Periodic Reporting for period 3 - ALIVER (Development of DIALIVE, a novel Liver Dialysis Device for the treatment of patients with Acute on Chronic Liver Failure (ACLF))
Periodo di rendicontazione: 2020-01-01 al 2021-01-31
Liver disease is a growing and lethal problem, with about 170K patients dying from liver failure each year in Europe alone. When a liver fails, toxins accumulate and the patient is increasingly susceptible to infection, multi-organ failure and early death. Liver transplantation is the only treatment known to prolong life but is limited by the availability of organs, and the financial cost of transplantation is high. Therefore there is a need for an effective ICU intervention for patients with advanced liver disease. The ALIVER Consortium has developed and optimised a novel ‘liver dialysis device”, called DIALIVE based upon discoveries that (i) albumin, a circulating protein involved in detoxification, is damaged irreversibly in these patients and (ii) endotoxemia (circulating toxins) contributes to increased risk of infection in liver failure. DIALIVE removes and replaces albumin and removes endotoxin. In animal models of liver failure, Dialive prolonged survival and was shown to be safe. It reduced endotoxemia and improved albumin and immune function.
The ALIVER Consortium, which comprises experts in liver failure, SMEs and charities, was created to test Dialive for the first time in humans. The ALIVER funding delivered a completed randomised controlled clinical trial in patients with acute on chronic liver failure (ACLF). The result of this trial was that DIALIVE met its primary endpoints and many secondary endpoints with statistical significance, an unexpectedly encouraging result. This means that DIALIVE has moved from TLR5 to TLR7/8 during the course of the ALIVER program.
Now that potential health benefits of DIALIVE have been identified, the groundwork has been laid for manufacturing, further trials, distribution and reimbursement. At the time of grant submission, it was considered that during the grant period a CE-mark would be obtainable. Since then, the rules on CE Marking have changed, leading to delays in the CE Marking process for all medical device companies, and it is now anticipated that a CE Mark will be secured after the end of the grant period. It is worth noting that during the grant period the only other innovative “liver dialysis system” in development (the US system called ELAD) was unsuccessful in clinical trials. This means that Dialive has established a substantial technical lead in extra-corporeal liver support. Additionally, the ALIVER Consortium have identified that DIALIVE could benefit a wider patient group. A patent has been filed.
The ALIVER Consortium, which comprises experts in liver failure, SMEs and charities, was created to test Dialive for the first time in humans. The ALIVER funding delivered a completed randomised controlled clinical trial in patients with acute on chronic liver failure (ACLF). The result of this trial was that DIALIVE met its primary endpoints and many secondary endpoints with statistical significance, an unexpectedly encouraging result. This means that DIALIVE has moved from TLR5 to TLR7/8 during the course of the ALIVER program.
Now that potential health benefits of DIALIVE have been identified, the groundwork has been laid for manufacturing, further trials, distribution and reimbursement. At the time of grant submission, it was considered that during the grant period a CE-mark would be obtainable. Since then, the rules on CE Marking have changed, leading to delays in the CE Marking process for all medical device companies, and it is now anticipated that a CE Mark will be secured after the end of the grant period. It is worth noting that during the grant period the only other innovative “liver dialysis system” in development (the US system called ELAD) was unsuccessful in clinical trials. This means that Dialive has established a substantial technical lead in extra-corporeal liver support. Additionally, the ALIVER Consortium have identified that DIALIVE could benefit a wider patient group. A patent has been filed.
WP 1 aimed to deliver on the regulatory and ethical aspects of the program and the documentation required for the conduct of this clinical trial. An ISO-13485 compliant Quality Management System was established to assure the product meets the essential requirements defined by the Medical Device Directive (93/42/EECO).
The focus of WP2 was the production, assembly, transport, training aspects of DIALIVE. It involved assembling, packaging and labelling the components that make up DIALIVE into a single clinical investigator pack. Each functional component is CE-marked and is commercially available in Europe: these parts are the oXiris filter, (which removes endotoxin), the septeX filter (which removes albumin), to which were added proprietary connection tubing, multilingual instructions for use, packaging and labelling. WP2 required the development of a full set of the Standard Operating Procedures (SOPs) and the planning and execution of all training on all clinical sites in conformance with international regulations.
The Hepalbin filter from Albutec (and ALIVER consortium member), was added to DIALIVE. Hepalbin is designed to purify commercial albumin, whose manufacturers process albumin which includes the addition of stabilizers to increase the shelf life. These stabilizers may limit the albumin’s binding capacity for that toxins that contribute to morbidity and mortality in severe liver disease, and it is Hepalbin’s role to address these concerns.
