Athersys, Inc. Announces Positive Results of MultiStem(R) Clinical Trial for Hematopoietic Stem Cell Transplant Support and Prevention of Graft-Versus-Host Disease
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.
Data highlights from the study include:
• The majority of patients participating in the study received transplants from unrelated donors (19 of 36), and nearly all of the patients received peripheral blood stem cell (PBSC) transplants (34 of 36), both of which are associated with a higher risk of GvHD;
• 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;
• Favorable relapse-free survival (RFS) rate at 100 days among all patients receiving MultiStem treatment relative to the historical clinical experience; and
• Limited infection-related complications over the first 100 days relative to historical clinical experience, consistent with the positive effect on engraftment rates.
Dr. Richard Maziarz, M.D., co-principal investigator of this study and Medical Director, Adult Stem Cell Transplantation Program at the Oregon Health & Science University Knight Cancer Institute, commented, "The results from this study are encouraging, and suggest that MultiStem therapy could provide clinical benefit to patients receiving allogeneic stem cell transplants. These patients are susceptible to GvHD and other complications from standard treatment regimens, and the data suggest that treatment with MultiStem could provide clinical benefits in several important ways. The data certainly justify additional clinical investigation, and I look forward to subsequent clinical studies to explore how MultiStem can help these individuals." The study results are being presented at the annual American Society for Bone Marrow Transplantation Tandem meeting in San Diego, California.
"We believe the results of this study are meaningful and suggest that administration of MultiStem could provide substantial benefits to patients receiving hematopoietic transplants, especially those patients that are traditionally considered to be in higher risk categories, such as those receiving transplants from unrelated donors or receiving peripheral blood stem cell transplants, both of which have historically been associated with a higher risk of GvHD," said Gil Van Bokkelen, CEO of Athersys, Inc. "We believe that these results could provide the basis for advancing this program clinically in an accelerated manner, and we look forward to discussing the data with the FDA."
These clinical results provide the foundation for further, accelerated development of MultiStem for the prevention and reduction of GvHD. Following final review of the data, and subject to input from its key scientific and clinical advisers, Athersys plans to meet with the FDA to discuss plans for the next phase of clinical development, which could include a blinded, controlled phase II/III study of MultiStem for GvHD prophylaxis and HSCT support. The study would be intended to help lay the groundwork for approval in this indication, but would also help continue to establish the scientific foundation for MultiStem in related areas including GvHD treatment, solid organ transplant and other areas of immune system dysfunction.
During the first 48 hours following MultiStem administration, patients were assessed for infusion-related toxicity and other acute adverse events. The primary endpoint for the study was the determination of the maximum tolerated dose, as determined by a continual reassessment methodology. Regimen-related toxicities and infusion-related allergic toxicities through 30 days after MultiStem administration were also monitored. Additionally, patients were evaluated for adverse events and infections through 100 days following the HSCT.
The administration of MultiStem was found to be well tolerated for all dosing groups in both the single and repeat dose administration arms. Immediately following dosing, there were no clinically significant changes to vital signs or evidence of allergic reaction associated with MultiStem administration. Over the 30-day observation period, no infusional toxicities or clinically significant adverse events definitively related to MultiStem occurred.
MultiStem had a favorable safety profile over the 100-day period following the HSCT. There were no graft failures, which compares favorably with historical graft failure rates of 5--15% for these types of patients. Of the 36 patients in the study, 30 patients completed 100 day follow-up and there were 6 withdrawals, including 2 relapses and 3 deaths (unrelated to treatment). Other serious adverse events in the first 100 days were consistent with expectations for this patient population.
HSCT Support Highlights
While the primary objective of this Phase I clinical trial was to evaluate the safety of MultiStem administered to HSCT recipients, additional data regarding secondary endpoints, GvHD incidence, infection and survival, have been collected and are being evaluated for safety and evidence of efficacy signals to facilitate planning for subsequent clinical studies. Specifically, following MultiStem administration, patients were assessed weekly by the attending physician for GvHD (and regimen-related toxicities), and information regarding infections and adverse events was collected as they occurred, through day 100.
Overall, MultiStem treatment was associated with a positive impact on blood and immune system recovery, as compared to expectations for this patient population based on historical experience and scientific literature, with 100% neutrophil and 86% platelet engraftment for study patients. The median time to engraftment was 15 days for neutrophils and 16 days for platelets.
