Leukemia and certain related conditions are often treated with radiation and chemotherapy to eliminate cancerous or diseased cells, but this process also severely compromises the native blood forming and immune system in the patient, leaving them susceptible to infection and other complications. To address this, a patient will often receive an allogeneic hematopoietic stem cell transplant (HSCT), whereby following radiation and chemotherapy treatment a patient's blood stem cells are replaced with a transplant of hematopoietic stem cells obtained from the bone marrow or peripheral blood of a healthy donor. Donors may be related or unrelated to the patient, but are matched according to tissue type in order to minimize the potential for Graft-versus-Host Disease (GvHD), where donor immune cells transplanted with the donor HSCT attack tissue and organs of the patient. Following the transplant, the patient will often remain hospitalized in specialized units until successful engraftment provides a sufficiently functional immune system. 

According to the Center for International Blood and Marrow Transplant Research, there are approximately 25,000 allogeneic HSCTs performed annually globally, although this number is projected to increase due to the anticipated growth in incidence of hematologic malignancies associated with an aging population. While this treatment approach can be an effective medical therapy for these types of cancer, it is often associated with substantial tissue damage and side effects, such as GvHD.

GvHD is a frequent complication associated with allogeneic HSCT, affecting approximately half or more of transplant recipients, and advanced GvHD can be severely debilitating or even fatal. Several factors affect a patient's likelihood of having GvHD and GvHD severity, including the treatment protocol used, the degree of tissue match between donor and recipient (with lower GvHD rates and severity associated with related donors and better tissue matches), and the condition of the patient among other factors. In addition, higher GvHD rates are typically observed in patients receiving peripheral blood stem cell (PBSC) transplants, as compared to patients receiving bone marrow-derived stem cell transplants. Current treatment approaches involve the prophylactic use of agents such as methotrexate, cyclosporine, or tacrolimus, but these are also associated with various risks and side effects. Treatment of GVHD relies on the use of immunosuppressive agents such as corticosteroids (e.g., prednisone), but these may be transiently effective or ineffective in many patients, and even where effective, these treatments may have other side effects (e.g., infection, organ damage).

Preclinical studies have demonstrated that MultiStem therapy can provide benefit following HSCT. Working with leading experts in the stem cell and bone marrow transplantation field, we have seen that this cell therapy reduces inflammation, tissue damage, and other effects of GvHD, and improves survival in rodent models. Additionally, in animal model systems testing immune reactivity of T-cells against unrelated donor tissue, MultiStem has been shown to suppress the T-cell-mediated immune responses that are an important factor in causing GVHD, and has had a beneficial impact on cytokines and other effectors contributing to the GvHD pathology.

We have recently completed an open label, multi-center phase I trial evaluating the safety and maximum tolerated dose of single or repeated dose administration of MultiStem following an allogeneic HSCT in patients being treated for leukemia or related cancers of the blood or immune system. The single dose arm (n=18) evaluated the infusion of a single dose of MultiStem administered intravenously two days following a peripheral blood or bone marrow HSCT, and included patients in three dose groups, based on cells per kilogram body weight — 1 million, 5 million and 10 million. The repeat dose arm (n=18) evaluated patients enrolled in two groups – 1 million and 5 million per kilogram body weight – with MultiStem administration scheduled for days 2, 9 and 16 and in a third group with MultiStem administration of 5 million per kilogram scheduled for days 2, 9, 16, 23 and 30.

The study demonstrated that MultiStem therapy was well tolerated in both the single infusion and repeat infusion arms and also suggested that the therapy may provide benefit to recipients of allogeneic HSCT, such as reducing the incidence and severity of Graft-versus-Host Disease (GvHD) as compared to historical clinical experience.

• All patients experienced successful neutrophil engraftment (median time of engraftment 15 days), and 86% of patients experienced successful platelet engraftment (median time of engraftment 16 days) which compares favorably to historical clinical experience for this patient population demonstrating a positive impact on blood and immune system recovery;
• Substantial reduction in acute GvHD incidence, relative to historical experience, at the highest single dose (11% grade II-IV GvHD, and 0% grade III-IV GvHD);
• Evidence of a dose response relationship, with patients receiving the highest single dose of MultiStem having a 33% lower absolute incidence of acute GvHD relative to patients who received a single low or medium dose, and patients receiving once weekly dosing of the medium dose through the first 30 days having reduced GvHD incidence relative to single or weekly dosing over the first two weeks post-transplant;  
• Limited infection-related complications over the first 100 days relative to historical clinical experience, consistent with the positive effect on engraftment rates; and
• Favorable relapse-free survival (RFS) rate at 100 days among all patients receiving MultiStem treatment relative to the historical clinical experience.

These clinical results could provide the foundation for further, accelerated development of MultiStem to prevent or reduce the severity of GvHD, a potentially life-threatening complication of such transplants. Athersys received orphan drug designation from the U. S. Food and Drug Administration for prevention of GvHD in September 2010. Orphan drug designation, which is intended to facilitate drug development, provides substantial potential benefits to the sponsor, including funding for certain clinical studies, study-design assistance, tax incentives and seven years of market exclusivity for the product upon regulatory approval.