Document resource
Background Kv1.3, a potassium channel highly expressed on effector memory T cells, sustains calcium influx required for T-cell activation. Targeting Kv1.3 offers a novel therapeutic approach for inflammatory bowel disease (IBD). This study evaluated the preclinical efficacy, selectivity, and developability of LUS012, a highly selective Kv1.3 inhibitor with gut-restricted exposure, in experimental colitis.Methods Colitis was induced in SD rats by intrarectal TNBS administration. Rats were orally dosed with LUS012 (1, 3, 10, 30 mg/kg, BID), mesalazine (150 mg/kg, QD), upadacitinib (30 mg/kg, QD), or vehicle from Day –1 to Day 6 (n=6/group). Disease Activity Index (DAI) was monitored daily. At termination, colon weight/length ratio (mg/cm) and histopathological scores were assessed. In vitro selectivity was evaluated against a broad panel of ion channels. Oral bioavailability and tissue distribution were determined in pharmacokinetic studies.Results LUS012 demonstrated >4,000-fold selectivity for Kv1.3 over related ion channels. In the TNBS-induced rat IBD model, LUS012 produced dose-dependent DAI reductions ( IDDF2026-ABS-0266 Figure 1(A) Efficacy of LUS012 in TNBS-induced rat IBD model); at 30 mg/kg, efficacy was comparable to mesalazine 150 mg/kg, with near-zero scores by study endpoint (p<0.0001 vs. vehicle). Colon weight/length ratio, a marker of edema, was reduced by LUS012 treatment (IDDF2026-ABS-0266 Figure 1(B) Efficacy of LUS012 in TNBS-induced rat IBD model); at 30 mg/kg, LUS012 showed improvement comparable to mesalazine 150 mg/kg and superior to upadacitinib 30 mg/kg (p<0.0001 vs. vehicle). Notably, LUS012 30 mg/kg achieved superior histopathological scores, nearing complete resolution (score 0.25), outperforming both mesalazine and upadacitinib (IDDF2026-ABS-0266 Figure 1(C) Efficacy of LUS012 in TNBS-induced rat IBD model; p<0.0001 vs. vehicle). LUS012 exhibited good oral bioavailability, linear PK across species, high gut-restricted exposure with minimal systemic levels, low CYP inhibition, and a wide safety window (>300x based on 14-day non-GLP tox studies).Conclusions LUS012, a highly selective Kv1.3 inhibitor with gut-restricted exposure, achieves near-complete histological resolution in a rat IBD model, with efficacy superior to standard therapies. Its favorable oral bioavailability and safety profile support further evaluation as an oral therapy for IBD.Abstract IDDF2026-ABS-0266 Figure 1