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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - CARBALIVE (Clinical evaluation of carbons of controlled porosity as a new therapeutic for the treatment of liver cirrhosis and non-alcoholic fatty liver disease.)

Teaser

Summary

The goal of CARBALIVE is to improve outcome in patients with cirrhosis and non-alcoholic liver disease (NAFLD). Chronic liver disease currently affects ~29-million Europeans accounting for ~170,000 deaths at a cost of ~â‚¬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 CARBALIVE is 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.

Work performed

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. An ISO-13485-compliant Quality Management System has been established and ISO 13485-documentation is in development to support transfer of manufacturing to a more efficient continuous rotary furnace process.

Pre-clinical toxicity studies required for translation to clinical trials have also been completed. The 13 week study (plus 4 week reversibility period) has been conducted in accordance with ISO 10993 guidelines. No safety concerns were identified. Mass balance studies have been completed, confirming that Yaq-001 is not retained within the gastrointestinal tract. These studies are an important prerequisite for regulatory approval. Confirmation of medical device status was obtained following a pre-CTA meeting with notified body TÃ¼V SÃ¼d.

Significant progress has been made in development of documentation for ethical approval including the SAFETY study trial protocol, patient information sheet and consent form. Development of the clinical trial documents has been coordinated by Alpha BioResearch (AlphaB) and in consultation with the wider consortium including clinical partners and the data management centre. Completion of the technical file is contingent upon stability and QC analysis of the Yaq-001 batch to be used in clinical trials. This will be obtained from the Yaq-001 batch obtained from the newer efficient continuous furnace process. Submission for ethical approval of the first trial will be made in January 2017 in the UK and Switzerland, other countries will follow after the technical file submission / approval.

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 will feed into providing data for generating the technical file to be used in WP1. The research activity relates to creating a Quality Management system that will be essential to ensure that the Yaq-001 meets the requirements of the Medical Devices Directorate. During the first 18 months, a new manufacturing facility has been established with appropriate support personnel to accommodate the new rotary furnace. This upgraded facility includes the more efficient rotary pyrolysis and vacuum solvent recovery. Consistent physical and adsorptive properties have been confirmed between batches and development and validation of QC methodology has been performed by UOB.

40kg batch test carbon produced to GMP standard for clinical studies is scheduled to be available by March 2017. Once the Yaq-001 for safety study has been produced, production will continue for remaining studies (220kg), through the rotary furnace (continual production). This will avoid significant lead times between carbon production and start of the second and third clinical trials. Following specialised production and QA and QC, the product, together with placebo, will be 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, integrate the technical files, co-ordinate the filing of the technical and Quality Management Systems documents for Regulatory approval. The final protocol has been developed, along with the required regulatory documentation. The data management system is under development.

WP8 Dissemination and Exploitation
During the first period the project website has been established and the first dissemination and exploitation plan has been developed. Additionally, the partners have initiated 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 inte

Final results

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.