The 2010 BMT Tandem Meetings were held in Orlando, Florida this past week [February 24-28, 2010]. Considered the premier event for hematopoietic cell transplantation [HCT] and cellular therapy, the annual event attracts more than 2,500 clinicians, transplant nurses, clinical research professionals, data managers, pharmacists, center administrators and mid-level practitioners.
With more than 200 abstracts being presented on the topic, the meeting provided an opportunity to validate some of the conclusions from our recent “Graft Versus Host Disease: Failures and Future Opportunities” article. In particular, we reviewed data presented during the meeting and interviewed several experts in the area of Graft-versus-Host disease [GvHD] to reconfirm our three key findings:
- Treatment of GvHD remains a large, unmet medical need
- Low-risk, steroid-sparing approaches are favored in the short-term
- High-risk strategies with immunomodulatory agents have been prone to failure
Unmet Medical Need
According to the National Marrow Donor Program, approximately 20,000 allogeneic hematopoietic cell transplants [bone marrow, peripheral blood hematopoietic cells, or cord blood transplants] are performed annually worldwide. Despite the use of prophylactic therapies, GvHD still develops in 30%-80% of patients in the second month following transplant.
“A typical complication of patients who have a transplant with a related or an unrelated donor is GvHD of the mouth, esophagus, etc.,” said bone marrow transplant survivor Susan Stewart with BMT InfoNet, a not-for-profit organization that provides information and support services to patients that are going through transplant or have survived a transplant as well as their family members and their donors. “It’s a serious complication – very hard to manage, very painful – so any topical or enteric medication that becomes available to help reduce it or the pain or the actual incidence of the complication is very welcome.”
While steroids, including prednisone, remain the gold standard therapy for GvHD treatment, only 25% to 41% of patients treated have complete GvHD remission. In addition, systemic treatment with prednisone or other steroids can lead to severe side effects and mortality.
“The root cause of the biology of GvHD still is a work in progress so that unless and until we can find a particular pathway to knock out, then what we’ll be doing is probably knocking out more immune system pathways then is needed to control GvHD,” said Keith M. Sullivan, M.D., James B. Wyngaarden Professor of Medicine, Division of Cellular Therapy at Duke University Medical Center. “Steroids for example, just knock about everything in its path down and thus the likelihood for increased infections and complications.”
While the use of prednisone is designed to suppress the T-cell mediated immune onslaught on the host tissues, it can raise the risk of infections and cancer relapse. For example, systemic treatment with steroids is associated with increased opportunistic infections, which are caused by bacteria, fungi or viruses that do not normally cause infections in people with healthy immune systems. Systemic steroid use may also reduce the graft-versus-tumor effect and increase the risk of cancer relapse.
“Some people will definitely relapse from their original disease and die, but many people will die from GvHD because their immune system is compromised in order to control the GvHD,” said Ms. Stewart. “In order to control the GvHD you have to put them on immunosuppressive drugs. That makes them susceptible to opportunistic infections and they die.”
Currently, no therapies are approved by the United States Food and Drug Administration [FDA] for either prevention or treatment of GvHD. GvHD represents a growing problem due to an increasing number of allogeneic hematopoietic cell transplants procedures. As a result there is an urgent need to find therapies for this disease.
“Is this an important area of continued investigation of new therapies for control and prevention of GvHD, the answer is yes,” added Dr. Sullivan.
Low Risk Approaches
Soligenix, Inc. (SNGX)
In view of how little is known about the biology of GvHD, lower-risk, steroid-sparing approaches have a higher likelihood of success in the short-term given the complexity of the disease based on our recent discussions with key opinion leaders.
In this regard, Soligenix, Inc. (SNGX), which sponsored a GvHD working committee in connection with the 2010 BMT Tandem Meetings, is developing orBec® [oral beclomethasone dipropionate] for the treatment of acute gastrointestinal [GI] GvHD. Beclomethasone [BDP] is a corticosteroid with potent topical activity used for inflammatory disorders affecting mucosal surfaces, such as the GI tract. While oral BDP’s mechanism of action is similar to other corticosteroids, it does not enter into the circulation thus avoiding many of the aforementioned negatives associated with systemic steroid uses.