The goals of WP3 are:
1. To ensure appropriate clinical trial support through the creation of a management system.
2. Conduct the trials in compliance with the currently approved protocol/amendments, following ISO 14155 GCP guidance and with the applicable regulatory requirements, and develop a plan for the regulatory procedures.
3. Ensure that the trials are adequately monitored for each site before, during and after the trials.
Both site activation and patient recruitment were slower than anticipated, which prompted the opening of more clinical sites.
WP 4 focuses on the conduct of the trial in adherence with the approved study protocol to determine the safety and tolerability of DIALIVE in patients with ACLF (DIALIVE safety) according to the Standard Operating Procedures used by Yaqrit and FAKKEL. It ensures that patients are managed in accordance with Good Clinical Practice (ISO 14155) and that clinical data is collected and handled correctly to achieve the primary and secondary endpoints. Although the trial was planned to be conducted in 8 widely distributed European referral hospitals for liver diseases, for different reasons only 5 hospitals were activated initially. New centres fulfilling the established requirements were identified and invited to join the study. Ultimately 14 sites were opened. Of these 8 enrolled the cohorts of eligible study patients.
WP 6 focuses on biobanking and analyses of clinical samples from DIALIVE – SAFETY (WP4); and DIALIVE – EFFICACY (WP5) study.
WP 8 focuses on the dissemination, exploitation and communication activities. During the first period of the programme a project website was established and the first dissemination and exploitation plan was developed. A patient awareness video has been approved. The IP portfolio management policy has been established along with the publication and authorship, and the DIALIVE has granted patents (or notification of grant) in major territories.
The focus of WP2 was the production, assembly, transport, training aspects of DIALIVE. It involved assembling, packaging and labelling the components that make up DIALIVE into a single clinical investigator pack. Each functional component is CE-marked and is commercially available in Europe: these parts are the oXiris filter, (which removes endotoxin), the septeX filter (which removes albumin), to which were added proprietary connection tubing, multilingual instructions for use, packaging and labelling. WP2 required the development of a full set of the Standard Operating Procedures (SOPs) and the planning and execution of all training on all clinical sites in conformance with international regulations.
The Hepalbin filter from Albutec (and ALIVER consortium member), was added to DIALIVE. Hepalbin is designed to purify commercial albumin, whose manufacturers process albumin which includes the addition of stabilizers to increase the shelf life. These stabilizers may limit the albumin’s binding capacity for that toxins that contribute to morbidity and mortality in severe liver disease, and it is Hepalbin’s role to address these concerns.
The goals of WP3 are:
1. To ensure appropriate clinical trial support through the creation of a management system.
2. Conduct the trials in compliance with the currently approved protocol/amendments, following ISO 14155 GCP guidance and with the applicable regulatory requirements, and develop a plan for the regulatory procedures.
3. Ensure that the trials are adequately monitored for each site before, during and after the trials.
Both site activation and patient recruitment were slower than anticipated, which prompted the opening of more clinical sites.
WP 4 focuses on the conduct of the trial in adherence with the approved study protocol to determine the safety and tolerability of DIALIVE in patients with ACLF (DIALIVE safety) according to the Standard Operating Procedures used by Yaqrit and FAKKEL. It ensures that patients are managed in accordance with Good Clinical Practice (ISO 14155) and that clinical data is collected and handled correctly to achieve the primary and secondary endpoints. Although the trial was planned to be conducted in 8 widely distributed European referral hospitals for liver diseases, for different reasons only 5 hospitals were activated initially. New centres fulfilling the established requirements were identified and invited to join the study. Ultimately 14 sites were opened. Of these 8 enrolled the cohorts of eligible study patients.
WP 6 focuses on biobanking and analyses of clinical samples from DIALIVE – SAFETY (WP4); and DIALIVE – EFFICACY (WP5) study.
WP 8 focuses on the dissemination, exploitation and communication activities. During the first period of the programme a project website was established and the first dissemination and exploitation plan was developed. A patient awareness video has been approved. The IP portfolio management policy has been established along with the publication and authorship, and the DIALIVE has granted patents (or notification of grant) in major territories.
With the ALIVER clinical trial, the DIALIVE system is now the world leader in innovative liver dialysis systems. Its main potential competitor, a US system called ELAD, made by US company Vital Therapies Inc., was withdrawn from development because it failed to demonstrate a survival benefit in late-stage clinical trials. DIALIVE is now well placed to reduce morbidity and even mortality in patients with ACLF. The opportunity for a substantial socio-economic benefit for this patient group and society as a whole is closer than it has ever been. In addition, and as stated above, new IP was filed in 2020 that is intended to enable development for an even broader patient group than was treated in the trial completed by the ALIVER Consortium.