Preclinical and clinical testing of a stem cell-based combination product for insulin-dependent diabetes

Funding Type: 
Strategic Partnership I
Grant Number: 
Award Value: 
Disease Focus: 
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 

Diabetes exacts a tremendous toll on patients, their families, and society. Autoimmune Type 1 diabetes, often called juvenile-onset diabetes, is caused by a person’s own immune system mistakenly destroying their insulin-producing cells in the pancreas, known as beta cells. When those beta cells are lost, the ability to produce insulin in response to consumed carbohydrates is lost, and blood sugar can increase to toxic levels. Although not due to autoimmunity, Type 2 diabetics often lose their ability to produce insulin as well. While pharmaceutical insulin is commonly used to control both types of diabetes, it is difficult to self-administer optimally, does not sufficiently replace beta cells, and the adverse short- and long-term effects of diabetes and risks associated with insulin usage remain, including potentially fatal hypoglycemic episodes, nerve damage, blindness, kidney failure, foot ulcers / amputations, and heart disease.

Ideally, one would like to replace lost beta cells, and attempts to do so have included the use of pancreas transplants, beta cell (islet) transplants, and transplants of animal cells. Unfortunately, those approaches are hindered by 1) a limited amount of donor tissue, and 2) issues regarding immunological incompatibility between donors and recipients. To solve the first problem, the group applying for this CIRM award has developed methods to make replacement beta cells from human embryonic stem cells (hESC), which can be reliably grown in large-scale batches. The hESC-derived beta cells have been shown to cure experimental diabetes in mice and rats. Regarding the issue of donor-recipient compatibility, the group has found that the cells can be administered under the skin in a simple device, essentially an envelope made of semi-permeable membrane, which is intended to protect the implanted cells from the patient’s immune system. Upon implant, the cell-loaded device, which also keeps the implanted cells in place, acquires its own dedicated circulation. This blood supply provides oxygen and nutrients to the implanted cells, and also allows them to respond to blood sugar by releasing pancreatic hormones such as insulin into the circulation. Thus, the implanted cell-loaded device in essence represents a “replacement endocrine pancreas” with its own protection from autoimmunity. This product could return a patient's blood sugar regulation to normal and alleviate both the day-to-day and long-term issues of diabetes.

The group has made tremendous progress in moving the product from concept through years of research and development. At this point an array of detailed work on the exact format to be tested in humans needs to be completed and submitted to the FDA on the way to clinical trials. The proposed award would provide critical funding, including potentially triggering matching funding from a large corporate partner, to advance the product through the first-in-human testing which will be very informative.

Statement of Benefit to California: 

Diabetes mellitus currently afflicts approximately 350 million people worldwide, with projections of over 500 million by the year 2030 (sources: World Health Organization; International Diabetes Federation). In the year 2000 there were an estimated 2,089,657 cases of diabetes in California (diagnosed + undiagnosed; source: Diabetes Control Program, California Department of Health Services). Further, the disease disproportionately affects certain minority groups and the elderly. Despite the use of insulin and advances in its delivery, the human cost of diabetes is underscored by the financial costs to society: tens of billions of dollars each year in California alone. The primary cause of Type 1 diabetes, and contributing significantly to Type 2 diabetes as well, is the loss of insulin-producing pancreatic beta cells. The proposed Partnership will develop a beta cell replacement therapy for insulin-dependent diabetes. If successful, the therapy will go beyond insulin function, and will perform the full array of normal beta cell functions, including responding in a more physiological manner than manual or mechanized insulin administration. Because they will be more physiological, the replacement cells should also reduce the long-term effects of diabetes. Moreover, the cell therapy will alleviate patients of the constant monitoring of blood glucose and painful insulin injections. For these reasons, it is possible that the product could transform the diabetes treatment landscape dramatically and even replace pharmaceutical insulin in the market. This product will be available in California first, through clinical testing, and if approved by the FDA for commercial production, will eventually help hundreds of thousands of Californians with diabetes. The product will substantially increase quality of life for patients and their families while significantly reducing the health care burden in the state. The proposed Partnership will employ Californian doctors and scientists, and success will generate accolades and notoriety for the state. Lastly, once commercially marketed, the product will yield additional jobs in manufacturing, sales, and related industries, and generate revenue for California. Given the market need and the clear feasibility, the product could become the most significant stem cell-based medical treatment of the coming decade, and that will be a great achievement for California, its taxpayers, and CIRM.

