Funding opportunities

Development of a Cell Replacement Therapy Product for Insulin Dependent Diabetes

Funding Type: 
Disease Team Planning
Grant Number: 
DT1-00672
Principle Investigator: 
Institution: 
Funds requested: 
$48 950
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
With a current prevalence of greater than 170 million individuals world-wide, diabetes has attained epidemic proportions. The widespread secondary complications this disease extract a relentless and costly toll on the patients and health care establishment required for their treatment. To date, cellular replacement therapies for the treatment of diabetes has been performed either by transplantation of whole pancreas, or via infusion of isolated primary pancreatic islets into the portal vein . While effective, the availability of such procedures is severely limited for the treatment of the general diabetes population since it relies upon the extremely limited supply of organs from deceased donors. One approach to overcoming the problem of insufficient organ and islet supply is to generate glucose responsive human insulin secreting pancreatic islet cells from stem cell populations. Only human embryonic stem cells (hES cells) demonstrate sufficient cell expansion capacity to achieve production levels needed to treat patients with diabetes. Furthermore, hES cells are capable of efficiently and rapidly progressing through a series of defined steps to generate most cell types found in the human body, but more importantly, pancreatic beta cells that release insulin in response to changing blood glucose levels. In a recent breakthrough, stem cell derived beta cells have been produced for the first time, providing confirmation that hES cells can serve as a realistic and renewable source of functional glucose responsive islet cells. To achieve the goal of producing a safe product for clinical trials in patients with diabetes, the disease team must meet the following objectives: 1.) Identification and characterization of the clinical cell product; 2.) Development of methods to sufficiently purify the clinical cell product; 3.) Development of scale-up methodologies sufficient for achieving clinical trial product supplies; 4.) Design and completion of safety studies; 5.) Identification of implantation site for human clinical trials; 6.) Design of clinical trial; 7.) Development of product shipping and storage procedures; 8.) Development of FDA approved manufacturing process; 9.) FDA approved product facility construction and validation; 10) Submission of product and process documentation to the FDA sufficient to begin human clinical trials. The disease team members critical to efficiently realizing these objectives include a consortium of scientists and managers who are currently fully focused on the realization of these goals. The team includes experienced stem cell researchers who have already developed glucose sensing pancreatic islet cells from hES cells. Together with these hES cell experts the team will include experts in the development, scale-up, manufacture and commercialization of cell-based therapies and on the safety and toxicology studies required for clinical trials with human cell therapy products.
Statement of Benefit to California: 
With a current prevalence of greater than 170 million individuals world-wide, diabetes has attained epidemic proportions. The widespread secondary complications of kidney failure, cardiovascular disease, peripheral nerve disease, and severe retinopathies, this disease extracts a relentless and costly toll on the patients and the health care establishments required for their treatment. Current estimates are that California spends minimally $12 billion on diabetes not including lost wages. There are more than 300,000 diabetes related hospitalizations costing $3.4 billion annually. To date, cellular replacement has been performed either by transplantation of whole pancreas organs, or via infusion of isolated primary pancreatic islets into the portal vein . While effective, the availability of such procedures is severely limited for the treatment of the general diabetes population since it relies upon the extremely limited supply of pancreas organs from deceased donors and usually requires life-long administration of immuno-suppressive drugs. The Disease team to be assembled to develop a cellular therapy for diabetes, has the best stem cell research and product development experience available in California. The team is internationally recognized for their ground-breaking work in stem cell derived production of glucose responsive islet cells and in technologies for the development, scale-up, delivery, manufacture and commercialization of cell-based therapies. In addition the team includes experts in the design and implementation of the safety studies required for production of FDA approvable human cell therapy products. The work carried out by this diabetes disease team may ultimately lead to commercial manufacturing of these products in California and may spawn related support industries. The hope is that these novel stem cell based cellular therapies and technologies will lead to a reduction of the the massive health care burden this disease inflicts on the patients and their families in California.
Review Summary: 
Executive Summary The applicant has recently shown that human embryonic stem cells (hESCs) can serve as a realistic and renewable source of functional pancreatic beta cells. The proposed multidisciplinary team intends to achieve clinical trials in patients with diabetes by identifying, characterizing, purifying and scaling-up production of a cell product; designing and completing safety studies; developing a clinical protocol and study logistics; addressing FDA regulatory requirements; and completing a submission to the FDA sufficient to begin human clinical trials. The disease team members critical to realizing these objectives include experienced stem cell researchers; experts in the development, scale-up, manufacture and commercialization of cell-based therapies; and experts in safety and toxicology studies. Reviewers concurred that the proposed concept is sufficiently mature to expect clinical trials within the 5 year timeframe specified in the RFA. Islet transplantation using deceased donor islets has been shown to work for achieving insulin independence in type 1 diabetics. However, the two main obstacles have been a reliable source of functional tissue and the need for immunomodulation. The group of scientists at the applicant institution has had stunning success with deriving functional beta cells from hESCs as documented in a recent publication. Their proposal for planning the steps necessary for developing the tissue for clinical trials is well thought out and divided into a number of goals. These issues are exactly what need to be determined before such tissues can be used in clinical trials. Currently this is the best bet for achieving a reliable source of functional beta cells, although it is not known how many hESC lines might be amenable to their protocols. Reviewers concurred that one major gap in the proposal is that there is little emphasis placed on how the cells will be tolerated by the immune system. Reviewers agreed that the PI is well qualified to lead the proposed multidisciplinary effort. The PI has a PhD in Molecular Neurobiology and 20 years experience in the biomedical industry. The PI is currently in a scientific leadership position at the applicant institution. The PI has lead the