Ex Vivo Pharmacologic Modulation of Hematopoietic Stem Cells

Hematopoietic stem cell transplantation represents a potentially life-saving treatment option for children and adults afflicted with hematologic malignancies (e.g., leukemia and lymphoma) or certain other non-malignant orphan diseases such as inherited metabolic disorders (IMDs), hemoglobinopathies (e.g., sickle cell disease, and beta-thalassemia), aplastic anemia and immune deficiencies. The number of procedures performed and the breadth of diseases treated has increased steadily over the past two decades – approximately 60,000 hematopoietic stem cell (HSC) transplants are performed on a worldwide annual basis in patients with hematologic malignancies alone, and more than 50 rare diseases have now been treated with curative intent through HSC transplantation.

The source of HSCs used for transplantation has also evolved considerably over the past several decades. Most recently, cord blood has emerged as an attractive source of HSCs for patients lacking a suitable donor: ease of collection, prompt availability and immunological naivete´ of immune cells (leading to reduced incidence and severity of graft-versus-host disease and less stringent HLA-matching requirements) are all superior characteristics unique to cord blood. Cord blood currently represents the fastest growing cell source for use in HSC transplantation.

Despite these significant advantages of cord blood as a stem cell source, the full clinical potential of cord blood for use in treating patients with hematologic malignancies and other rare diseases is currently limited by the low numbers of HSCs present in a given cryopreserved cord blood unit. This low stem cell dose leads to higher rates of graft failure, delayed neutrophil recovery and a higher risk of serious infections and early mortality compared to standard donor transplants.

Our lead product candidate, PROHEMA, is a pharmacologically modulated HSC therapeutic derived from umbilical cord blood. Produced through a proprietary, two-hour, ex vivo cell modulation process that results in rapid and supra-physiologic changes in key cell properties, PROHEMA has been shown to enhance hematopoietic reconstitution in preclinical models through several unique mechanisms of action, including enhanced homing, or migration, of HSCs to the bone marrow niche as well as increased HSC proliferation and survival. Our goal is to deliver a pharmacologically-optimized HSC therapeutic that can support rapid and durable hematologic and immunologic reconstitution, and enable the curative potential of HSC transplantation in patients across a wide range of ages and a broad spectrum of life-threatening malignant and rare genetic disorders.

We have established initial human proof-of-concept for PROHEMA in the clinical setting by demonstrating accelerated and durable engraftment of HSCs within the bone marrow. We are presently advancing PROHEMA in clinical development for hematologic malignancies in adults and pediatric patients. We are also pursuing the development of pharmacologically optimized HSC therapeutics for the treatment of selected IMDs (e.g. Krabbe disease, Hurler syndrome, certain leukodystrophies and others) in pediatric patients. In these conditions, HSCs have demonstrated the ability to reconstitute the blood system as well as home to and engraft within the central nervous system, where they can provide normal enzyme replacement.

The PUMA Study (PROHEMA in UMbilical cord blood transplant in Adults)

The PUMA study is an open-label, randomized, controlled, multi-center Phase 2 clinical trial designed to enroll 60 subjects, age 15 to 65 years with hematologic malignancies. The PROHEMA manufactured for use in this study is prepared with the Company’s Nutrient Rich Media (NRM) formulation. Patients are being randomized at a ratio of 2:1, with approximately 40 patients receiving PROHEMA plus an unmanipulated cord blood unit and approximately 20 patients receiving two unmanipulated cord blood units. At the discretion of the treating physician, patients will be conditioned using an intensive myeloablative or a reduced intensity regimen. The primary endpoint of the PUMA study is the cumulative incidence of time to neutrophil engraftment as compared to a pre-specified control median, which will be adjusted based upon the median time to neutrophil engraftment calculated for the patients enrolled in the control arm. Secondary endpoints include additional measures of neutrophil and platelet engraftment, rates of graft failure, acute graft versus host disease and serious infection, and disease-free and overall survival.

In August 2014, the PUMA independent Data Monitoring Committee (iDMC) conducted its first of two scheduled interim reviews of the randomized, controlled Phase 2 clinical trial of PROHEMA. A total of 10 patients, including seven patients that received PROHEMA plus an unmanipulated cord blood unit and three control patients that received two unmanipulated cord blood units, were included in the first interim review, which assessed safety, time to engraftment, rates of graft failure, early mortality, infection, and graft versus host disease (GvHD). The iDMC did not identify any safety signals and, based on its consideration of the data available on the first ten patients, supported continuation of the PUMA study. A second data review by the iDMC is scheduled after the first 12 patients have been treated with PROHEMA, and the Company intends to provide a clinical update following the completion of this review, which is expected in the second half of 2014. Full data on the primary endpoint is expected by mid-2015.

The PROMPT Study (PROHEMA for the treatment of hematologic Malignancies in PediaTric Patients)

In April 2014, the U.S. Food and Drug Administration (FDA) cleared the Company’s Investigational New Drug Application (IND) amendment to evaluate PROHEMA in pediatric patients undergoing single umbilical cord blood transplantation for the treatment of various hematologic malignancies, such as acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), following myeloablative conditioning. In the US alone, over 3,500 children are diagnosed with leukemia each year, many of whom ultimately require HSC transplantation. The Phase 1b PROMPT study is designed to enroll up to 18 patients, between the ages of 1 and 18, at three leading U.S. pediatric transplant centers. The primary endpoint of the PROMPT study is safety as assessed by neutrophil engraftment. The study will also evaluate various parameters of efficacy, including additional measures of neutrophil engraftment, platelet engraftment, rates of graft failure, GvHD and serious infection, and disease-free and overall survival. Full data on the primary endpoint is expected by mid-2015, in a similar time frame to the PUMA study.

The PROVIDE Study (PROHEMA eValuation for the treatment of Inherited metabolic Disorders)

In July 2014, the FDA cleared the Company’s IND to initiate its clinical investigation of PROHEMA in pediatric patients undergoing single umbilical cord blood transplantation for the treatment of inherited metabolic disorders (IMDs). IMDs include a range of genetic enzyme deficiencies that interfere with critical metabolic pathways necessary to maintain normal organ function. In many of these disorders, the enzyme deficiency leads to cellular accumulation of toxic intermediates within the brain, causing progressive neurological damage that cannot be addressed with enzyme replacement therapy. For those inherited metabolic disorders, which include over 20 lysosomal and peroxisomal storage diseases such as Hurler and Hunter syndromes, Krabbe disease and multiple leukodystrophies, allogeneic HSCT holds potential as a one-time, definitive therapy. Following allogeneic HSCT, donor-derived cells can migrate to and engraft in the brain, providing a long-term supply of an otherwise deficient enzyme to the central nervous system in a process known as cross-correction.

The Phase 1b PROVIDE study is designed to enroll up to 12 patients with various forms of IMDs, between the ages of 1 and 18, at up to three leading U.S. pediatric transplant centers. The study inclusion criteria allow for the enrollment of patients with different types of lysosomal and peroxisomal storage diseases such as Hurler and Hunter syndromes, Krabbe disease and various other leukodystrophies, among others. The primary endpoint of the PROVIDE study is safety as assessed by neutrophil engraftment. In in vivo murine models of allogeneic HSC transplantation, Fate demonstrated that the use of PROHEMA, as compared to unmodulated HSCs, led to a significant increase both in the engraftment of donor HSCs and in the donor-derived expression of enzyme in the brain. The Company intends to begin enrolling this study in the fourth quarter of 2014.

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