Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications
More firms stepping into Phase I should counter pessimism from mid- and late-stage clinical trial upsets.
Even as regulatory agencies express abundant caution, adult stem cell therapies are moving steadily toward the clinic and through development for multiple applications. Investors have become more sophisticated about distinguishing between adult stem cell therapies and embryonic stem cell therapies as well as the potential risks, complications, and costs involved in each.
Osiris is a contender to be the first to obtain positive Phase III results for an adult stem cell product. In May the company restarted patient enrollment into a late-stage trial evaluating Prochymal in patients with treatment-resistant Crohn disease; the trial was stopped in March 2009 due to concerns that there was a flaw in the trial design. In February, though, Osiris reported that it showed potential when used as a rescue therapy in children suffering from severe treatment-resistant graft vs. host disease (GvHD). The product is also in Phase II trials in heart attack, type 1 diabetes, and COPD patients.
The development path for Prochymal, derived from mesenchymal stem cells, has not been easy. This will not come as a surprise since most new complex technologies face similar hurdles. The therapy previously failed in late-stage trials in steroid-resistant GvHD and acute GvHD. Osiris thus has a close eye on meeting all its clinical endpoints in the Crohn disease trial to stand the best possible chance of being the first to enter the market with an adult stem cell-based therapy.
In Late-Stage Trials
TCA Cellular Therapy has six stem cell-based clinical trials including a Phase III study in limb ischemia. The company hopes to gain FDA approval for the condition in 2012. In January the FDA approved the protocol for a Phase I trial in amyotrophic lateral sclerosis (ALS). “We only need to enroll six ALS patients but need to wait two weeks between each intrathecal transfusion of the cell preparation,” Janet Jones, Ph.D., COO of TCA, told GEN. “We think we will have preliminary results within the next six months.”
TCA’s stem cell therapy uses one or both of two types of bone-marrow derived adult stem cells. For central nervous system (CNS) indications, mesenchymal cells obtained from the patient’s bone marrow are separated, purified, tested, and then expanded in vitro to several million cells. For cardiac and vascular conditions mesenchymal cells are mixed with the patient’s mononuclear cells obtained from a bone marrow aspiration. Results reported in May from a Phase I study treating patients after acute myocardial infarction (AMI) suggested that development of new capillaries could be a leading event involved in the improvement observed in patients six months post treatment.
Phase I Candidates
Athersys is also taking on AMI with Multistem, which is obtained from adult bone marrow or other nonembryonic tissue sources. In February Athersys completed patient enrollment in a Phase I trial. Results are expected mid-year upon completion of a four-month patient follow-up period and analysis of results. Athersys reports that it also received clearance to initiate a clinical trial in patients who have suffered an ischemic stroke. Multistem, which is an allogeneic stem cell-based product, is also being studied as an oncology treatment support as well as in a range of conditions involving immune system function.
StemCells is trying to tackle CNS disorders with neural stem cells. It uses a library of mAbs against cell surface antigens to identify, purify, and characterize the stem cells of interest, which are then sorted and tested in vitro or in vivo. Purified populations of stem cells are then expanded, banked, and retested in vivo.
The company says that its lead candidate, HuCNS-SC, can adapt in host brain environments and behave like host neural cells, dividing, migrating, and differentiating. And because cells are normal, genetically unmodified, and highly purified human CNS stem cells, they may prove safer and more effective than unpurified mixtures of cell types, it adds.
In November 2009, StemCells begun a Phase I study in Pelizaeus-Merzbacher disease, a myelination disorder that primarily affects young children. And on April 27, StemCells submitted a protocol to the FDA for initiation of a second clinical trial in neuronal ceroid lipofuscinosis, a brain disorder seen in children.
On May 7, Cytori Therapeutics reported results from its clinical trial using adipose tissue-derived stem and regenerative cells (ADRCs), prepared using the company’s Celution device. The cells were tested in 27 patients with chronic myocardial ischemia. The trial demonstrated a statistically significant improvement in several measures of cardiac function including maximum oxygen consumption and patients’ aerobic capacity measured as metabolic equivalents. The treatment also reduced the extent of infarct size in the left ventricle.
ADRCs, also called stromal vascular fraction cells, consist of a heterogeneous or mixed population of cells found in adipose tissue, including adult stem cells, endothelial progenitor cells, leukocytes, endothelial cells, and vascular smooth muscle cells. The Celution device allows relatively easy access to the adipose tissue via liposuction and then separation of these cells without the need for cell culture, Cytori explains.
While stem and progenitor cells usually make up less than 5% of all ADRCs, this is 2,500-fold more than such cells in tissues such as bone marrow (0.002%). Also, the abundance of ADRCs in adipose tissue and the ability to easily collect large amounts of adipose tissue via liposuction at the point of patient care eliminates the need for tissue, says the company.
Cytori says that its technology will be regulated as a device. It plans to file an investigational device exemption (IDE) application by the end of this year to initiate a clinical trial, although the indication has not been decided. An IDE allows a device to be used in a clinical study to collect safety and efficacy data to support a PMA application or a 510K submission to the FDA.
In May the company was notified by the agency that it will be required to conduct a clinical program prior to final approval of the Celution System. Cytori’s device is currently marketed in Europe and Asia for reconstructive surgery applications.
Placenta as a Source
Celgene uses human placenta-derived cells obtained through its proprietary processes. It too is investigating therapy-resistant Crohn disease with PDA-001 in Phase I. Celgene CEO, Robert Hariri, told GEN, “We believe that the placenta provides an ideal source of highly diverse stem cells. While we have advanced only one type of cell derived from the placenta, we have recovered several classes of cells with many different phenotypes.”
Dr. Hariri further points out that “what is particularly interesting is that the placenta is a foreign tissue accepted by the mother, a foreign tissue that resides in the host without rejection. This is due to specific molecular mechanisms in the placenta that induce a state of tolerance in the mother, unique enzymes in the placenta, and surface markers that prevent T-cell mediated organ rejection.”
The company has reportedly developed a highly scalable process for collecting placental cells. Hariri says that the objective is to “pharmaceuticalize” human cells to create a highly consistent product that can be easily delivered by physicians by the same systems that are currently in use.
On April 8, Celgene reported that positive results from a Phase I study. Twelve patients with moderate-to-severe Crohn disease who were unresponsive to at least one prior therapy were given two infusions of PDA-001 one week apart. The study met its primary safety goal and demonstrated encouraging signs of clinical benefit, including clinical remission among four patients out of six in the low dose group, the company said.
The interest in stem cell technology is evident and companies have deals to show for it, Ren Benjamin, a senior biotech analyst from Rodman & Renshaw, pointed out to GEN. For example, Osiris has a collaboration with Genzyme, and together they have a contract with the DoD. The firm also has deals with JCR Pharmaceuticals and Boston Scientific. Athersys has strategic partnerships with Pfizer and Angiotech. Cytori has agreements with GE Healthcare, Green Hospital Supply, and Olympus related to its devices including Celution, StemSource® 900/MB Tissue Processing System, and StemSource® 9000 series Cell Bank.
While setbacks that occur in mid- and late-stage trials certainly serve to temper investor enthusiasm, the fact that more small biotech companies are getting the go-ahead to move these complex therapies into clinical development is a good sign. “Biotechnology moves forward in baby steps, and stem cell technology isn’t any different,” Benjamin noted. Further clinical investigations will bear out the risks associated with these products and, in turn, fine-tune stem cell technology in general. Issues such as tumorgenicity and immunorejection still need to be worked out and carefully regulated.
Patricia F. Dimond, Ph.D., is a principal at BioInsight Consulting. Email: [email protected].