Article Text

Download PDFPDF
Original research
Clinical, experimental and pathophysiological effects of Yaq-001: a non-absorbable, gut-restricted adsorbent in models and patients with cirrhosis
  1. Jinxia Liu1,2,
  2. Jane MacNaughtan1,
  3. Annarein J C Kerbert1,
  4. Theo Portlock3,
  5. Javier Martínez Gonzalez4,5,
  6. Yi Jin3,
  7. Frederick Clasen3,
  8. Abeba Habtesion1,
  9. Huoyan Ji6,
  10. Qin Jin7,
  11. Alexandra Phillips1,
  12. Francesco De Chiara1,
  13. Ganesh Ingavle8,9,
  14. Cesar Jimenez5,
  15. Giacomo Zaccherini10,11,
  16. Katherine Husi12,
  17. Miguel Angel Rodriguez Gandia13,
  18. Paul Cordero9,
  19. Junpei Soeda1,
  20. Lynda McConaghy14,
  21. Jude Oben1,
  22. Karen Church14,
  23. Jia V Li15,
  24. Haifeng Wu2,
  25. Aarti Jalan16,
  26. Pere Gines17,
  27. Elsa Solà17,
  28. Simon Eaton18,
  29. Carrie Morgan14,
  30. Michal Kowalski14,
  31. Daniel Green14,
  32. Amir Gander19,
  33. Lindsey A Edwards20,21,
  34. I Jane Cox22,23,
  35. Helena Cortez-Pinto24,
  36. Thomas Avery25,
  37. Reiner Wiest26,
  38. Francois Durand27,
  39. Paolo Caraceni10,28,
  40. Roberto Elosua29,
  41. Joan Vila29,
  42. Marco Pavesi30,
  43. Vicente Arroyo30,
  44. Nathan Davies1,
  45. Rajeshwar P Mookerjee1,
  46. Victor Vargas5,
  47. Susan Sandeman8,
  48. Gautam Mehta1,
  49. Saeed Shoaie3,
  50. Julian Marchesi31,
  51. Agustín Albillos32,
  52. Fausto Andreola1,
  53. Rajiv Jalan1,30
  1. 1Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
  2. 2Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
  3. 3Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London, UK
  4. 4Hospital Ramón y Cajal, IRYCIS, CIBEREHD, Universidad de Alcalá, Madrid, Spain
  5. 5Liver Unit, Hospital Vall d’Hebron, Universitat Autónoma, CIBERehd, Barcelona, Spain
  6. 6Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
  7. 7Department of Pathology, Affiliated Hospital of Nantong University, Nantong, China
  8. 8Centre for Regenerative Medicine and Devices, School of Applied Sciences, University of Brighton, Brighton, UK
  9. 9Symbiosis Centre for Stem Cell Research (SCSCR), Symbiosis School of Biological Sciences (SSBS), Symbiosis International (Deemed University), Pune, India
  10. 10Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
  11. 11Unit of Semeiotics, Liver and Alcohol-related Diseases, University of Bologna Hospital of Bologna Sant'Orsola-Malpighi Polyclinic, Bologna, Italy
  12. 12Department of Gastroenterology, Inselspital University Hospital Bern, Bern, Switzerland
  13. 13Hospital Universitario Ramon y Cajal, Madrid, Spain
  14. 14Yaqrit Discovery Limited. The Elms Courtyard, Bromesberrow, Ledbury, UK
  15. 15Department of Surgery and Cancer, Imperial College London, London, UK
  16. 16King's College Hospital, London, UK
  17. 17Liver Unit, Hospital Clinic of Barcelona, IDIBAPS, Faculty of Medicine and Health sciences, University of Barcelona, Barcelona, Spain
  18. 18Institute of Child Health, University College London, London, UK
  19. 19Tissue Access for Patient Benefit, University College London, London, UK
  20. 20Centre for Host Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, Guy's Tower, Guy's Hospital, King’s College London, London, UK
  21. 21Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK
  22. 22The Roger Williams Institute of Hepatology, Foundation for Liver Research, London, UK
  23. 23Faculty of Life Sciences and Medicine, King's College London, London, UK
  24. 24Clínica Universitária de Gastrenterologia, Laboratório de Nutrição, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
  25. 25Yaqrit Limited, London, UK
  26. 26UVCM Gastroenterology, University Bern, Bern, Switzerland
  27. 27Hepatology and Liver Intensive Care, Hospital Beaujon, Clichy, University paris Cité, Paris, France
  28. 28Unit of Semeiotics, Liver and Alcohol Related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
  29. 29C/de Joan Güell, Barcelona, Spain
  30. 30European Foundation for the Study of Chronic Liver Failure (EF CLIF), Barcelona, Spain
  31. 31Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, St Mary’s Hospital, Imperial College London, London, UK
  32. 32Department of Gastroenterology and Hepatology, Hospital Universitario Ramon y Cajal, Universidad de Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
  1. Correspondence to Professor Rajiv Jalan, UCL Institute for Liver & Digestive Health, London NW3 2PF, UK; r.jalan{at}ucl.ac.uk

