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.
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.
This program aims to complete early clinical development of a therapy for type I insulin dependent diabetes (T1D). The therapeutic candidate consists of a pancreatic progenitor population derived from human embryonic stem cells (hESC) encapsulated in a device to both contain the cells and protect them from immune rejection. Following subcutaneous implantation, the cells mature in vivo to beta cells that secrete insulin in response to blood glucose. This combination product candidate is intended to replace the beta cells that are lost in T1D and restore glucose regulation. During the four-year award period, the applicant and the biopharmaceutical partner plan to complete IND enabling studies, file an IND and initiate and complete a Phase 1/2 clinical trial. The primary endpoint of the trial is safety, with a secondary efficacy endpoint. The applicant and the partner also plan to conduct process scale up and perform preclinical and clinical comparability studies to support a larger scale pivotal clinical trial (Phase 3).
Significance and Impact
- Reviewers characterized the goal of the proposed therapy as the “holy grail” of diabetes treatments. The product candidate could have a transformative impact if successfully developed.
- The proposed program is a direct outgrowth of CIRM funded work. It has attracted a biopharmaceutical partner who will co-fund and, assuming success, conduct the pivotal trial and commercialize the product. This program is an excellent fit for both the RFA and CIRM’s overall goals.
- The approach is highly clinically competitive. Direct glucose sensing and insulin secretion offers an advantage over therapies such as insulin injection and frequent glucose monitoring, insulin pumps, and new closed loop and continuous glucose monitoring technologies. Encapsulation could obviate the immune rejection that plagues islet transplants; the hESC source for the pancreatic progenitor population eliminates supply issues.
- The TPP is appropriate and achievable.
- Containment of the cells in a removable device minimizes risk to patients. Benefit is readily determined and could be dramatic, although it may only be seen in the higher dose cohorts of the early stage trial.
- Reviewers noted the extensive cell, device and combination product characterization and testing which contributes to risk reduction.
- Reviewers raised questions about the potential number of cell-containing devices required for implantation to achieve insulin independence, the frequency of replacement and the kinetics of insulin release but agreed that the proposed clinical protocol would provide important data addressing these points.
Design and Feasibility
- The project plan is well conceived, includes appropriate Go/No-Go decision points and delineates program risks and solutions. All components, including preclinical, manufacturing, engineering, regulatory and clinical, are well developed. Reviewers further commented that the program would provide insight regarding safety, preliminary clinical efficacy and mechanism of action of the candidate therapeutic in humans and pave the way for pivotal studies and commercialization.
- While additional scale up must be performed to support a Phase 3 trial, the applicants’ strength in bioengineering and the “off the shelf” nature of the cells used in the candidate therapeutic, including their scalability and ability to be cryopreserved, strengthen the manufacturing strategy.
- The class of this proposed therapy for this indication is novel to the FDA, and the agency may request additional studies that could delay the timeline. However, this risk has been mitigated by the applicant’s proactive, forthright and constructive engagement with the agency.
- Preclinical data are impressive. However, the inability to model allogeneic immune responses to the candidate therapeutic in large animals limits assessment of in vivo durability of the device and immune responses to the therapy. These will be addressed in the Phase 1/2 study but constitutes a risk.
- Reviewers agreed that the technology was at a point where it should be tested in humans and that the proposal was a solid plan to do that.
Principal Investigator (PI), Development Team and Leadership Plan
- The team is appropriate, has demonstrated a long-term focus on the candidate diabetes treatment and has made excellent progress to date.
- Clinical investigators and sites are highly qualified and possess the appropriate experience to execute the proposed Phase 1/2 trial.
Collaborations, Assets. Resources and Environment
- Collaborators, resources and environment are excellent. Productive relationships with contractors are already established; however, some personnel remain to be named.
- Applicant reports a broad patent portfolio.
(Assessment of the budget was conducted separately from the overall scientific evaluation and points or concerns raised in this section did not contribute to the scientific score. This section highlights items that must be addressed should the application be approved for funding.)
- The budget appears reasonable and appropriate.
- - Applications were addressed individually during programmatic review. A motion was made to recommend funding this application and a panelist highlighted that the project meets all the programmatic criteria of the RFA. The motion passed.
- Olle Korsgren