Clinical Trial to Assess the Safety and Tolerability of Anti‐IL 23 Monoclonal Antibody Guselkumab in Patients With Alcohol‐Associated Liver Disease

ABSTRACT Background There are no FDA‐approved therapies for alcohol‐associated liver disease (ALD). Preclinical studies indicate that blocking IL‐23/IL‐17 signalling may reverse liver injury. Guselkumab, an IL‐23‐specific antibody approved for psoriasis, may be beneficial for ALD. Aims We aimed to assess the safety and tolerability of guselkumab in patients with ALD. Methods This phase‐1 dose‐escalation study included patients with ≥ 2 DSM‐5 criteria for alcohol use disorder, significant steatosis (MRI‐PDFF ≥ 8%) and MRE < 3.63 kPa (to exclude advanced disease). Guselkumab was given subcutaneously on Days 1 and 29 in 30, 70 or 100 mg dose cohorts. Primary endpoints were adverse events (AEs) and dose‐limiting toxicity. Results We enrolled 13 patients (three 30 mg, three 70 mg, and seven 100 mg). Eleven completed the study and two early discontinued in the 100 mg group. Of them, 77% were men, and the median age was 53 [IQR 49–61] years. The median MRI‐PDFF and MRE were 18.4% [IQR 8.4%–34.0%] and 2.5 [2.2–2.6] kPa, respectively. The most frequent AEs were hyperuricemia (13%, mild only) and elevated lipase (11%, mild and moderate). There were no serious adverse events or significant variations in liver enzymes. There was a suppression of peripheral interleukin (IL)‐17, IL‐23, IL‐1b and TNF‐α in the 70 and 100 mg groups, and a significant decrease in alcohol consumption over time (AUDIT‐C: 6 [3–7] vs. 5 [1–6], p = 0.023). Conclusions Guselkumab is safe in doses up to 100 mg and may reduce inflammation markers in ALD. These findings support further phase 2 studies to evaluate the efficacy of guselkumab in ALD, particularly in patients with severe phenotypes.