The cumulative incidence of acute GvHD for all subjects enrolled in the study (i.e. irrespective of administered dose) was generally in line with expectations for this patient population based on historical experience and scientific literature, using Kaplan-Meier estimates censored for study withdrawal due to relapse and death. However, in the highest single dose group (10 million cells per kilogram body weight, infused on day 2 following HSCT), the 100-day cumulative incidence of moderate to severe acute GvHD was just 11%, which compares favorably with historical experience for this patient population (generally 40-60% grade II-IV GvHD), and, among the patients in this group, no patient developed severe GvHD. Additionally, at the 5 million cells per kilogram body weight dose level, once weekly dosing of the intermediate dose through the first 30 days provided apparent additional benefit over single or weekly dosing over the first two weeks post-transplant.
Importantly, the incidence of infections and mortality over the observation period appear to be in line with or better than what would be expected for this high risk patient population. Consistent with the positive impact on hematopoietic recovery, MultiStem was associated with a relatively low level of late stage infection and only one case of infection-related mortality occurred through 100 days, which compares favorably with historical experience with this patient population. Overall, the Kaplan-Meier estimate of relapse-free survival at 100 days was 81%, compared to an expectation of around 65-70% based on published results from previously published clinical studies using comparable treatment approaches and patient groups.
About the Disease Condition and Study Design
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 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 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 HSCT 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.
The Phase I clinical trial was an open label, multi-center 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 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 (n=6), 5 million (n=3) and 10 million (n=9). The repeat dose arm evaluated patients enrolled in two groups -- 1 million (n=3) and 5 million (n=3) per kilogram body weight -- with MultiStem administration scheduled for days 2, 9 and 16 and in a third group (n=12) with MultiStem administration of 5 million per kilogram scheduled for days 2, 9, 16, 23 and 30. The clinical trial was conducted at transplant centers in the United States and Europe, including the Oregon Health & Science University, University Hospitals Case Medical Center, Texas Transplant Institute, University of Pennsylvania, Mayo Clinic Hospital Arizona, and UZ Leuven.
Twenty male and sixteen female subjects enrolled in the study, ranging in age from 20-62 years old. Nineteen patients received HSCT from matched unrelated donors (MUD), including two with a slight degree of mismatch, and seventeen received HSCT from matched related donors (MRD). With respect to HSCT source, 34 grafts were from peripheral blood and two were from bone marrow, with 16 of 18 patients receiving PBSC transplants in the single dose arm of the study, and all 18 patients in the multiple dose arm of the study receiving PBSC transplants. All patients received MultiStem therapy from the same product bank, reflecting MultiStem's manufacturing scalability and shelf-life stability, an advantage over other cell therapies and an important potential commercial advantage for the company.
MultiStem(R) cell therapy is a patented product that has shown the ability to promote tissue repair and healing in a variety of ways, such as through the production of multiple therapeutic factors produced in response to signals of inflammation and tissue damage. MultiStem has demonstrated therapeutic potential for the treatment of inflammatory and immune disorders, neurological conditions, and cardiovascular disease, as well as other areas, and represents a unique "off-the-shelf" stem cell product that can be manufactured in a scalable manner, may be stored for years in frozen form, and is administered without tissue matching or the need for immune suppression. The product is extensively characterized for safety, consistency and potency. Athersys has forged strategic partnerships with Pfizer Inc. to develop MultiStem for inflammatory bowel disease and with RTI Biologics, Inc. to develop cell therapy for use with a bone allograft product in the orthopedic market.
Athersys is a clinical stage biotechnology company engaged in the discovery and development of therapeutic product candidates designed to extend and enhance the quality of human life. The Company is developing its MultiStem(R) cell therapy product, a patented, adult-derived "off-the-shelf" stem cell product platform for disease indications in the cardiovascular, neurological, inflammatory and immune disease areas. The Company currently has several clinical stage programs involving MultiStem, including for treating inflammatory bowel disease, ischemic stroke, damage caused by myocardial infarction, and for the prevention of graft versus host disease. Athersys has also developed a diverse portfolio that includes other technologies and product development opportunities, and has forged strategic partnerships and collaborations with leading pharmaceutical and biotechnology companies, as well as world-renowned research institutions in the United States and Europe to further develop its platform and products. More information is available at www.athersys.com.
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