Periodic Reporting for period 4 - CARBALIVE (Clinical evaluation of carbons of controlled porosity as a new therapeutic for the treatment of liver cirrhosis and non-alcoholic fatty liver disease.)
Berichtszeitraum: 2019-11-01 bis 2021-01-31
The goal of the CARBALIVE consortium was to improve outcomes in patients with cirrhosis and non-alcoholic liver disease (NAFLD). During the course of the grant period, the Consortium members agreed to focus on the cirrhotic patients as a means of ensuring the delivery of a completed clinical trial. The trigger for this change was the withdrawal from the Consortium of the party responsible for manufacturing Carbalive, and their replacement as a manufacturer by another Consortium member which had to build manufacturing capacity from scratch.
Chronic liver disease affects about 29-million Europeans accounting for about 170,000 deaths at a cost of around €15.8bn. Translocation of gut-derived endotoxins and bacterial metabolites are key factors in the pathogenesis of both cirrhosis and fatty liver disease. Long-term antibiotic use is the standard therapy to reduce bacterial translocation and prevent recurrent complications of advanced cirrhosis and fatty liver disease. Unfortunately, this strategy is associated with risks of antibiotic drug resistance and Clostridium difficile colitis associated with significant morbidity, mortality and high economic costs to healthcare systems. Treatment of fatty liver and modulation of bacterial translocation in cirrhosis to prevent complications remains an unmet clinical need with the potential for reducing the economic burden as well.
Our academic-industrial consortium developed a novel, patented macroporous carbon (Yaq-001 or Carbalive) which effectively and safely modulates the effects of bacterial translocation in models of liver disease. The Consortium successfully established medical grade manufacturing and completed a first-in-humans clinical trial of Carbalive. The data met the primary endpoint of safety and tolerability, and in addition, generate encouraging biomarker data both systemically (whole body) and locally in the gut.
Chronic liver disease affects about 29-million Europeans accounting for about 170,000 deaths at a cost of around €15.8bn. Translocation of gut-derived endotoxins and bacterial metabolites are key factors in the pathogenesis of both cirrhosis and fatty liver disease. Long-term antibiotic use is the standard therapy to reduce bacterial translocation and prevent recurrent complications of advanced cirrhosis and fatty liver disease. Unfortunately, this strategy is associated with risks of antibiotic drug resistance and Clostridium difficile colitis associated with significant morbidity, mortality and high economic costs to healthcare systems. Treatment of fatty liver and modulation of bacterial translocation in cirrhosis to prevent complications remains an unmet clinical need with the potential for reducing the economic burden as well.
Our academic-industrial consortium developed a novel, patented macroporous carbon (Yaq-001 or Carbalive) which effectively and safely modulates the effects of bacterial translocation in models of liver disease. The Consortium successfully established medical grade manufacturing and completed a first-in-humans clinical trial of Carbalive. The data met the primary endpoint of safety and tolerability, and in addition, generate encouraging biomarker data both systemically (whole body) and locally in the gut.
WP1 Regulatory and Ethical Approval
The focus of WP1 is to deliver on the regulatory and ethical aspects of the program and to deliver the documentation required for the conduct of clinical trials. This activity includes the establishment of an ISO 13485-compliant Quality Management System, completion of pre-clinical studies to obtain ethical approval and approvals from National Competent authorities for the Carbalive Safety and Tolerability study in Cirrhosis. All deliverables for Work Package 1 were completed on time, or ahead of schedule (per amendment to grant).
WP2 Production of Yaq-001 and placebo for clinical studies
WP2 deals with the production of Yaq-001 for clinical studies outlined in WPs 4, 5 and 6 and feeds into providing data for generating the technical file to be used in WP1. The research activity relates to the creation of a viable manufacturing process of a material that had never before been made for use as an oral medication. This work was transferred to Yaqrit following the withdrawal from the Consortium of Mast Carbon International. Although this change extended timelines, it enabled the establishment of a manufacturing capability designed to make human medications, within which the new manufacturing team was able to make a series of innovations to overcome unforeseen obstacles inherent in previous manufacturing processes.
Yaqrit also oversaw all aspects of blending sieving, packaging, labelling and distribution to appropriate medical standards. It also performed all of the above for the placebo also used in the clinical trial.
WP3 Clinical Trials Management
The CARBALIVE – Safety study was conducted in compliance with Good Clinical Practice, as set out in in ISO 14155 and ICH E6.
WP4 Dose escalating study of the safety of Yaq-001 in patients with cirrhosis `CARBALIVE-SAFETY)
The 4 gram dosing cohort screened 32 patients of whom 28 patients were randomised. No serious adverse events were observed in either treatment group. 2 patients were withdrawn due to non-compliance, 5 patients withdrew themselves from the study of which 2 had not been initiated on treatment. Median compliance with treatment for active subjects was 101% (99-120%).
