Year 4 + NCE
In the years just prior to the establishment of the CIRM Diabetes Disease Team, scientists at ViaCyte (then known as Novocell) clearly demonstrated in mice the great promise of using pancreatic progenitor cells as a potential cell replacement therapy for type 1 diabetes.
In type 1 diabetes, the insulin-producing cells of the pancreas are lost to autoimmunity. ViaCyte has shown that human pancreatic progenitors, derived from human embryonic stem cells (hESC) in culture, will further mature to human pancreatic islet cells including glucose-responsive insulin-producing cells after implantation, and that these cells can rescue or protect mice from experimentally induced diabetes [Kroon et al., 2008, Nature Biotechnology, 26(4): 443-452]. Further, the group demonstrated that the pancreatic progenitor cells could effectively protect mice from experimental diabetes when implanted in a “macro-encapsulation” device, which is designed to protect the cells from allo- and auto-immunity.
In short, the ViaCyte team developed a procedure and a strategy to replace the insulin-producing cells lost in type 1 diabetes, leveraging the great potential of hESC as an approach to large-scale production of replacement cells, and macro-encapsulation as a way to avoid immunosuppressant drugs typically needed in same-species cell and organ transplantation. The next crucial steps were to translate this promising research into a clinically acceptable process, assure the safety and efficacy of the approach in independent animal studies, establish a plan to test in patients with type 1 diabetes, and submit the complete data package to the regulatory authorities, including the FDA, in order to allow clinical trials to commence.
Over the past four and half years, the CIRM Diabetes Disease Team achieved the goals and milestones that it proposed at its inception in 2009. Substantial progress was made in advancing the stem cell-derived cell therapy and delivery device combination product from research phase to clinical development, including initiation of a Phase 1/2 clinical trial upon completion of this work.
In cell product development, the achievements included manufacture of Master and Working Cell Banks of the specific hESC starting material under Good Manufacturing Practices (GMP), development of a robust, reliable, scalable manufacturing process for differentiation of hESC into pancreatic progenitor cells (PEC-01™ cells), and development of cryopreservation and thawing and recovery methods for preparation of PEC-01 cells prior to loading into macro-encapsulation (Encaptra®) devices.
In device development, achievements included assessing and establishing materials and methods, and formalizing procedures for manufacturing Encaptra devices. Devices and their materials were thoroughly tested for biocompatibility and safety under ISO 10993 regulations. Custom manufacturing and testing methods and protocols were established.
In parallel with cell and device development, the team established custom materials and methods for combining these two main components into the product candidate (VC-01™ product). This included aseptic processes for loading cells into devices, sealing the devices, and placing them into custom packaging for delivery to the clinic.
Extensive Quality Control and Quality Assurance (QC/QA) systems were designed and implemented to assure standardized, reliable, safe and efficacious VC-01 product would be produced for clinical research. As biologicals (the cells) and devices fall under different regulations, the team needed to develop a custom hybrid quality management system that addressed both sets of regulations.
Numerous pre-clinical studies were performed in preparation for clinical testing, including three safety and efficacy studies of the VC-01 combination product under Good Laboratory Practices (GLP) at independent contract research organizations. Scientists in the immunology laboratories at University of California, San Francisco, and the La Jolla Institute for Allergy and Immunology further examined and demonstrated the utility of macro-encapsulation to protect implanted cells from allo- and auto-immunity in several animal models. The pre-clinical studies collectively indicated that proceeding to human testing was warranted and appropriate.
In the final years of the project, a Phase 1/2 first-in-human clinical trial was prepared. The trial is designed to provide critical insights into safety and the potential efficacy of the product concept. Lastly, the team had successful interactions with regulatory authorities, including a pre-IND submission and meeting with the FDA, and as a culmination of all of the work, a device master file (MAF) and investigational new drug application (IND) were submitted to the FDA. In the last month of the project the regulatory documents were accepted by the FDA, and the path was set to commence clinical testing of the product in patients with type 1 diabetes.