research reported in three recent publications that have shown a protocol for deriving functional beta cells from human ES cells; these papers have pushed this field to the potential of clinical trials. The PI has successfully led phase 1 and 2 trials of other commercial products in previous positions. The planning approach is focused on 5 areas needed to bring their hESC science to clinical trials; currently these groups are all within the applicant institution. However, the plan is to recruit additional expertise for scale-up, manufacture and commercialization of cell-based therapies and for the safety and toxicology studies; these will all be from collaborating institutions. Two islet transplant investigators are included in the team for designing and facilitating the trials. More investigators are likely to be needed for conduct of the trials, but that may be fleshed out later in the actual proposal. Other consultants have been enlisted to support the effort including a collaborator to facilitate future GMP scale-up manufacturing procedures, a consultant in regulatory affairs, and a clinical pathologist. All personnel appear to be highly qualified. Discussion among the panel followed the presentation of the proposal. One panelist asked whether immune rejection was addressed in the application. It was not stated in the application; however the reviewers felt confident that the applicant would address immune rejection in the final proposal given their work in this area. This discussion did not dampen the enthusiasm of the panel for this strong proposal that is likely to get hESC-derived beta cells into the clinic. Reviewer Synopsis The applicant has recently shown that human embryonic stem cells (hESCs) can serve as a realistic and renewable source of functional glucose-responsive beta-cells. To achieve clinical trials in patients with diabetes, the disease team must: 1) identify and characterize the clinical cell product; 2) develop methods to sufficiently purify this product; 3) develop scale-up methodologies sufficient for achieving clinical trial product supplies; 4) design and complete safety studies; 5) identify implantation sites; 6) design clinical trial; 7) develop product shipping and storage procedures; 8) develop FDA approved manufacturing process, product facility construction and validation; 10) complete submission to FDA sufficient to begin human clinical trials. The disease team members critical to realizing these objectives include experienced stem cell researchers who have already developed glucose sensing pancreatic islet cells from hESCs, experts in the development, scale-up, manufacture and commercialization of cell-based therapies and in the safety and toxicology studies. Reviewer One Comments Concept: Islet transplantation using cadaveric islets has been shown to work for achieving insulin independence in type 1 diabetics. However, the two main obstacles have been a reliable source of functional tissue and the need for immunomodulation. The task of obtaining glucose responsive beta cells has been the goal for producing a reliable source of human cells for beta cell replacement therapy. The group of scientists at Novocell has had stunning success with deriving functional glucose responsive beta cells from human ES cells as documented in their recent Nature Biotechnology paper (2008). Their proposal for planning the steps necessary for developing the tissue for clinical trials is well thought out and divided into a number of goals, including: 1) Identify and characterize the clinical cell product; 2) Develop methods to sufficiently purify this product; 3) Develop scale-up methodologies sufficient for achieving clinical trial product supplies; 4) Design and complete safety studies; 5) Identify implantation sites; 6) Design clinical trial; 7) Develop product shipping and storage procedures; 8) Develop FDA approved manufacturing process, product facility construction and validation; 10) Submission to FDA sufficient to begin human clinical trials. These issues are exactly what need to be determined before such tissues can be used in clinical trials. Currently this is the best bet for achieving a reliable source of functional beta cells. However, it is surprising that there is little emphasis placed on how the cells will be tolerated by the immune system. The issue of immune rejection should be addressed in the Disease Team research award application. Principal Investigator: Dr. Baetge has a PhD in Molecular Neurobiology from Cornell Medical College and 20 years experience in biomedical industry. He currently is Chief Scientific Officer of Novocell. He has lead the research reported in three yearly Nature Biotechnology articles that have shown a protocol for deriving functional beta cells from human ES cells; these papers have pushed this field to the potential of clinical trials. Planning Approach: The planning approach is focused on 5 areas needed to bring their hES cell science to clinical trials; currently these groups are all within the company of Novocell. However, the plan is to recruit additional expertise for scale-up, manufacture and commercialization of cell-based therapies and on the safety and toxicology studies; these will all be from other companies. It is surprising that the only clinical transplant personnel included for designing the clinical trials and for facilitating the trials are consultants Drs James Shapiro and Jeff Bluestone, but that may be fleshed out later in the actual proposal. Reviewer Two Comments Concept: Concept/ Rationale. The application from Dr. Baetge and Novocell, Inc proposes to use hESC derived beta cells in a transplant setting to correct diabetes. The rationale is sound as long as the immune system component of this disease is also considered. Maturity: Novocell has some of the best data published on the generation of insulin positive beta-like cells from hESCs. They include a new, yet unpublished reference suggesting that the new protocols result in glucose responsive insulin secretion. Of course it is not known how many ES lines might be amenable to their protocols, but the preliminary data is good. Significance. High Principal Investigator: Excellent. Dr. Baetge has extensive experience in the biotechnology field including top positions at Modex and CytoTherapeutics prior to his position as CSO of Novocell. He has successfully led phase 1 and 2 trials of other commercial products with these other companies. Planning Approach: The team at Novocell has in place a useful hESC prototype product. They list several areas which will enhance the scale up and clinical testing of a product, and have carefully considered the different stages needed prior to clinical testing and have addressed the problems in the application. These areas include in vivo animal modeling, toxicology testing, product characterization and enrichment, GMP, GLP and regulatory issues etc. The team includes Stewart Craig of Progenitor Cell Technologies for future GMP scale-up manufacturing procedures. Dr. Melissa Carpenter is part of the Novocell team and her experience with hES cells will be invaluable to the overall effort. The proposed plan is well thought out and presented. Collaborators/consultants include: James Shapiro and Jeff Bluestone for clinical design, Dr. Vasconcells for regulatory affairs, Dr. Ulbright, a clinical pathologist, Scott Burger for regulatory affairs and GMP manufacturing. All personnel appear to be highly qualified.
Conflicts: 

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