Allogeneic Glial Restricted Progenitor Cell Transplantation for Neuroprotection of Motor Neurons in Amyotrophic Lateral Sclerosis (Lou Gehrig’s Disease)
Disease Team Therapy Development III
$18 606 067
The disease amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s Disease) affects roughly 5,600 people in the U.S. per year and as many as 30,000 Americans currently suffer from this disease. ALS is a nervous system disorder characterized by the progressive loss of the brain and spine cells which control muscle movement. When these “motor” nerve cells die the result is muscle wasting, which leads to weakness, paralysis and ultimately death because your brain can’t make your breathing muscle work correctly. Most patients only survive for 2 to 5 years after their diagnosis. In some ways ALS has similarities to cancer. After decades of research, scientists realized that cancer is actually many different diseases, which look similar, but are, in fact, caused by different problems in the body. It is likely that this is also true of ALS. If the disease is so variable, being caused by different problems which all end up hurting those “motor” nerve cells, how can we find one pill that fixes many different problems? Drugs (or pills) are in general very specific – they fix one problem (hit one target), which is usually a good thing because then you are less likely to accidentally hurt innocent bystander cells. This is where stem cells come into the picture. Stem cells are natural living cells that in order to survive have to do many things (they have many properties). But one of the problems is we aren’t certain which of these properties are the right properties for different diseases. So we are going to use stems cells that replace some of the diseased cells in people with ALS that hurt the “motor” nerve cells, these are called glia. We will let healthy glia do the many things they normally do. And they will be doing it in their normal environment. Since the cells are natural, and have many different properties, there is hope that they can help in many of the “different diseases” that we call ALS. Our study is designed to complete a clinical trial in up to 32 ALS patients. We hope that by looking very hard, and using cells which naturally are capable of many different ways of helping, we will begin to see hints that the cells provide benefit. Once we have hints we will be on the path to cures.
Statement of Benefit to California:
California will benefit from this grant not only in the healthcare sector but also economically, both in the short and long term. Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig’s disease) patients will benefit from a new treatment that can stop the relentless progression of ALS, and the economy will benefit from new revenues and job creation during the development process and subsequent commercialization. ALS is a devastating progressive neurodegenerative disease. There are ~3500 patients with ALS in CA, with approximately 2 new cases diagnosed in CA every day. Health care costs can run us high as $200,000-500,000/year in the later stages of the disease. Current standard of care consists of management, care and support of ALS patients; patients die on average 2-5 yrs after diagnosis. There is only one drug, riluzole, approved for treatment of ALS, which extends survival on average by 90 days. Clearly a new approach needed to attack this multi-faceted disease. The Cell Therapy product under development by this grant uses pathways that are effective in a healthy person’s spinal cord, with the goal to preserve motor neurons that otherwise die in ALS patients. This may provide a new treatment to halt the relentless progression of ALS, preserving the patient’s ability to function. Not only would this provide major health benefits to Californian’s suffering from ALS, but would also provide economic benefits to the patients, their families and the state from reduced health care costs.
EXECUTIVE SUMMARY This application describes development of an allogeneic human glial restricted progenitor cell (hGRPC) population that would be administered into the spinal cord in an effort to slow the progression of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by muscle wasting and early death, for which there is currently no effective treatment. The proposal includes manufacturing clinical grade hGRPCs, developing assays to more fully characterize the cells, examining the safety of delivering the cells in preclinical models, submitting the information to the FDA and, if approved, initiating and completing a Phase 1/2a clinical trial to assess safety and biological activity of the hGRPC in up to 32 patients with ALS. Significance and Impact - ALS is a fatal disease for which a cellular therapeutic could potentially provide clinical benefit and be an improvement over the current standard of care. - Transplantation of the hGRPCs into a rodent model of ALS did not lead to motoneuron (MN) protection or any therapeutic benefits on functional outcome measures. While the applicant proposes that glial progenitor cells may have clinical benefit in patients with ALS, there are no translational data with the therapeutic candidate that support this hypothesis. - Reviewers noted that this is a competitive area of research and there are other cell therapies currently under development for ALS. Scientific Rationale and Risk/Benefit - It is not apparent that local delivery of hGRPCs would have a significant impact on a neurodegenerative disease that affects MNs throughout the brain and spinal cord. - The applicant presents data from preclinical studies showing that hGRPCs engraft in rodents and differentiate to more mature glial cell types, but do not have functional effects in a rodent model of ALS. Cells described as similar to hGRPCs, but obtained from rats, were shown to provide benefit in this rodent model. - The proposed clinical trial includes a logical, staged progression in administration procedures that start with transplantation into the most conservative region for treatment risk in the spinal cord. Therapeutic Development Readiness - Disease-modifying activity of hGRPCs (preclinical proof-of-concept evidence in a relevant preclinical model of the target disease) has not been demonstrated. - Appropriate regulatory interactions have occurred to support a program at this stage of preclinical development. Design and Feasibility - Reviewers expressed concern that the number of clinical trial sites proposed could introduce unnecessary logistical challenges and an unacceptable degree of variability within the complex Phase 1/2a trial proposed. - The scope of the proposed preclinical and clinical safety studies was viewed as appropriate, although reviewers thought it was unlikely that the activities could be completed within the aggressive timeline proposed. - Reviewers questioned the judiciousness of plans to transfer the current GMP manufacturing to a new Contract Manufacturing Organization during the scope of the application, noting that a transfer could introduce additional expense and programmatic risk. - During the development of a cellular therapeutic, the FDA may comment on monoclonal antibodies used in manufacturing processes. Reviewers noted that if such an evaluation resulted in a request for additional antibody characterization, the development program could experience a delay. - Reviewers remarked that validation of additional analytical assays to more fully characterize the hGRPC population should be a high priority to facilitate success of the development program. - The manufacturing strategy, scale, and contracts in place appear sufficient to supply hGRPCs for the projected preclinical studies and the Phase 1/2a clinical trial. Principal Investigator (PI), Development Team and Leadership Plan - The clinical investigators associated with the application are outstanding and have experience conducting ALS trials. - The PI has extensive experience in neuroscience and preclinical development of hGRPCs as a cellular therapeutic. - Reviewers noted that a number of key hires have not yet been identified. Budget - The proposal to transfer manufacturing to a new Contract Manufacturing Organization was viewed as likely to result in redundant effort at considerable cost. - Reviewers commented that subcontracts proposed in the application described research activities that would be of low priority to support the success of the hGRPC development program. Collaborations, Assets, Resources and Environment - The resources and environment of the proposed clinical trial sites are excellent. - Consultants and collaborators required to support the development plan are in place.
- Joy Cavagnaro