A Proof‐of‐Concept Phase 2a Partly Randomised Study Evaluating Leronlimab in Patients With Presumed Non‐Cirrhotic Metabolic Dysfunction–Associated Steatohepatitis

ABSTRACT Chemokine receptor type 5 (CCR5) is upregulated in the livers of patients with metabolic dysfunction–associated steatohepatitis (MASH). Leronlimab, a humanised IgG4κ monoclonal antibody, directly binds the extracellular domains of CCR5, modulates downstream signalling and potentially can slow, reverse or prevent fibrosis. The aim of this study was to evaluate the safety and efficacy of leronlimab in participants with MASH. Phase 2a, multicentre, two‐part study evaluated two doses of once‐weekly subcutaneous leronlimab for 13 weeks in participants with non‐cirrhotic MASH diagnosed either histologically, by FibroScan, or by Shearwave ultrasound. 87 participants were enrolled: 60 were randomised to leronlimab 700 mg ( n = 30) or to placebo ( n = 30) (Part 1) and n = 27 allocated to the leronlimab 350 mg arm (Part 2 open‐label). Baseline demographics and clinical characteristics were generally similar between Parts 1 and 2. The primary efficacy endpoint, absolute change from baseline in liver fat content assessed by MRI‐PDFF at week 14, was not met for Part 1 (absolute increase of 0.42% leronlimab 700 mg versus 1.15% placebo) but was met for Part 2 (1.09% absolute reduction in the leronlimab 350 mg arm versus 1.12% increase placebo). The secondary efficacy endpoint, absolute change from baseline in MRI‐cT1 at week 14, was not met for Part 1 but was met for Part 2. All drug‐related adverse events were mild or moderate. This proof‐of‐concept study demonstrated that leronlimab has a favourable safety profile and was well tolerated. While in the open‐label 350 mg arm of the study, leronlimab was associated with numerically mild antisteatotic and antifibrotic activity in patients with non‐cirrhotic MASH, further evaluation in a randomised controlled trial is necessary to substantiate these results. Trial Registration: ClinicalTrials.gov identifier: NCT04521114; https://clinicaltrials.gov/study/NCT04521114 . The trial was first posted on 20 August 2020.