Disease Team Therapy Development III
$15 992 447
Recommended if funds allow
This project involves developing a novel treatment for a common form of progressive blindness. The target disease is called retinitis pigmentosa (abbreviated RP), which starts with poor night vision in young adults and progresses to legal blindness by age 40 to 50. The disease is inherited and involves slow loss of the cells in the back of the eye that normally detect light. There are estimated to be about 150,000 people in the USA with RP and there is currently no cure. Therefore, the cost of medical care and lost productivity from blindness caused by RP is considerable. In this project, we plan to slow or halt the progression of RP by injection of stem cells into the eye. These stem cells are primitive brain cells called neural progenitor cells. After injection into the eye, they can survive within the light sensitive part of the eye and help the light-detecting cells to survive. The feasibility of this approach is already established by successfully preventing vision loss in animals that develop RP similar to humans. In order to ensure this treatment is safe and effective in humans we have developed a plan consisting of three steps. Firstly, the progenitor cells will be manufactured in a clean room facility so they are uncontaminated and safe for human use. Secondly, prior to injection of the neural progenitor cells into humans, they will be administered to rodents to ensure that they do not have harmful side effects. Finally, the neural progenitor cells will be injected into the eye of a small number of consenting subjects with RP to ensure they are safe and effective. The cells will be injected in one eye and vision test will be performed to see if the vision in the treated eye is subsequently better than that of the untreated eye. All these processes will be done under the oversight of the Food and Drug Administration and State Regulatory Authorities to ensure that studies are safe and ethical. If successful, this will pave the way for development of these progenitor cells as an approved drug to treat people with RP. This one time treatment could dramatically reduce costs of long term medical care and improve vision for thousands of affected people.
Statement of Benefit to California:
This project involves developing a novel treatment for a common form of progressive blindness and provides several benefits to the State of California. Firstly, the project itself will employ new administrative, managerial, medical and scientific personnel in California with a spillover effect on local businesses and other support jobs. Secondly, the development of this stem cell based drug in California helps ensure that the state retains its lead in the commercialization of stem cell technologies. Biotechnology in general has provided clean, high technology jobs and attracted well-educated and highly compensated personnel from around the country and around the world. Thirdly, the development of new drugs within the academic institutions of California ensures that the hospitals and medical training are at the cutting edge thereby attracting more resources. Finally, if successful, this treatment would provide a substantial improvement to the vision of the 15,000 Californians who are suffering from progressive blindness. It is also anticipated that the same strategy would apply to other forms of progressive blindness including age-related macular degeneration that is number one cause of blindness in California’s seniors.
EXECUTIVE SUMMARY This application describes development of an allogeneic human neural progenitor cell (hNPC) population that would be administered to slow or halt the progression of retinitis pigmentosa (RP), a common form of progressive blindness for which there is currently no cure. The applicants present data from preliminary studies showing long term engraftment of hNPC and maintenance of visual function in preclinical models of progressive retinal disease. The proposal includes manufacturing clinical grade hNPC, examining the activity and safety of the hNPC in preclinical models, submitting the supporting data to the FDA and, if approved, conducting a Phase 1/2a clinical trial to assess the safety and efficacy of the hNPC in patients with RP. Significance and Impact - RP is a progressive disease for which a cellular therapeutic could provide significant clinical benefit and be a significant improvement over the current standard of care. - The Target Product Profile was not well developed and failed to include some potential treatment risks. - There are other cell therapies currently under development for treatment of RP. - The application is responsive to the RFA. Scientific Rationale and Risk/Benefit - Reviewers thought the scientific rationale is not very strong to support the mechanism through which the applicants propose the hNPC would act in this disease. - Some reviewers thought that the inclusion criteria proposed for the Phase 1/2a clinical trial would select an inappropriate patient population for a first-in-human indication. - The same hNPC source line is under development for other clinical indications, which may help streamline preclinical requirements for this program. However, diseases with different prognoses may support treatments with different tolerance levels for possible risks associated with a new treatment. Thus, clinical use of a given therapeutic in one disease indication would not necessarily result in its approval for another indication. Therapeutic Development Readiness - The application describes a single therapeutic candidate with preclinical proof of concept data that support disease modifying activity in a preclinical model of progressive blindness. - Appropriate regulatory interactions have occurred to support a program at this stage of preclinical development. Design and Feasibility - Reviewers expressed concern that the regulatory pathway for approval of the hNPC source line may be challenging. If the team chose to make changes to the manufacturing plan, which might be necessary for longer term development of the therapeutic, this could lead to a significant interruption in the program. - Reviewers noted that the application did not present a very comprehensive characterization of the hNPCs; a detailed characterization of the population would be necessary for demonstration of comparability after changes to the manufacturing plans or transition to an alternative cell line. - It does not appear possible to conduct the proposed study designs within the 4 year project plan timeline. - The application describes RP as “a slowly progressing disease” which reviewers noted could require a prolonged patient observation period to identify clinical effects of treatment. Principal Investigator (PI), Development Team and Leadership Plan - The PI is an active, experienced clinical researcher and has assembled a team that has expertise working with hNPC and RP. - Reviewers thought the application lacked sophistication in the area of translational development and recommended that the team add expertise in regulatory strategy, immunology and biostatistics. - Reviewers appreciated the inclusion of an external advisory team of specialists in ophthalmology. Budget - The budget to support preclinical and clinical studies appears justified; however, reviewers thought the requested funds for equipment upgrades and medical monitoring of the clinical trial seemed excessive. Collaborations, Assets, Resources and Environment - Resources and environment are appropriate to meet the objectives of the application. - An experienced and highly regarded facility has been contracted for manufacturing the clinical grade hNPC.
- Derek J Hei