Cell Therapy for Diabetes

The CIRM Diabetes Disease Team is developing a cell therapy to treat insulin-dependent diabetes. The ultimate goal under CIRM Award DR1-01423 is to file an IND with the FDA to allow first-in-human clinical testing of the cell therapy product. To reach that goal, numerous research and development activities need to be successfully executed in parallel, and the project requires careful planning and agile management. This is particularly critical because the planned product is complex and, as a cutting-edge technology, extends into new regulatory territory. In Year 1 of this Award, virtually all aspects of the project remained on track and the 4-year time line to filing an IND remains the same. The planned product is a combination therapy that is expected to alleviate a diabetic’s need to perform frequent blood monitoring and insulin injections. It will essentially replace or provide needed support to the endocrine pancreas that is lost or damaged in diabetes. The product consists of a human pancreatic progenitor cell population administered in a durable delivery device. Following administration, the progenitor cells mature into human pancreatic islets including functional insulin-producing glucose-responsive beta cells. Prototypes of the product have been tested in hundreds of rodents, and in proof-of-concept studies, this cell-device combination has cured rodents of drug-induced diabetes. The pancreatic progenitor cells are manufactured from human embryonic stem (ES) cells through a series of precise steps in cell culture. Using ES cells as starting material allows for the mass production of progenitor cells that will be required if the product is successful, as ES cells are remarkably proliferative while still remaining stable. In Year 1 of the Disease Team Award, frozen cell banks of ES cells were manufactured under Current Good Manufacturing Practice (cGMP), as required to clinically test and commercialize a cell therapy. Additionally in Year 1, the specific details of the pancreatic progenitor cell manufacturing process were finalized, and documentation was put in place to allow cGMP manufacture of pancreatic progenitor cells for future animal and human studies. The cell delivery device is a small flat sealed chamber made from a semi-permeable membrane. The device serves multiple purposes. It is intended to protect the cells from the patient’s immune system, which is particularly important in autoimmune (Type 1) diabetes. It retains the cells at the site of administration for ease of monitoring and possible removal if necessary. Importantly, while cells cannot pass through it, the semi-permeable membrane allows sugars, oxygen, and other nutrients in, to sustain and regulate the islet cells, and allows insulin and other endocrine proteins out, to regulate blood sugar and other metabolic physiology. In Year 1, numerous prototype configurations of the delivery device were tested in animals, and a final configuration was determined. A device manufacturing facility was designed and built. Manufacturing and testing equipment was installed, and documentation put in place for production of clinically compliant devices. As with cell manufacturing described above, device manufacturing can now proceed at a scale and level of quality that will facilitate pre-clinical and clinical testing of the combination product. It is possible that the device alone will not be sufficient to protect the cells from a diabetic patient’s immune system. In anticipation of this possibility, the Diabetes Disease Team includes world-renowned immunologists who are establishing animal models to test and address this question accordingly. Fortunately, there are many pharmaceutical options, including cutting-edge technologies, that have proven effective in protecting transplanted human islets from immune rejection, and those might be applied to administration of this cell therapy product as well. The Disease Team’s clinical group is developing plans for the first-in-human testing and will incorporate a regimen of immune modulation as appropriate. In Year 1, the animal models to test the requirement for immune modulation and various regimens were established. In Year 2, these models will be used to investigate these questions.

The CIRM Diabetes Disease Team is developing a cell therapy to treat insulin-dependent diabetes. The ultimate goal under CIRM Award DR1-01423 is to file an IND with the FDA to allow first-in-human clinical testing of the cell therapy product. To reach that goal, numerous research and development activities need to be successfully executed in parallel, and the project requires careful planning and agile management. This is particularly critical because the planned product is complex and, as a cutting-edge technology, extends into new regulatory territory. In Year 2 of this Award, virtually all aspects of the project remained on track and the 4-year time line to filing an IND remains the same. The planned product is a combination therapy that is expected to alleviate diabetes patients’ need to perform frequent blood monitoring and insulin injections. It will essentially replace or provide needed support to the endocrine pancreas that is lost or damaged in diabetes. The product consists of a human pancreatic progenitor cell population administered in a durable delivery device. Following administration, the progenitor cells mature into human pancreatic islets including functional insulin-producing glucose-responsive beta cells. Prototypes of the product have been tested in hundreds of rodents, and in proof-of-concept studies this cell-device combination has cured rodents of drug-induced diabetes. The pancreatic progenitor cells are manufactured from human embryonic stem (ES) cells through a series of precise steps in cell culture. Using ES cells as starting material allows for the mass production of progenitor cells that will be required if the product is successful, as ES cells are remarkably proliferative while still remaining stable. In Year 1 of the Disease Team Award, frozen cell banks of ES cells were manufactured under Current Good Manufacturing Practice (cGMP), as required to clinically test and commercialize a cell therapy. In Year 2, these cGMP ES cell banks were tested to confirm that they performed similarly to previous banks. The cell manufacturing protocol was finalized and several batches of progenitor cells were manufactured to demonstrate the reliability of the protocol, in particular, with the new cGMP ES cells. The cell delivery device is a small flat sealed chamber made from a semi-permeable membrane. The device serves multiple purposes. It is intended to protect the cells from the patient’s immune system, which is particularly important in autoimmune (Type 1) diabetes. It retains the cells at the site of administration for ease of monitoring and possible removal if necessary. Importantly, while cells cannot pass through it, the semi-permeable membrane allows sugars, oxygen, and other nutrients in, to sustain and regulate the islet cells, and allows insulin and other endocrine proteins out, to regulate blood sugar and other metabolic physiology. In Year 1, numerous prototype configurations of the delivery device were tested in animals, and a final configuration was determined. A device manufacturing facility was designed and built. Manufacturing and testing equipment was installed, and documentation put in place for production of clinically compliant devices. In Year 2, several batches of delivery devices were manufactured and tested under development phase-appropriate Quality Systems Regulations. A Good Laboratory Practice (GLP) study of the combination product, comprised of cells and devices manufactured with the newly developed systems, was performed to establish safety and efficacy in mice, prior to human testing. The results of the GLP study were favorable, suggesting the combination product will likely be safe and effective in the clinic. It is possible that the device alone will not be sufficient to protect the cells from a patient’s immune system. In anticipation of this possibility, the Diabetes Disease Team includes world-renowned immunologists who are establishing animal models to test and address this question accordingly. In Year 2, preliminary data were collected using these animal models. The preliminary data suggest that the device will protect cells from autoimmunity. In Year 3, the clinical protocol will be drafted, further refinements to product manufacturing including device loading will be established, and further pre-clinical testing will be performed. The Team plans to present the candidate product and development plans to regulatory agencies in order to obtain valuable feedback. The goal is to establish sufficient pre-clinical assurance to facilitate clinical testing at the end of the 4-year award period.

