An Open-Label, Dose-Escalation Study to Assess the Safety and Efficacy of IL-22 Agonist F-652 in Patients With Alcohol-associated Hepatitis

Abstract

Background and aims: Interleukin-22 has beneficial effects on inflammation and impaired hepatic regeneration that characterize alcohol-associated hepatitis (AH). F-652 is a recombinant fusion protein of human interleukin-22 and immunoglobulin G2 fragment crystallizable. This study aims to assess the safety and efficacy signals of F-652 in patients with moderate and severe AH.

Approach and results: A phase-2 dose-escalating study was carried out. F-652 (10 μg/kg, 30 μg/kg, or 45 μg/kg) administered on days 1 and 7 was tested in 3 patients each with moderate (Model for End-Stage Liver Disease [MELD] scores: 11-20) and severe AH (MELD scores: 21-28). Safety was defined by absence of serious adverse events and efficacy was assessed by Lille score, changes in MELD score, and serum bilirubin and aminotransferases at days 28 and 42. Three independent propensity-matched comparator patient cohorts were used. Plasma extracellular vesicles and multiplex serum cytokines were measured to assess inflammation and hepatic regeneration. Eighteen patients (9 moderate and 9 severe AH) were enrolled, 66% were male, and the mean age was 48 years. The half-life of F-652 following the first dose was 61-85 hours. There were no serious adverse events leading to discontinuation. The MELD score and serum aminotransferases decreased significantly at days 28 and 42 from baseline (P < 0.05). Day-7 Lille score was 0.45 or less in 83% patients as compared with 6%, 12%, and 56% among the comparator cohorts. Extracellular vesicle counts decreased significantly at day 28 (P < 0.013). Cytokine inflammatory markers were down-regulated, and regeneration markers were up-regulated at days 28 and 42.

Conclusions: F-652 is safe in doses up to 45 μg/kg and associated with a high rate of improvement as determined by Lille and MELD scores, reductions in markers of inflammation and increases in markers of hepatic regeneration. This study supports the need for randomized placebo-controlled trials to test the efficacy of F-652 in AH.

Fig. 1.. CONSORT Flowchart.

CONSORT flowchart from enrolled patients.

Fig. 2.. Safety and Pharmacokinetics.

(A) Safety and tolerability of F-652 as determined by absence of significant adverse events (SAE). There were no SAE related to the study drug leading to discontinuation. (B) Pharmacokinetics showing half-life of F-652. The half-life of F-652 following the first dose was 61-85 h.

Fig. 3.. Δ MELD score in the total group and subgroups.

(A) There was a significant reduction in MELD (Δ MELD) in the composite group as well as in subgroups divided according to disease severity (B and C).

Fig. 4.. Clinical parameters at day 0, 28 and 42 of follow-up.

Improvement in (A) Δ total bilirubin, (B) C-reactive protein, (C) ALT, and (D) AST from the entire cohort at days 0, 28 and 42.

Fig. 5.. Lille score responders at day 7 for all cohorts.

(A) The F-652 treatment cohort had 82% subjects that responded to therapy as evident by Lille score of ≤ 0.45. (B) A prospective historical AH cohort had 12% responders and (C) a retrospective historical AH cohort had 6% responders in comparison. (D) A prospective, steroid treated AH cohort had 56% responders.

Fig. 6.. Extracellular vesicles and cytokine and chemokine profiles.

(A) Reduction from baseline in non-invasive biomarker extracellular vesicles (EV) count (*p<0.05 compared to day 0). Reduction in EV counts here acting as surrogate for improvement in inflammation associated with AH. (B) Improvement from baseline in cytokine and chemokine profiles using multiplex analyses at days 28 and 42 (*p<0.05).