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GvHD is a complication that can occur after a stem cell or bone marrow transplant from a donor, in which the newly transplanted donor cells attack the patient’s body as if it were “foreign”. The most commonly used method of stem cell and bone marrow transplantation is Hematopoietic Stem Cell Transplantation, or HSCT, which is the transplantation of multipotent hematopoietic stem cells, or stem cells usually derived from bone marrow, peripheral blood or umbilical cord blood. HSCT may be autologous, in which case the patient’s stem cells are used, or allogenic, in which case a donor’s stem cells are used. HSCT is most often performed on patients with certain disorders or cancers of the blood or bone marrow, such as multiple myeloma, aplastic anemia, leukemia or lymphoma. In these cases, the patient’s immune system is often destroyed with radiation and chemotherapy before stem cell transplantation. As a result, infection and GvHD are major complications of allogenic HSCT because the grafted cells from the donor must accept the patient (i.e., the host) rather than the patient accepting the graft.
In GvHD, T-cells, which are lymphocytes involved in the regulation of the immune system, in the donor’s blood are activated by host antigen presenting cells, and trigger an immune response by the graft against the patient’s organs and tissues. Such an attack can occur at any time after transplantation and is typically categorized as “acute” if it occurs within the first 100 days of transplantation or “chronic” if it occurs after the first 100 days; however, the National Institutes of Health recently classified a “late-onset” acute GvHD, which occurs after day 100, and an overlap classification with features of both acute and chronic GvHD. Acute GvHD is generally characterized by selective damage to the liver, skin, mucosa and the gastrointestinal tract, including rashes, intestinal inflammation, mucosal damage to the vagina and oral cavity, any of which can lead to severe infections or death. Acute GvHD is typically measured on a scale of severity ranging from Grade I through Grade IV, with the higher-grades being more severe and Grade I being an indicator of immune activity Chronic GvHD is generally characterized by the same indications, but the symptoms can last a lifetime and often relapse. Allogeneic HSCT patients may experience either or both chronic or acute GvHD, despite the use of prophylactic immunosuppressive drugs, which is currently the clinical standard treatment for most HSCT patients. Despite the use of such prophylactic treatment, according to scientific literature, the rate of patients who develop GvHD ranges from 30% to 70%. Those patients who develop GvHD or show signs of acute GvHD are then typically treated with corticosteroids, such as prednisone. In other cases, phototherapy is used, which produces both apoptotic and necrotic cells, thereby inducing a simultaneous pro- and anti-inflammatory response, and antibodies and small molecule antibody treatments are prescribed and used off-label (i.e., in a manner that is inconsistent with the approved label). Such treatment regimens for GvHD, however, are known in the scientific and medical communities to have poor efficacy profiles, compromise the patient’s ability to respond to immunological challenges, which expose the patient to severe adverse side effects, including hypertension, hyperglycemia, peptic ulcers and liver and kidney injury, and an increased risk of infection and cancer, and in most cases (including in the United States for the prevention or treatment of GvHD), these treatments are not approved for their intended uses by applicable regulatory authorities.
According to the Worldwide Network for Blood and Marrow Transplantation, more than 50,000 HSCT procedures are performed annually worldwide, of which approximately 23,500 are allogeneic. According to the Center for Internatinal Blood and Marrow Transplant Research,the average cost of a bone-marrrow transplantation in the U.S. was $203,000. According to the the Clinical Journal of Oncology Nursing in 2007, approximately 35% to 50% of patients undergoing HSCT develop GvHD, with patients receiving transplants from unrelated donors developing the disease at the high end of such range. We believe that new technologies, including more effective treatments for GvHD and procedures that lower the criteria for genetic matching will continue to expand the size of this market, and we believe that the number of HSCT procedures will likely continue to increase for currently established indications and may expand to additional indications.
Allocetra is a patient-specific drug successfully tested in a Phase I/IIa clinical trial in GvHD patients for the prevention of acute GvHD, particularly high-grade, acute GvHD. In March 2013, the FDA granted our orphan drug designation request for the active moiety of Allocetra for the prevention of acute GvHD, in July 2014, Allocetra received an ATMP certification from the EMA for the prevention of acute GvHD, and in December January 2015, the EMA granted orphan medicinal product designation for the Allogeneic peripheral blood mononuclear cells induced to an early apoptotic state is designated as an orphan medicinal product for the indication: Prevention of graft-versus-host disease. Treatment with Allocetra consists of retrieving a blood sample from the patient or a matched donor, treating it at the cellular level to generate an early apoptotic cell population undergoing apoptosis and injecting it into the patient. Our process for ex-vivo manipulation of a specific fraction of the cell population produces a stable, high-cell dose of early apoptotic cells, with a very low rate of necrotic cells, which are dead cells that cause inflammation.