The CIRM Diabetes Disease Team is developing a stem cell-derived cell therapy to treat insulin-dependent diabetes. The ultimate goal under the 4-year CIRM Award DR1-01423 is to file an IND (Investigational New Drug application) with the FDA to allow first-in-human clinical testing of the cell therapy product. To reach this goal, numerous research and development activities need to be successfully executed in parallel. The project requires careful planning and agile management particularly because the planned product is complex and, as a cutting-edge technology, extends into new territory from a regulatory perspective. In Year 3 of this Award, all aspects of the project remained close to the original schedule. One study report from an external Contract Research Organization (CRO) was delivered two months later than planned, which delayed a meeting with the FDA and subsequent downstream activities. Accordingly, two months has been added to the original 4-year time line to filing an IND. The new target for IND filing is March 2014. The planned product is a combination therapy that is expected to alleviate diabetes patients’ need to perform frequent blood monitoring and insulin injections. It will essentially replace or provide needed support to the endocrine pancreas that is lost or damaged in diabetes. The product consists of a human cell population containing pancreatic progenitors administered subcutaneously in a durable delivery device. Following administration, the progenitor cells mature into human pancreatic islet-like tissue including functional insulin-producing, glucose-responsive beta cells while in the device. Prototypes of the product have been tested in hundreds of rodents, and in proof-of-concept studies this cell-device combination has cured rodents of chemically-induced diabetes. The pancreatic cells are manufactured from human embryonic stem (ES) cells through a series of precise steps in cell culture. In Year 3, a Cell Manufacturing Cleanroom was built and commissioned in preparation for manufacturing cells for clinical testing. Two new cell manufacturing formats, both amenable to the scale-up that will be required for commercial manufacturing, were also developed. At the end of Year 3, a Pilot Plant was established for process development and technology transfer of the cell manufacturing protocol. The cell delivery device is essentially a small sealed envelope made from a semi-permeable membrane. It is expected to protect the cells from the patient’s immune system and retain the cells at the site of administration. At the same time it will allow sugars, oxygen, and other nutrients in, to sustain and regulate the islet-like tissue, and allow insulin and other endocrine proteins out, to regulate blood sugar and other metabolic physiology. In Years 1-2, prototype (‘animal-sized’) devices were produced and tested, the configuration was finalized, and a Device Manufacturing Facility with equipment for quality control testing was built. In Year 3, the clinical (‘human-sized’) device was designed and built. Also in Year 3, all ISO10993 (safety standards for medical devices from the International Organization for Standardization) testing was completed, establishing that the device and its component materials will be safe for human use. A prototype system to load the progenitor cells into the device was designed and built in Year 3. The Team established and staffed a Combination Product Group. In Year 3, a GLP (good laboratory practice) study of the combination product to test safety and efficacy in mice, prior to human testing, was completed by an independent CRO. The results were favorable, providing further rationale for advancement of the product into clinical testing. To evaluate the potential of the device to protect the implanted cells from a patient’s immune system, the Diabetes Disease Team includes world-renowned immunologists who are establishing animal models to test and address this question. In Year 3, animal studies demonstrated that the device indeed protects animal cells from allo-immunity (addressing differences between donor and recipient tissues), suggesting the human pancreatic cells will also be protected in the product planned for human use. In Year 3, the Team met with the FDA in a Pre-IND meeting. This meeting was informative and provided clarity on the remaining activities before an IND can be submitted and a clinical trial initiated. During Years 1-3, the clinical protocol was drafted, and in Year 4 it will be finalized while the clinical sites are prepared. Also in Year 4, refinements to product manufacturing including device loading will be established, and additional pre-clinical testing will be performed to further assure safety of all aspects of the clinical plan. The goal is to establish a body of pre-clinical data that supports clinical testing at the end of the 4-year award period.

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.