According to the National Institutes of Health’s [NIH] stem cell primer, stem cells have the ability to develop into many different cell types in the body during early life and growth. In many tissues they serve as an internal repair system, dividing essentially without limit to replenish other cells. When a stem cell divides, each new cell has the potential either to remain a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell.
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:
- 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. 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 a 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.
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 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.
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.
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
|Company||Cell Type||Source||Type||Latest Phase||Disease(s)|
|Aastrom Biosciences||Non-embryonic||Bone marrow||Autologous||Phase IIb||Critical limb ischemia|
|Aldagen (private, S-1 filed)||Non-embryonic||Bone marrow||Autologous||Phase I/II||Critical limb ischemia|
|Advanced Cell Tech [ACTC.OB]||Embryonic||in vitro fertilized blastocysts||Allogeneic||Phase I/II||Stargardt’s macular dystrophy|
|Athersys||Non-embryonic||Bone marrow||Allogeneic||Phase I||Acute myocardial infarction|
|BioHeart [BHRT.OB]||Non-embryonic||Thigh muscle||Autologous||Phase II/III||Congestive heart failure|
|BrainStorm||Non-embryonic||Bone marrow||Autologous||Pending approval||ALS|
|Celgene||Non-embryonic||Placenta||Allogeneic||Phase I||Crohn’s disease|
|Cytori Therapeutics||Non-embryonic||Liposuction||Autologous||Phase I||Acute myocardial infarction|
|Geron||Embryonic||in vitro fertilized blastocysts||Allogeneic||Phase I||Spinal cord injury|
|Int’l Stem Cell [ISCO.OB]||Non-embryonic||unfertilized parthenogeneticaly activated oocytes||Allogeneic||Preclinical||Age-related macular degeneration|
|NeuralStem||Non-embryonic||Spinal cord of 8-week fetus||Allogeneic||Phase I||ALS|
|Opexa Therapeutics (OPXA)||Non-embryonic||Peripheral blood||Autologous||Preclinical||Diabetes|
|Osiris Therapeutics||Non-embryonic||Bone marrow||Allogeneic||Phase III/II||Crohn’s/Acute myocardial infarction|
|Pluristem Therapeutics||Non-embryonic||Placenta||Allogeneic||Phase I||Critical limb ischemia|
|ReNeuron Group plc||Non-embryonic||n/a||Allogeneic||Phase I in UK||Ischaemic stroke|
|Stem Cells||Non-embryonic||Fetus||Allogeneic||Preclinical/Phase I||Spinal cord injury/Batten Disease|
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