Shortly after recruitment for the second dosing cohort, at 8g per day began, the COVID-19 pandemic affected clinical trials globally. The Carbalive Consortium met and agreed to uses the 4g cohort as a standalone clinical trial rather than defer the start of the 8g cohort for an unknown period of time. The trial sponsor, Yaqrit, undertook to continue testing Carbalive at higher doses after the grant period ended, subject to good data at the 4g dose.
WP7 Biobanking and Biomarkers
Biobanked samples were collated and were to the UCL-Royal Free Biobank. A comprehensive panel of assays to determine companion biomarkers is scheduled to be conducted on these specimens.
WP8 Dissemination and Exploitation
During the final period of the project, the preliminary results of the first CARBALIVE trial were presented. A press announcement was made in January 2021 along with broad social media dissemination. One of the largest liver conferences in the world, the International Liver Congress 2021, selected data from the Carbalive trial for an oral presentation at its annual conference in June 2021. The project website will be maintained for at least 2 years to allow for continual updating on progress with the clinical trials and regulatory approvals after the end date of the project.
The focus of WP1 is to deliver on the regulatory and ethical aspects of the program and to deliver the documentation required for the conduct of clinical trials. This activity includes the establishment of an ISO 13485-compliant Quality Management System, completion of pre-clinical studies to obtain ethical approval and approvals from National Competent authorities for the Carbalive Safety and Tolerability study in Cirrhosis. All deliverables for Work Package 1 were completed on time, or ahead of schedule (per amendment to grant).
WP2 Production of Yaq-001 and placebo for clinical studies
WP2 deals with the production of Yaq-001 for clinical studies outlined in WPs 4, 5 and 6 and feeds into providing data for generating the technical file to be used in WP1. The research activity relates to the creation of a viable manufacturing process of a material that had never before been made for use as an oral medication. This work was transferred to Yaqrit following the withdrawal from the Consortium of Mast Carbon International. Although this change extended timelines, it enabled the establishment of a manufacturing capability designed to make human medications, within which the new manufacturing team was able to make a series of innovations to overcome unforeseen obstacles inherent in previous manufacturing processes.
Yaqrit also oversaw all aspects of blending sieving, packaging, labelling and distribution to appropriate medical standards. It also performed all of the above for the placebo also used in the clinical trial.
WP3 Clinical Trials Management
The CARBALIVE – Safety study was conducted in compliance with Good Clinical Practice, as set out in in ISO 14155 and ICH E6.
WP4 Dose escalating study of the safety of Yaq-001 in patients with cirrhosis `CARBALIVE-SAFETY)
The 4 gram dosing cohort screened 32 patients of whom 28 patients were randomised. No serious adverse events were observed in either treatment group. 2 patients were withdrawn due to non-compliance, 5 patients withdrew themselves from the study of which 2 had not been initiated on treatment. Median compliance with treatment for active subjects was 101% (99-120%).
Shortly after recruitment for the second dosing cohort, at 8g per day began, the COVID-19 pandemic affected clinical trials globally. The Carbalive Consortium met and agreed to uses the 4g cohort as a standalone clinical trial rather than defer the start of the 8g cohort for an unknown period of time. The trial sponsor, Yaqrit, undertook to continue testing Carbalive at higher doses after the grant period ended, subject to good data at the 4g dose.
WP7 Biobanking and Biomarkers
Biobanked samples were collated and were to the UCL-Royal Free Biobank. A comprehensive panel of assays to determine companion biomarkers is scheduled to be conducted on these specimens.
WP8 Dissemination and Exploitation
During the final period of the project, the preliminary results of the first CARBALIVE trial were presented. A press announcement was made in January 2021 along with broad social media dissemination. One of the largest liver conferences in the world, the International Liver Congress 2021, selected data from the Carbalive trial for an oral presentation at its annual conference in June 2021. The project website will be maintained for at least 2 years to allow for continual updating on progress with the clinical trials and regulatory approvals after the end date of the project.
The project has resulted in the development and validation of new processes to result in medically compliant manufacturing of clinical grade Carbalive. Capacity has since been expanded in readiness for the next clinical trial of Carbalive, now that safety has been established and a number of signs of efficacy have been observed. In summary, this means that Carbalive shows significant promise as a safe, non-antibiotic therapy with the potential to reduce morbidity and mortality in cirrhosis. The socio-economic impact of this will be highly significant if efficacy is proven in future phase 2 and phase 3 clinical studies.