Clinical, experimental and pathophysiological effects of Yaq-001: a non-absorbable, gut-restricted adsorbent in models and patients with cirrhosis.

Objective: Targeting bacterial translocation in cirrhosis is limited to antibiotics with risk of antimicrobial resistance. This study explored the therapeutic potential of a non-absorbable, gut-restricted, engineered carbon bead adsorbent, Yaq-001 in models of cirrhosis and acute-on-chronic liver failure (ACLF) and, its safety and tolerability in a clinical trial in cirrhosis.
Design: Performance of Yaq-001 was evaluated in vitro . Two-rat models of cirrhosis and ACLF, (4 weeks, bile duct ligation with or without lipopolysaccharide), receiving Yaq-001 for 2 weeks; and two-mouse models of cirrhosis (6-week and 12-week carbon tetrachloride (CCl4)) receiving Yaq-001 for 6 weeks were studied. Organ and immune function, gut permeability, transcriptomics, microbiome composition and metabolomics were analysed. The effect of faecal water on gut permeability from animal models was evaluated on intestinal organoids. A multicentre, double-blind, randomised, placebo-controlled clinical trial in 28 patients with cirrhosis, administered 4 gr/day Yaq-001 for 3 months was performed.
Results: Yaq-001 exhibited rapid adsorption kinetics for endotoxin. In vivo , Yaq-001 reduced liver injury, progression of fibrosis, portal hypertension, renal dysfunction and mortality of ACLF animals significantly. Significant impact on severity of endotoxaemia, hyperammonaemia, liver cell death, systemic inflammation and organ transcriptomics with variable modulation of inflammation, cell death and senescence in the liver, kidneys, brain and colon was observed. Yaq-001 reduced gut permeability in the organoids and impacted positively on the microbiome composition and metabolism. Yaq-001 regulated as a device met its primary endpoint of safety and tolerability in the clinical trial.
Conclusions: This study provides strong preclinical rationale and safety in patients with cirrhosis to allow clinical translation.
Trial Registration Number: NCT03202498.
Competing Interests: Competing interests: JMacNaughtan: Shareholder in Yaqrit—no payments received; LM: Yaqrit Employee; KC: Yaqrit consultant; CM: Full-time employee of Yaqrit—salary, Share options in Yaqrit Discovery—no payment received; TA: Full-time employee of Yaqrit—Salary; MK: Full-time employee of Yaqrit—salary, Shares and Share options in Yaqrit Discovery—no payment received; DG: Share options—Yaqrit; AG: Shareholder—Yaqrit; RPM: Shareholder in Yaqrit —No payments received; SShoaie: Co-founder of Gigabiome, Bash Biotech and DAS Microbiome; JMarchesi: JMarchesi has received consultancy fees from EnteroBiotix and Cultech, and speaker fees from Falk Forum; RJ: RJ is the inventor of OPA, which has been patented by UCL and licensed to Mallinckrodt Pharma. He is also the founder of Yaqrit Discovery, Hepyx (spin out companies from University College London), and Cyberliver. He has research collaborations with Yaqrit Discovery. Yaq-001 was licensed by Yaqrit from UCL.
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