Year 2

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.