Abstract

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.

  • BACTERIAL TRANSLOCATION
  • ENDOTOXIN
  • LIVER CIRRHOSIS
  • LIVER FAILURE

Data availability statement

Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information.

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Data availability statement

Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information.

View Full Text

Footnotes

  • JL and JM are joint first authors.

  • X @Zac_MD, @DrLAEdwards, @Ijcox_nmr, @drgautammehta

  • JL and JM contributed equally.

  • Deceased Dr Soeda is deceased

  • Correction notice This article has been corrected since it published Online First. Figure 4A has been replaced.

  • Contributors JL: performed CCl4 animal experiments; data acquisition and analysis; intestinal organoid experiments; paper organisation, drafting and writing; JMacNaughtan and RJ: concept; study design; performed animal experiments; data acquisition and analysis; clinical trial lead; paper organisation, drafting and writing; AJCK, JMG, CJ, GZ, KH, MARG, PG, ES, HC-P, FD, PCordero, VV, GM and DG: Clinical trial; TP and YJ: Analysis of the microbiome data and correlation analyses; FC and SS: analysis of the microbiome data, correlation analyses and transcriptomics analyses; AH: performed all the bile duct ligation animal studies; sample analyses; HJ, QJ and HW: performed CCl4 animal experiments; data acquisition and analysis; AP: BDL animal experiments; data acquisition; FDC: BDL animal experiments; data acquisition and analysis; GI: BDL animal experiments; data acquisition and analysis; PCaraceni and JS: data acquisition and cell studies; LM, TA, MK and DG: Yaq-001 characterisation and manufacture; JO: concept; study design; data acquisition and cell studies; KC: regulatory and clinical trial design; JVL: analysis of metabolomics data; AJ: data acquisition and analysis; data organisation; SE: analysis of metabolic effects of Yaq-00; CM: clinical trial; study design; AG: data acquisition and analysis biobanking; LAE: data acquisition and analysis; IJC: analysis of metabolic effects of Yaq-001; RW and VA: clinical trial; study design; RE, JV and MP: statistics; ND: concept; study design; performed animal experiments; data acquisition and analysis; RM: concept; study design; paper organisation, drafting and writing; SSandeman: concept; study design; in vitro studies of Yaq-001; SShoaie: analysis of the microbiome data, correlation analyses and transcriptomics analyses; JMarchesi: microbiome sequencing and analysis of the microbiome data; AA: clinical trial and trial design; FA: concept; study design; data acquisition and analysis. RJ accepts full responsibility for the work presented in this paper. the conduct of the study, has access to all the data and controlled the decision to publish the study.

  • Funding This study was performed with support from a grant from the EU H2020, Grant Agreement number: 634579—CARBALIVE—H2020-PHC-2014-2015/H2020-PHC-2014 programme. JMarchesi and the Division of Digestive Diseases at Imperial College London receives financial support from the NIHR Imperial Biomedical Research Centre.

  • 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.

  • Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

  • In the PDF this Figure is extremely squashed. It meeds to be on a full page or even 2 pages to allow full visibility

  • This Figure is very squashed in the PDF I saw. Should be expanded to a full page or even 2 pages please to allow readability

  • Once these have been corrected, please share the revised version with me to recheck please.