Hematopoietic stem cell transplantation represents a potentially life-saving treatment option for children and adults afflicted with hematologic malignancies. The number of procedures performed has increased steadily over the past two decades – approximately 60,000 hematopoietic stem cell (HSC) transplants are performed on a worldwide annual basis.
Our lead product candidate, PROHEMA, seeks to enable the curative potential of HSC transplantation in patients across a wide range of ages and a broad spectrum of life-threatening malignant disorders. PROHEMA is a pharmacologically-modulated hematopoietic cellular therapeutic derived from umbilical cord blood, which has been optimized to enhance the therapeutic potential of hematopoietic cells. PROHEMA is produced through a proprietary, two-hour, ex vivo programming process using a small molecule modulator (FT1050) that promotes rapid and supra-physiologic activation of genes involved in the homing, proliferation and survival of HSCs, which are key biological properties necessary for durable engraftment and hematopoietic reconstitution. In our initial Phase 1b clinical trial in adult patients with hematologic malignancies undergoing double umbilical cord blood transplant (dUCBT), the median time to neutrophil recovery (> 500 cells/µL) with PROHEMA was 17.5 days, which compares favorably to historical norms for patients undergoing dUCBT, and 100-day survival with PROHEMA was 100%.
Ex vivo programming using FT1050 may also enhance the immuno-modulatory properties of T cells, as our initial Phase 1b clinical trial also suggested that PROHEMA may promote immune reconstitution and viral immunity following HSC transplantation. An analysis of the CD8+ T cell compartment of patient samples from our Phase 1b clinical trial revealed that, at Day 100, subjects who received PROHEMA showed a two-fold increase in the percentage of naïve and early memory T cell fraction within the CD8+ T cell compartment, as compared to subjects who received two unmanipulated cord blood units. These naïve and early memory CD8+ T cell populations are believed to play a key role in promoting immune reconstitution and viral immunity following cord blood transplantation. Consistent with these reported immuno-modulatory effects on CD8+ T cells, low rates of viral reactivation were observed in our Phase 1b clinical trial. Specifically, cytomegalovirus (CMV) reactivation occurred in only two of 12 PROHEMA subjects (17%), which compares favorably to rates of CMV reactivation reported in the literature of 36-56%.
We are currently investigating the therapeutic potential of PROHEMA in a Phase 2 clinical trial (PUMA) in adult patients and a Phase 1b clinical trial (PROMPT) in pediatric patients. In 2010, the FDA granted PROHEMA orphan designation for the enhancement of stem cell engraftment in patients undergoing allogeneic cord blood HSC transplantation.
PROHEMA Phase 2 PUMA Study
The PUMA study (PROHEMA in UMbilical cord blood transplantation in Adults) is an ongoing, open-label, randomized, controlled, multi-center Phase 2 clinical trial designed to enroll 60 subjects, age 15 to 65 years with hematologic malignancies. 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 neutrophil engraftment as compared to a pre-specified control median. Secondary endpoints include additional measures of neutrophil and platelet engraftment, rates of graft failure, acute graft versus host disease (GvHD) 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 GvHD. The iDMC supported continuation of the PUMA study, and a second data review by the iDMC is scheduled after the first 12 patients have been treated with PROHEMA, which is expected in the second half of 2014. Full data on the primary endpoint is expected by mid-2015.
PROHEMA Phase 1b PROMPT Study
In the US alone, over 3,500 children are diagnosed with leukemia each year, many of whom ultimately require HSC transplantation. In April 2014, the U.S. Food and Drug Administration (FDA) cleared our 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. The PROMPT study (PROHEMA for the treatment of hematologic Malignancies in PediaTric Patients) 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. We are currently enrolling patients in our Phase 1b PROMPT study, and full data on the primary endpoint is expected by mid-2015.