Since the atomic bombings against the cities of Hiroshima and Nagasaki in Japan during World War II, radiation exposure to large populations has been largely limited to industrial accidents, including the April 1986 event at the Chernobyl Nuclear Power Plant in the Ukraine.  Ironically, radiation accidents involving medical uses have accounted for more acute radiation deaths than from any other source, including Chernobyl [Reference 1].

The effects of radiation exposure manifest quickly and depend on a variety of factors, including the dose absorbed by different parts of the body, the route and rate at which it is delivered, and the type of radiation [alpha, beta, gamma, or neutrons].  The effects from various levels of radiation exposure can be found in Table 1 [adapted from Reference 2].

Table 1. Effects from Various Levels of Radiation Exposure

Acute Radiation Syndrome and Treatment

Acute radiation syndrome [ARS], also known as radiation toxicity or radiation sickness, is caused by exposure to a high dose of radiation over a short period of time, usually in a manner of minutes [Reference 3].  The cells that are lost the earliest following exposure are rapidly dividing hematopoietic stem cells and progenitor cells of the bone marrow that are highly sensitive to the effects of radiation, whereas the nervous system is generally regarded as the least sensitive.  These differences in cellular sensitivity help categorize ARS into three syndromes, which occur with increasing dose exposure in the following order:

• Hematopoietic or bone marrow syndrome [HP/BM]
• Gastrointestinal syndrome [GI]
• Central nervous system or cardiovascular syndrome [CNS/CV]

Depending on the level and location of radiation exposure, the management of early-onset ARS is mainly supportive, including supportive care with fluids, antibiotics, and growth factors such as Amgen, Inc.’s (AMGN) Neupogen® [filgrastim] and Neulasta® [peg-filgrastim].  While these growth factor products have not been approved by the U.S. Food and Drug Administration [FDA] for treating radiation-induced neutropenia, they have been recommended by the Strategic National Stockpile [SNS] Radiation Working Group [Reference 4].

When patients survive HP/BM and GI syndromes, respiratory failure may become a major cause of morbidity.  Radiation can impair lung cells either directly via generation of reactive oxygen species [ROS] or indirectly via the action on parenchymal and inflammatory cells through biological mediators [Reference 5].

Protective Measures

There are no approved products to treat or prevent ARS.

Potassium iodide [KI] was approved by the FDA in 1982 to reduce the risk of thyroid cancer in radiation emergencies involving the release of radioactive iodine. For example, the Chernobyl reactor accident resulted in massive releases of I-131 [radioactive iodine] and other radioiodines. Beginning approximately 4 years after the accident, a sharp increase in the incidence of thyroid cancer among children and adolescents in areas covered by the radioactive plume was observed.

By saturating the body with a source of stable iodide prior to exposure, inhaled or ingested I-131 tends to be excreted.  Accordingly, following the Chernobyl incident approximately 10.5 million children under age 16 and 7 million adults in Poland received at least one dose of KI as a prophylactic measure against accumulation of I-131 in the thyroid gland.

However, it is important to note that KI cannot protect against any other causes of radiation poisoning, nor can it provide any degree of protection against dirty bombs that produce radionuclides other than isotopes of iodine.

Ethyol® [amifostine], a prescription drug by MedImmune, a member of AstraZeneca plc (AZN), is administered as a 15-minute i.v. infusion prior to each postoperative radiation treatment session for head and neck cancer when the radiation area includes a large part of the parotid glands.  Ethyol is used to lower the rate of moderate to severe xerostomia [dry mouth] and is not approved for use in combination with other radiation therapy.

Investigational Approaches to Treat ARS

In view of the fact that many potential chemical, biological, radiological, and nuclear [CBRN] terrorism agents lack available countermeasures, the Project BioShield Act was passed into law in July 2004.  Subsequently, Congress has passed additional measures to further encourage countermeasure development.  For example, the 109th Congress passed the Pandemic and All-Hazard Preparedness Act, which created the Biomedical Advanced Research and Development Authority [BARDA] in the Department of Health and Human Services [HHS].  This office oversees all of HHS’ Project BioShield activities, among other duties.

Project BioShield Act has three main provisions: (1) relaxing procedures for some CBRN terrorism-related spending, including hiring and awarding research grants; (2) guaranteeing a federal government market for new CBRN medical countermeasures; and (3) permitting emergency use of unapproved countermeasures [reference 6].  The HHS has used each of these authorities, including the approval of BARDA contract awards for the development of new treatments for radiation exposure and using its authority to guarantee a government market to obligate approximately $2.3 billion to acquire countermeasures against anthrax, botulism, radiation, and smallpox.