Progress Report: 

In type 1 diabetes, the insulin-producing beta cells of the endocrine pancreas are destroyed by a person’s own immune system in a disease process known as autoimmunity. Consequently, those with type 1 diabetes are unable to produce insulin, which is necessary for control of blood glucose, and ultimately, for life. While pharmaceutical insulin provides life-saving relief, numerous risks and complications exist for those contending with this disease. A large body of research indicates that replacing the lost beta cells of the endocrine pancreas would represent a substantially more effective approach to treating type 1 diabetes.

To address this need, ViaCyte is developing a cell replacement therapy for type 1 diabetes. The proposed product is comprised of human pancreatic progenitor cells, known as PEC-01™ cells, loaded into and implanted within a flat encapsulation device or packet, known as the Encaptra® drug delivery system. PEC-01 cells are manufactured in the laboratory from human embryonic stem cells using a proprietary process that was developed at ViaCyte. The Encaptra device is made of biocompatible materials and is designed to retain PEC-01 cells in a specific location in the body, and protect them from a patient’s immune system. Together, PEC-01 cells within the Encaptra device are known as the VC-01™ combination product candidate, and animal studies have shown that following implant, the cells mature into functional human pancreatic endocrine cells (including insulin producing cells) that respond to changes in blood glucose appropriately, including the release of insulin into the circulation when blood glucose levels are increased.

The Strategic Partnership Award provides funding to support the preparation and launch of clinical testing of the VC-01 product candidate. The first year of the award was to support pre-clinical work including the preparation and filing of regulatory documents including, importantly, an Investigational New Drug (IND) application with the FDA, to allow testing in human subjects to commence.

The team made great progress in the first year of the award and achieved all planned milestones in a timely fashion. Specifically, the group was able to complete the necessary animal safety and efficacy studies (performed under Good Laboratory Practices) that are prerequisite to human testing, obtain a license from the California Food and Drug Branch to allow product manufacturing to proceed, and manufacture PEC-01 cells (under Good Manufacturing Practices) and Encaptra devices (under Quality Systems Regulations) for the Phase 1/2 first-in-human clinical trial. Moreover, the group established and finalized materials and methods to load PEC-01 cells into Encaptra devices and prepare the sealed VC-01 combination product for transport to the point of service. The group also established storage conditions for the VC-01 product consistent with the logistics of the clinical trial. Lastly, the clinical plan and protocol were completed and the IND was submitted. Within 30 days the IND was allowed by the FDA, and the first clinical site was prepared to launch the trial.

Following the allowance of the IND by the FDA in August 2014, the open-label VC01-101 STEP ONE* clinical trial launched in September 2014 and has continued through Year 2 of the Strategic Partnership, with the primary goals of demonstrating safety and tolerability, and developing administration procedures to establish effective cell engraftment. This Phase 1/2 clinical trial, designed to evaluate the VC-01 product candidate directly in patients with type 1 diabetes (T1D), was initially launched at the UC San Diego Health System, with the support of the UC San Diego Sanford Stem Cell Clinical Center, under the direction of Principal Investigator Robert Henry, MD. In January 2015 the team received a No Objection Letter from Health Canada providing clearance to proceed with sites in Canada and in July 2015, a second clinical site was opened at the University of Alberta Hospitals in Edmonton, Alberta under the direction of Principal Investigator James Shapiro, MD PhD. Dr. Shapiro is credited with developing effective pancreatic islet transplant methods as a treatment for T1D, and is a valuable addition to the team.

Over the first year of the trial, preparation of the VC-01 test article for the trial has been successful and without issue: all VC-01 lots have been produced on time, with no contaminations, and no meaningful quality control issues. All have been delivered to the clinical sites for administration on time and without issue.

As of October 2015, ten T1D patients have been enrolled serially at the two sites in Cohort 1 and implanted with the VC-01 product candidate at a sub-therapeutic dose of cells. The goals of Cohort 1 are to evaluate the safety of the product candidate, and to develop and optimize surgical procedures and post-surgical care required for the successful engraftment of the cells. The number of patients to be studied in this first phase of the trial is data-driven and based primarily on histological examination of sentinels. When the procedures are successfully optimized, Cohort 1 results will be compiled and reported to the Data Safety Monitoring Board (DSMB). The DSMB will make a recommendation regarding continuation to Cohort 2, which will evaluate safety and efficacy of the VC-01 product candidate, administered at what is calculated to be a therapeutic dose of cells.

* Safety, Tolerability, and Efficacy of the VC-01 Combination Product in Type One Diabetes