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Clinical evaluation of carbons of controlled porosity as a new therapeutic for the treatment of liver cirrhosis and non-alcoholic fatty liver disease.

Periodic Reporting for period 3 - CARBALIVE (Clinical evaluation of carbons of controlled porosity as a new therapeutic for the treatment of liver cirrhosis and non-alcoholic fatty liver disease.)

Okres sprawozdawczy: 2018-05-01 do 2019-10-31

The goal of the CARBALIVE consortium is to improve outcome in patients with cirrhosis and non-alcoholic liver disease (NAFLD). Chronic liver disease currently 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 implicated in the pathogenesis of cirrhosis and fatty liver disease. Long-term antibiotic use constitutes the current state-of-the-art therapy to reduce bacterial translocation and prevent recurrent complications of advanced cirrhosis and fatty liver disease. This strategy is however associated with a significant risk of resistance and Clostridium difficile colitis associated with significant morbidity, mortality and with high costs to the health care system. Treatment of fatty liver and modulation of bacterial translocation in early cirrhosis to prevent complications remains an unmet clinical need.

Our academic-industrial consortium has developed a novel, patented, safe and cheap bimodal nanoporous carbon (Yaq-001), which modulates the effects of bacterial translocation in models of liver disease. We propose to investigate the safety and efficacy of this novel nanoporous carbon in patients with fatty liver disease and cirrhosis. If successful, we will be able to confirm an innovative, cost-effective and novel strategy for the management of this chronic disease in a European population.

The objectives of the consortium are to:

1) Further develop and manufacture Yaq-001 to the quality required by the Medical Devices Directive, to be used in the clinical trials.
2) Achieve regulatory and ethical approval for clinical trials to test Yaq-001 in clinical trials.
3) Undertake 3 multicentre clinical trials to establish the safety and efficacy in patients with liver disease
a. Safety, tolerability and dose finding study of Yaq-001 in patients with cirrhosis [CARBALIVESAFETY]
b. Randomised controlled clinical trial to determine the safety and efficacy of Yaq-001 in patients with decompensated cirrhosis [PREVENT-ACLF]
c. Randomised controlled clinical trial to determine the safety and efficacy of Yaq-001 in patients with Non alcoholic fatty liver disease [TREAT-NAFLD]
4) Disseminate widely the results of these trials and the therapeutic potential of Yaq-001.
5) Exploit the results of the CARBALIVE to raise commercial interest in the continued development of Yaq-001.
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, finalisation of the technical file for Yaq-001, completion of pre-clinical studies to obtain approvals for Yaq-001 and successful ethical approval and National Competent Authority Approval 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 Quality Management system that is essential to ensure that the Yaq-001 meets the requirements of the Medical Devices Directorate. During the first 18 months, a new manufacturing facility was acquired with appropriate support personnel to accommodate the new rotary furnace. This upgraded facility included the more efficient rotary pyrolysis and vacuum solvent recovery. Consistent physical and adsorptive properties wee confirmed between batches and development and validation of QC methodology has been performed by UOB.

Sufficient batch test carbon was produced to GMP standard for clinical studies. Once the Carbon for safety study was produced, production began for the remaining studies using the rotary furnace (continual production). Following specialised production and QA and QC, the product, together with placebo, was transferred to a GMP-compliant packaging facility and subsequently released to the clinical trial sites.

WP3 Clinical Trials Management
AlphaB has been working with the clinical partners to consolidate the protocols for all clinical trials, integrate the technical files, co-ordinate the filing of the technical and Quality Management Systems documents for Regulatory approval. The final protocol for the Carbalive-Safety study was approved, along with the required regulatory documentation. The data management system has now been completed.

WP4 Dose escalating study of the safety of Yaq-001 in patients with cirrhosis `CARBALIVE-SAFETY)
Recruitment to the 4 gram dosing cohort is now complete. 32 patients have been screened in the study. Of this, 28 patients in the 4 gram dosing cohort were randomised. Of this 13 patients have completed treatment and 5 remained on treatment at the end of the reporting period. 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%).

WP7 Biobanking and Biomarkers
Biobanked samples have been collated and are scheduled for transfer 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 reporting period, the project website has been established and the dissemination and exploitation plan has been completed. The first meeting of the Committee took place at University College London on 23rd September 2015 during which the members initiated the development of the IP portfolio management policy, publication policy including authorship, and dissemination strategy and also considered the communication strategy for the Project including the website and social media portals for internal and external communication. The project website now includes a member’s only area which holds project specific information and a secure file store has now been established to further increase security associated with clinical trial documentation. On-going dissemination activity raising awareness of the CARBALIVE project has included press releases, presentations at workshops, the project website, and twitter feeds.
The project has resulted in the development and validation of more efficient processes to result in consistent, high output manufacturing of Yaq-001 to facilitate application to clinical trials. Development of QC systems to optimize this process has been developed. This program has established the safety and efficacy of Yaq-001 in pre-clinical systems. Further in vitro validation studies have established additional pathogenic targets of Yaq-001 relevant to pathogenesis in liver disease, which account for favourable efficacy profile in pre-clinical studies. Yaq-001 therefore shows significant promise as a safe, new non-antibiotic state-of-the-art therapy to impact morbidity and potentially mortality in cirrhosis and NAFLD. The socio-economic impact of this will be highly significant if efficacy is proven in scheduled phase 2 clinical studies.