“In 30 years worth of controlled trials for acute GvHD treatment, there is only one agent in two publications, two different trials, that has shown an advantage of controlling GvHD and an advantage of improving survival, and that agent is oral beclomethasone,” said Dr. Sullivan.
Formulated for oral administration as a single product, orBec is a single product consisting of two separate pills. One tablet is intended to release BDP in the upper portions of the GI tract, and the other tablet is intended to release BDP in the lower portions of the GI tract. This novel delivery system ensures that BDP is delivered to the entire GI tract – an important competitive advantage.
“There are two phenotypes of the disease, there’s what I call the upper gut phenotype, which is 60-70% of all GvHD – people just lose their appetites, can’t eat, start getting nauseated and in the severe case have a lot of vomiting,” said George B. McDonald, MD, Professor of Medicine, University of Washington School of Medicine and Head, Gastroenterology/Hepatology Section, Fred Hutchinson Cancer Research Center. “Then there’s the mid gut phenotype, with lots of diarrhea and intestinal ulceration and bleeding. These two phenotypes appear to me as different sorts of diseases. The upper gut phenotype is what the orBec is being aimed at, which is the dominant phenotype in gut GvHD.”
In a prior Phase III trial with orBec, the primary endpoint was the “time to GvHD treatment failure through study day 50,” which included a 10-day induction period of high-dose prednisone, noted David M. Hockenbery, M.D., Member, Division of Clinical Research, Fred Hutchinson Cancer Research Center, and Professor, Department of Medicine, University of Washington. Unfortunately, twice as many prednisone “failures” during the initial 10 days of the trial counted against orBec and the primary endpoint was not achieved [p=0.1177]. By designating the first 10 days of treatment as a guarantee period, the risk of GvHD treatment failure by study day 50 was statistically significantly reduced for the orBec group relative to placebo (p=.009). For the entire 80-day study period in the prior Phase III trial, the risk of treatment failure was statistically significantly reduced for patients in the orBec group relative to placebo (p=.02) and even further strengthened in an analysis using the 10-day guarantee period (p=.001).
“You have data suggesting that this is very effective, it’s very safe, and our mortality data from two different randomized trials showed that this approach, which spares prednisone, reduces mortality by 45%,” said Dr. McDonald. “Two different randomized trials with the identical mortality result. So, if you use less prednisone, you have less cytomeglaovirus, less mold infections, less bacteremia, and for some reason that still escapes me the FDA didn’t view that as a hard enough endpoint.”
In October 2009, Soligenix began enrolling patients in a confirmatory, pivotal Phase III trial under a special protocol assessment [SPA] cleared by the FDA. The European Medicines Agency also agreed that should the new confirmatory Phase III study produce positive results, the data would be sufficient to support a marketing authorization approval in all 27 European Union member states. The primary endpoint for this new study, treatment failure rate at day 80, is more clinically relevant and was statistically significant in the prior Phase III trial [p=0.005].
Soligenix has partnered with Sigma-Tau Pharmaceuticals, Inc. for commercialization of orBec, which is now the only product candidate for the treatment of acute GvHD in active Phase III development.
High Risk Approaches
Osiris Therapeutics, Inc. (OSIR)
During the 2010 BMT Tandem Meetings, Osiris Therapeutics, Inc. (OSIR) presented results from its Phase III trial evaluating Prochymal, a preparation of adult mesenchymal stem cells, for the treatment of steroid-refractory acute GvHD [abstract #41]. In September 2009, Osiris Therapeutics announced that neither of its two Phase III trials evaluating Prochymal for the treatment of GvHD achieved its primary endpoint. There was no statistical difference between Prochymal and placebo for the steroid-refractory (35% vs. 30%, n=260) or first-line GVHD trials (45% vs. 46%, n=192), which did not come as a surprise to some researchers.