Several companies developing product candidates for the treatment and/or prevention of ARS have received government awards under the Project BioShield Act, including those referenced in Table 2.

Table 2. Select Companies with Government Contracts for ARS

Summary

What is now happening with troubled nuclear power plants in Japan could happen in the U.S., as there are nuclear power plants situated near significant seismic areas in the Midwest [reference 7].  This risk is much greater than other places, like California, because seismic energy is conveyed over 10-times more efficiently due to less fractured basement rocks.  Combined with the threat of nuclear terrorism, there is a worldwide concern about exposure to radiation.  Given the lack of prophylactic treatment options and the fact that management of ARS is mainly supportive, a large unmet need exists in this area.

References:

1. The importance and unique aspects of radiation protection in medicine. Holmberg O, Czarwinski R, Mettler F. Eur J Radiol. 2010 Oct;76(1):6-10. Epub 2010 Jul 17.
2. Medical response to a major radiologic emergency: a primer for medical and public health practitioners. Wolbarst AB, Wiley AL Jr, Nemhauser JB, Christensen DM, Hendee WR. Radiology. 2010 Mar;254(3):660-77. Review.
3. Acute radiation syndrome: assessment and management. Donnelly EH, Nemhauser JB, Smith JM, Kazzi ZN, Farfán EB, Chang AS, Naeem SF. South Med J. 2010 Jun;103(6):541-6. Review.
4. Medical management of the acute radiation syndrome: recommendations of the Strategic National Stockpile Radiation Working Group. Waselenko JK, MacVittie TJ, Blakely WF, Pesik N, Wiley AL, Dickerson WE, Tsu H, Confer DL, Coleman CN, Seed T, Lowry P, Armitage JO, Dainiak N; Strategic National Stockpile Radiation Working Group. Ann Intern Med. 2004 Jun 15;140(12):1037-51.
5. Radiation effects on the respiratory system. Hill RP. BJR Suppl. 2005;27:75-81.
6. CRS Report for Congress, Prepared for Members and Committees of Congress, dated July 6, 2009, “Project BioShield: Purposes and Authorities” by Frank Gottron, Specialist in Science and Technology Policy. http://www.fas.org/sgp/crs/terror/RS21507.pdf
7. Overview of likely consequences of a magnitude 6.5+ earthquake in the central United States. J. David Rogers, Missouri University of Science & Technology. http://web.mst.edu/~rogersda/nmsz/Rogers-Consequences%20M6.5+%20Quake%20in%20CEUS.pdf

For an industry segment known for both hope and hype, it is no surprise that stem cell therapies are once again making headlines.  On July 30, 2010, the U.S. Food and Drug Administration [FDA] lifted the clinical hold on Geron Corporation’s (GERN) Phase I trial using its embryonic stem cell-based therapy for the treatment of patients with acute spinal cord injury.  Within days of the news, shares of Geron increased more than 30%, going from $4.80 to $6.39.

More recently, StemCells, Inc. (STEM) announced the publication of preclinical data demonstrating that its non-embryonic stem cell therapy was able to restore lost motor function in mice with chronic spinal cord injury.  The August 19, 2010, news sent shares of StemCells as high as $1.19 compared to the prior day closing price of $0.87 with volume greater than 17 million shares.

While Geron is already in human trials for the acute phase and StemCells plans to initiate its clinical trial in the chronic setting next year, two competitors vying for the treatment of spinal cord injury using allogeneic approaches [“off-the-shelf,” like a traditional pharmaceutical product] highlights yet another risk for investors in the already complex stem cell sector: competition.

In fact, of the mere 15 publicly traded biotechnology companies currently developing stem cell therapies [see Table 1], more than half of them have competing programs in three major disease areas:

• Cardiovascular
• Gastrointestinal
• Central nervous system [CNS]

Accordingly, the purpose of this article is to review the key players in each of these segments and contrast their different approaches.

Cardiovascular – critical limb ischemia

Critical limb ischemia [CLI] is a severe obstruction of the arteries that seriously decreases blood flow to the extremities [hands, feet and legs] and is manifested by pain at rest, non-healing wounds, and tissue necrosis [gangrene].

