,570 h·ng/mL (120 mg) and 6,400 h·ng/mL (160 mg), with minimal accumulation (Table 1). Histologic improvement was observed in 41.7% (5/12) of evaluable patients. The 120 mg cohort showed higher clinical response (33.3% vs. 12.5%) and histologic improvement (66.7% vs. 33.3%) than the 160 mg cohort. No histologic improvement or clinical response was observed in the placebo group. Endoscopic improvement signals were observed in the 120 mg cohort, with 33.3% achieving a 1-point reduction in the Mayo Endoscopic Subscore (MES) and all patients (100%) exhibiting a 1-point reduction in rectal bleeding subscores. Conclusion APL-1401 120 mg QD was well tolerated and demonstrated promising efficacy signals in patients with moderate-to-severe UC over 4 weeks, supporting further evaluation in a 12-week study. Conflict of interest: Dr. Liu, Xiaowei: No conflict of interest Reiss, Gary: No conflict of interest Lopez, Lius: No conflict of interest Zheng, Changqing: No conflict of interest Zhang, Xiaolan: No conflict of interest An, Ping: No conflict of interest Zhang, Yingjian: No conflict of interest Yuan, Haipeng: No conflict of interest Cao, Yu: No conflict of interest Qin, Qun: No conflict of interest Yuan, Xiaoliang: No conflict of interest