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.