Strategic Partnership I
Sickle cell disease (SCD) is an autosomal recessive disease in which a mutation in the beta globin gene results in the sickling of red blood cells. Affected individuals are predisposed to infection, and may present with pain crises, acute chest syndrome, and stroke. Pediatric patients with sickle cell disease (SCD) receive daily hydroxyurea, which controls disease by activating the gamma globin gene (shut down in infancy), thus reducing adverse effects of mutant beta globin. The clinical benefit of this has been shown by the reduction in the incidence of pain or acute chest syndrome, and a reduction in the need for blood transfusions. However, the effects of hydroxyurea are palliative and chronic therapy has been reported to be carcinogenic in isolated cases. Furthermore, most adults will become refractory to hydroxyurea treatment. Contemporaneous with the development of hydroxyurea, other investigators have been exploring the potential of curing SCD with hematopoietic stem cell (HSC) transplantation. To date, approximately 400 patients have undergone allogeneic HSC transplantation following myeloablative conditioning. However, it is estimated that HLA-compatible HSC transplants are available to less than 20% of affected individuals and long term toxicities are substantial. The latter includes the need for chronic immunosuppression and the development of graft versus host disease (GVHD). The proposed therapeutic intervention aims to provide a widely available functional cure for SCD and beta-thalassemia. During infancy, gamma-globin-containing fetal hemoglobin protects SCD and beta-thalassemia patients from developing disease symptoms until gamma globin is replaced by adult-type beta globin chains. The proposed approach combines the benefits of activating the gamma globin gene with the curative potential of HSC transplantation while abrogating the toxicities associated with hydroxyurea, chronic immunosuppression and GVHD. We hypothesize that harvesting HSCs from a patient with SCD or beta-thalassemia, using genome editing to permanently activate the gamma globin gene, and returning these edited HSCs to the patient could provide a lifetime of relief from SCD and beta-thalassemia symptoms. The use of a patient’s own cells is anticipated to be safer since the conditioning regimen would be nonmyeloablative, there is no need for chronic immunosuppression, and there would be no risk of GVHD. Importantly, this approach addresses all patients with SCD/beta-thalassemia with one treatment.
Statement of Benefit to California:
Our treatment for hemoglobinopathies will benefit the approximately 5,000 SCD patients in the State of California by providing them with a better treatment option for this severe disease with significant unmet medical need (1). SCD is an ongoing health concern in California, with the California Newborn Screening Program detecting approximately 125 cases of SCD each year (2) . In addition to benefitting patients, our proposed curative treatment will also benefit California’s State Medicaid Program, Medi-Cal, through significant cost savings. Acute and chronic clinical manifestations of SCD (vaso-occlusive crisis, acute chest syndrome, stroke, etc.) lead to significant healthcare utilization, especially of the emergency department (ED). The majority of SCD Californians visit an ED more than once during the year; ED visits often result in hospital admission lasting 5-6 days on average for SCD patients. Of importance to the State of California, SCD patients are heavily reliant on Medicaid (~46%). The total lifetime health care costs for an average sickle cell patient are approximately $1 million (3). This translates to approximately $2.5 billion in total costs for the ~50% of SCD Californians covered by Medi-Cal. Thus, our proposed treatment has the potential to provide Medi-Cal significant savings by reducing the number of expensive inpatient hospitalizations and Emergency Department visits by SCD Californians. 1. J. A. Wolfson, S. M. Schrager, T. D. Coates, M. D. Kipke, Sickle-cell disease in California: a population-based description of emergency department utilization. Pediatr Blood Cancer 56, 413 (Mar, 2011). 2. California Department of Public Health: California Newborn Screening Program. http://www.cdph.ca.gov/programs/nbs/Pages/NBSSCDProviders.aspx -- accessed on 6/25/2012. 3. S. K. Ballas, The cost of health care for patients with sickle cell disease. Am J Hematol 84, 320 (Jun, 2009).
EXECUTIVE SUMMARY The goal of this proposal is to develop a new cell therapeutic based on genetic modification of the patient’s own blood stem cells (hematopoietic stem, progenitor cells, HSPC), for treating sickle cell disease (SCD) and beta-thalassemia (BT), common and debilitating illnesses. The proposed genetic modification would result in knockout of a gene whose product regulates expression of a fetal globin gene, allowing this gene to be expressed. The patient’s genetically modified HSPC would be returned to the patient via a bone marrow transplant following a non-ablative conditioning regimen. Following engraftment, the genetically modified cells would give rise to red blood cells that do not sickle. Key project activities include an observational trial in SCD patients, a preclinical safety studies, process development and manufacturing, filing an Investigational New Drug (IND) application and initiation and completion of a Phase 1 clinical trial in sickle cell disease. Significance and Impact - Sickle cell disease is a widespread and devastating genetic disorder for which current treatment options are limited. If successful, the proposed innovative genetically modified cell therapy would address a critical unmet need. - Reviewers noted that success of the proposed less toxic non-ablative conditioning regimen in this indication would be a significant development that could make HSPC transplantation more widely utilized in this and similar patient populations. Risk/Benefit - Reviewers pointed out that the biological effects of disruption of the targeted regulatory gene in HSPC are not well understood and are likely to extend beyond effects on the fetal globin gene. - While preliminary data on genotoxicity of the gene modification technology is encouraging, reviewers considered that more stringent tests should be performed with the HSPC cell source. - There have been no discussions with the regulatory agency on the preclinical and clinical plans for the proposed therapeutic candidate. Reviewers considered this a risk given the targeted HSPC population, the gene modification technology and the patient population. - Reviewers considered the proposal for a non-ablative conditioning regimen to be a key aspect of this project and noted that the risk of the project is increased if there is a switch to an ablative regimen, presented as an option in the application. Design and Feasibility - The reviewers raised a number of concerns on the overall readiness and feasibility of the proposed project. They considered the project to be too premature for clinical development. They found the preclinical data to be very preliminary and insufficient to fully evaluate the feasibility of the project. - It is unclear from the application whether a potentially therapeutic level of gene targeting can be reproducibly achieved in adult bone marrow stem cells. Reviewers also commented on the lack of preclinical evidence supporting the feasibility and durability of cell candidate engraftment to therapeutic levels especially in a competitive engraftment setting. - Reviewers had several concerns with the proposed Phase 1 study including the feasibility of achieving engraftment given the starting conditioning regimen and the number of HSPC proposed for infusion especially in the non-ablative setting. - Reviewers considered the observational study in SCD patients to be of little value and commented that no criteria were specified for the selection of the subset of patients from that study for the Phase 1 study. Principal Investigator (PI), Development Team and Leadership Plan - The PI and the applicant team have considerable experience in the development of proposed platform technology. - The clinical sites are appropriate for the proposed project with clinical experience in the proposed clinical indication. Collaborations, Assets. Resources and Environment - Resources for development, manufacturing and clinical work are appropriate - A collaborator on the biology of targeted gene may be helpful. - It is not clear if the applicant organization has access to the IP covering the targeted gene Budget (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 reviewers considered the per patient cost as high considering that the first year of the study is observational requiring data management only - The reviewers commented that certain GMP manufacturing costs appear to be underestimated.