Three stem cell developers are currently conducting clinical trials with competing approaches for the treatment of CLI:

Aastrom Biosciences, Inc. (ASTM)

Aastrom represents the most advanced clinical stage company that is developing a stem cell therapy for the treatment of CLI.  The company is completing a Phase IIb clinical trial in patients with CLI and interim data were presented at the Society for Vascular Surgery annual meeting.  Similar to Dendreon Corporation’s (DNDN) personalized vaccine for prostate cancer, Aastrom’s procedure is autologous – meaning that a small amount of bone marrow cells are taken from the patient and processed to expand the number of early stem and progenitor cells before being administered to the patient to promote healing of the affected tissues.  In July 2010, Aastrom announced plans to pursue a Phase III clinical program for CLI through the FDA’s special protocol assessment [SPA] process.

Aldagen, Inc. (private, S-1 filed)

Similar to Aastrom, Aldagen is also developing an autologous product [ALD-301] derived from a patient’s bone marrow for the treatment of CLI.  In a 21-patient Phase I/II clinical trial, ALD-301 was well tolerated – although four of the 11 patients in the ALD-301 treatment group and two of the 10 patients in the unsorted bone marrow treatment group experienced serious adverse events that investigators determined were related to the underlying disease [CLI].  Accordingly, the company expects to commence enrollment in a Phase II clinical trial in 2010.

Pluristem Therapeutics, Inc. (PSTI)

In contrast to the autologous approaches by both Aastrom and Aldagen, Pluristem is conducting a Phase I trial of an allogeneic stem cell therapy for the treatment of CLI.  Similar to Celgene Corporation (CELG), Pluristem obtains stem cells for its product from human placenta.  In April 2010, Pluristem reported interim top-line results from Phase I clinical trials of PLX-PAD that demonstrated the cell therapy is potentially safe, well tolerated and effective in patients with CLI.  The company is currently planning two Phase IIb trials in CLI.

Cardiovascular – myocardial infarction

Myocardial infarction [MI] or acute myocardial infarction [AMI], commonly known as a heart attack, is the interruption of blood supply to part of the heart, causing heart cells to die.  Cardiac muscle cells do not have the ability to regenerate, so if enough dead tissue forms, patients suffer heart failure and may eventually die.

Three stem cell developers are conducting clinical trials with competing approaches for the treatment of AMI:

Osiris Therapeutics, Inc. (OSIR)

Osiris is developing Prochymal, one of the most advanced stem cell therapeutic product candidates for the treatment of AMI.  Prochymal is an allogeneic stem cell product derived from bone marrow that is currently being studied in a Phase II clinical trial for the treatment of AMI [ClinicalTrials.gov identifier NCT00877903].  Results from the two-year follow-up of the Phase I clinical trial demonstrated that a single dose of Prochymal administered within 10 days after the patient’s first AMI was safe and well tolerated.  Prochymal also showed significant improvements, including a reduction in chest pain events and cardiac arrhythmias and improvement in cardiac and lung function compared to placebo.  Osiris has partnered with Genzyme Corporation (GENZ) for the development and commercialization of Prochymal.

Athersys, Inc. (ATHX)

Similar to Osiris, Athersys is developing its allogeneic stem cell therapy product, MultiSem®, in collaboration with Angiotech Pharmaceuticals for the treatment of AMI.  MultiStem consists of a special class of stem cells obtained from adult bone marrow or other non-embryonic tissue sources.  In July 2010, Athersys announced positive results from an ongoing Phase I study of Multistem [ClinicalTrials.gov identifier NCT00677222] demonstrating that the product candidate was well-tolerated at all three dose levels studied and also suggested improvement in heart function in treated patients.  Athersys and Angiotech are working on plans for a Phase II trial.

Cytori Therapeutics (CYTX)

In May 2010, Cytori reported results from a European clinical study using its medical device, called the Celution® System, as an autologous treatment for AMI.  As part of the company’s procedure, small amounts of fat tissue are removed from a patient’s abdomen.  Stem and regenerative cells are then separated at the point-of-care and subsequently injected into the patient’s coronary artery.  The six-month results from the fourteen patient, double-blind, placebo controlled trial demonstrated an improvement in the infarct size, the amount of blood supply to the heart muscle, and functional improvement in the amount of blood supply to the heart muscle.  Cytori expects to initiate a 150-250 patient pivotal study for European approval in late 2010 or early 2011.

Gastrointestinal

Crohn’s disease is an inflammatory disease of the intestines that may affect any part of the gastrointestinal tract, mainly causing abdominal pain, diarrhea, vomiting, and weight loss.   There is no known pharmaceutical or surgical cure for Crohn’s disease and treatment options are restricted to controlling symptoms, maintaining remission, and preventing relapse.

