Targeting the CCL24 Pathway with nebokitug in Primary Sclerosing Cholangitis: Safety and Biological Activity from a Phase 2 Study

Introduction: Nebokitug (CM-101) is an anti-CCL24 monoclonal antibody with anti-inflammatory and antifibrotic activities.This phase 2 study aimed to assess the safety, tolerability, and biological activity of nebokitug in patients with primary sclerosing cholangitis (PSC).Methods: SPRING is a randomized, double-blind (DB), placebo-controlled trial with an open-label extension phase.Patients with large-duct PSC and ALP >1.5 ULN were randomized to receive intravenous nebokitug (10 mg/kg or 20 mg/kg) or placebo every 3 weeks for 15 weeks (five doses total).Following the DB period, eligible participants could enter a 33-week open-label treatment phase and a subsequent 15-week follow-up.The primary endpoint was safety and tolerability.Secondary endpoints included changes from baseline to week 15 in liver stiffness measurement (LSM), enhanced liver fibrosis (ELF) score, liver biochemistry, and pharmacokinetic (PK)/pharmacodynamic (PD) parameters.Biological activity and responder analyses were conducted in a prespecified subgroup with baseline LSM >8.7 kPa.Results: Seventy-six patients received at least one dose (placebo n=20; nebokitug n=56).Sixty-six patients (placebo n=16; nebokitug 10 mg/kg n=22; 20 mg/kg n=28) completed the DB period, received all five doses, and had baseline and at least one post-baseline measurement for ALP and ELF.Baseline characteristics were comparable: mean age 52 years (range 23-75), 74% male, 71% with IBD, and 72% on UDCA.Treatment-emergent adverse events (TEAEs) were similar between groups (nebokitug: 82%; placebo: 75%).Most frequent TEAEs included fatigue, headache, and pruritus.Serious TEAEs occurred in three patients (1 placebo, 2 nebokitug), none of which were treatment related.PK analysis demonstrated dose-proportional increases in nebokitug levels and target engagement.Patients treated with nebokitug 20 mg/kg showed consistent reductions in liver biochemistries compared to nebokitug 10 mg/kg and placebo.Biomarkers including PRO-C3, IL-6, IL-8, and TGF improved in a dose-dependent manner, especially among patients with baseline LSM >8.7 kPa.In this subgroup, patients receiving nebokitug 10 mg/kg and 20 mg/kg had mean LSM reductions of 1.5 and 1.4 kPa, respectively, compared to a 3.0 kPa increase in placebo (p=0.01 for both groups).Majority of nebokitug 20mg/kg treated patients in this subgroup had ELF scores that did not increase > 0.19, a threshold predictive of worse clinical outcomes.