Abstract

Background: Cirrhosis is characterised by severe liver fibrosis, organ dysfunction and liver-related complications. Presently, there are no approved anti-fibrotic or pro-regenerative therapies for cirrhosis. Preclinical studies have shown bone marrow-derived macrophage injections can resolve hepatic fibrosis, stimulate regeneration and reduce inflammation. We previously demonstrated the safety of peripheral infusion of ex vivo-matured autologous monocyte-derived macrophages in patients with compensated cirrhosis in a Phase 1 trial.

Methods: In a multicentre, open-label, parallel-group, Phase 2, randomised controlled trial (ISRCTN10368050), we evaluated the efficacy of autologous monocyte-derived macrophage therapy, compared with standard medical care, in a cohort of adult patients with compensated cirrhosis and MELD score ≥10 and ≤17. Participants were randomised 1:1, based on a minimisation algorithm using the key variable aetiology of disease (alcohol-related liver disease, non-alcoholic fatty liver disease, other). Treatment was of either three cycles of apheresis and macrophage infusion (n=3) or a single apharesis and macrophage infusion (n=23) of up to 10⁹ macrophages; n=24 participants received standard of care. Initially, the trial was designed to administer three infusions in the treatment arm, but due to the challenge of undergoing three apheresis sessions, and completing the trial within the proposed time frame, a single infusion protocol was adopted. The primary outcome was the difference in baseline to day 90 change in MELD score (ΔMELD) between treatment and control groups (ΔΔMELD). Secondary outcomes included: adverse clinical outcomes; non-invasive fibrosis markers (Liver Stiffness Measurement (LSM), serum enhanced liver fibrosis test (ELF) and Pro-C3/C3M, corrected T1 (cT1) MRI); and health-related quality of life (HRQoL) at 90, 180, 360 days.

Results: The ΔΔMELD between day 0 and day 90 in the treated group compared with the standard of care group was -0.87 (95% CI 1.79, 0.0; p = 0.06). The treatment group had less variable MELD scores than the control group (see Figure). Within the 360 days follow-up there were: 5/24 participants in the control group developed a total of 10 liver-related severe adverse events including 2 deaths, whilst no liver-related severe adverse events or deaths occurred in the treated group. There were no statistically significant differences in non-invasive fibrosis markers or HRQoL on per protocol analysis; exploratory analyses are awaited.

Conclusion: This study reinforces the safety of macrophage cell therapy in patients with compensated cirrhosis, suggests their therapeutic potential and supports further development of macrophage therapy for liver disease.