Two stem cell developers are conducting clinical trials with competing approaches for the treatment of Crohn’s disease:

Celgene Corporation (CELG)

In April 2010, Celgene Corporation (CELG) reported positive results from a Phase I study of patients with Crohn’s disease receiving PDA-001, an allogeneic stem cell product candidate derived from human placental tissue.  The Phase I trial consisted of 12 patients with active moderate-to-severe Crohn’s who were unresponsive to at least one prior therapy.  Patients received two infusions of PDA-001, with six patients receiving a lower dose of the cells and the remaining six patients receiving a higher concentration.  According to the company, the study met its primary safety goal and demonstrated encouraging signs of clinical benefit, including clinical remission among four patients in the low dose group.  ClinicalTrials.gov currently lists a Phase IIa study with PDA-001 for the treatment of adults with moderate-to-severe Crohn’s disease that is not yet open for patient recruitment [identifier NCT01155362].

Osiris Therapeutics, Inc. (OSIR)

In May 2010, Osiris Therapeutics resumed enrollment in its Phase III trial of Prochymal for treatment-resistant Crohn’s disease [ClinicalTrials.gov identifier NCT00482092].  Enrollment was suspended in 2009 over concerns the trial design would make it difficult to detect a treatment effect with its allogeneic stem cell product derived from bone marrow.  According to the company, an interim analysis of 207 patients enrolled in the study revealed that the difference between the Prochymal and placebo response rates was consistent with the original statistical assumptions of the protocol in one active arm and is significantly outperforming placebo, although it is not clear whether this active arm is the low or high dose Prochymal group.  It is also worth noting that Prochymal previously failed to meet the primary endpoints of two Phase III studies for the treatment of graft-versus-host disease [GVHD].

Central nervous system

Beyond the aforementioned competition between Geron and StemCells in the area of spinal cord injury, two stem cell companies are pursuing treatments for amyotrophic lateral sclerosis [ALS], often referred to as “Lou Gehrig’s Disease.”  ALS is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord, resulting in the loss of muscle control and paralysis.

Neuralstem, Inc. (CUR)

In September 2009, Neuralstem received FDA approval to commence a Phase I trial to treat patients with ALS using its allogeneic stem cell therapy derived from human spinal cord stem cells.  The trial is designed to study the safety of Neuralstem’s cells and the surgical procedures and devices required for multiple injections directly into the grey matter of the spinal cord.

The FDA has approved the first stage of the trial, which consists of 12 patients who will receive five-to-ten stem cell injections in the lumbar area of the spinal cord.  The patients will be examined at regular intervals post-surgery, with final review of the data to come about 24 months later.

Preclinical work has shown that Neuralstem’s cells extended the life of rats with ALS and also reversed paralysis in rats with ischemic spastic paraplegia.

BrainStorm Cell Therapeutics, Inc. (BCLI.OB)

In February 2010, BrainStorm entered into a collaborative agreement with the Hadassah Medical Center to conduct a Phase I/II clinical trial in ALS patients at the Hadassah Ein Kerem Hospital.  BrainStorm’s NurOwn™ technology uses stem cells obtained from adult bone marrow and the company’s research team is among the first to have successfully achieved the in vitro differentiation of adult bone marrow cells into characteristic neuron-like cells capable of releasing dopamine as well as into astrocyte-like cells capable of releasing several neurotrophic factors, including glial-derived neurotrophic factor [GDNF].

Unlike the injections in the lumbar area of the spinal cord, BrainStorm expects that early ALS subjects will receive intramuscular injections into clinically unaffected [or only mildly affected] upper arm biceps and triceps muscles.  Progressive ALS subjects will receive intrathecal cell transplantation via a standard lumbar puncture.

According to the company, BrainStorm initiated manufacturing runs using its proprietary cell growth process in preparation of producing clinical trial materials under good manufacturing practice [GMP] standards at the Hadassah Medical Center GMP facility.  Upon completion of this process, the Phase I/II trial for patients with ALS is expected to begin pending approval from the Israeli Ministry of Health, which BrainStorm expects during the second half of 2010.

Summary

Given their unique regenerative abilities, stem cells offer new hope for treating cardiovascular, gastrointestinal, CNS, and other diseases.  However, with more than half of the 15 publicly traded biotechnology companies currently developing stem cell therapies in three major disease areas, competitive positioning will be an important additional consideration for prospective investors.

Table 1. Stem cell companies

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:

1. Treatment of GvHD remains a large, unmet medical need
2. Low-risk, steroid-sparing approaches are favored in the short-term
3. 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.

Conclusion

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.

Disclosures:

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.