“We participated in the mesenchymal stem cell trials, which were negative, and the dog mesenchymal stem cell studies done here were totally negative, so I don’t think we’re particularly surprised that the human studies were negative,” said Dr. McDonald. “The model that best mimics human GvHD is the dog model, whereas the mouse models have given lots of false leads. Mouse GvHD, in the intestine in particular, is not the same as human GvHD and things that look marvelous in the mouse, for example keratinocyte growth factor, failed miserably in human trials. So I think there is a word of caution there about transposing animal species results to human beings.”
However, in patients with steroid-refractory liver GVHD, treatment with Prochymal significantly improved response [76% vs. 47%, p=0.03, n=61] and patients treated with Prochymal had significantly less progression of liver GvHD compared to placebo [37% vs. 65%, p=0.05]. While Osiris Therapeutics previously disclosed plans to file an amendment with the FDA to its current expanded access program, broadening the entry criteria to include patients with severe GvHD of the liver, some physicians expressed skepticism about the significance of liver GvHD.
“For GvHD, the three primary target organs are the skin, the liver, and the gastrointestinal tract,” said Dr. McDonald. “Severe liver GvHD has become a thing of the past and that’s largely because of a drug called ursodeoxycholic acid [ursodiol], which is a bile acid that hepatologists use for cholestatic liver disease. It’s almost completely wiped out liver GvHD.”
Indeed, previously published results [Blood. 2002 Sep 15;100(6):1977-83] demonstrated that treatment with ursodiol reduced hepatic problems and severe acute GvHD and improved survival. Among the patients given ursodiol, the survival at one year was significantly better, 71% versus 55% (P =.02), and the non-relapse mortality rate was lower, 19% versus 34% (P =.01), than in the control group.
“There was a highly statistically significant lowering of mortality in the Nordic Study Group’s ursodiol trial,” said Dr. McDonald. “So, if you’re not using that therapy and you’re doing trials aimed at liver GvHD I think there’s some ethical issues there, I mean there’s a way of preventing it that’s way simpler than mesenchymal stem cells.”
Celgene Corporation (CELG)
These same alloreactive donor T cells that cause GvHD can provide a beneficial graft-versus-tumor effect. Because regulatory T cells [Tregs] have been shown to suppress GvHD while preserving the graft-versus-tumor effect, their use in the allogeneic transplant setting may represent a promising strategy to treat GvHD.
“Back in the day, 30 years ago, it was assumed that the reason people got cured of end stage leukemia with a hematopoietic stem cell transplant was because of the massive doses of chemotherapy and sometimes radiation that is given upfront,” said Dr. McDonald. “We’ve now discovered that is only half of it. Most of the leukemia killing comes from what’s called a graft-versus-tumor effect. That is, the donor cells that are causing GvHD are also seeking out leukemia and leukemia stem cells and immunologically curing the leukemia.”
During the 2010 BMT Tandem Meetings, Celgene Corporation (CELG) presented data [abstract #383] demonstrating that administration of the company’s DNA methyltransferase inhibitor azacitidine [Vidaza®] after allogeneic stem cell transplant dramatically reduced GvHD while maintaining both donor engraftment and a potent graft-versus-tumor effect in a murine bone marrow transplant model. While the results provide a foundation for future human clinical trials, recall Dr. McDonald’s caution that the model that best mimics human GvHD is the dog model, whereas the mouse models have given lots of false leads.
Based on a review of data presented at the 2010 BMT Tandem Meetings and our discussions with several experts in the area of GvHD, we believe that the disease remains a large, unmet medical need. Among the novel agents currently in clinical development, low-risk, steroid-sparing approaches are favored in the short-term as opposed to high-risk strategies with immunomodulatory agents that have been prone to failure. Future results from Soligenix’s ongoing pivotal trial could provide optimism for both patients and investors in the GvHD space.
Keith M. Sullivan, M.D., is a scientific advisor to Soligenix, Inc. and investigator in the pivotal Phase III trial.
George B. McDonald, M.D., is the inventor of orBec, Chair of Soligenix’s North American Medical Advisory Board, and maintains an equity position in Soligenix.