Anand Basu, Reuters
Pluristem is an Israeli company that is publicly traded on NASDAQ and has been working on a “universal donor” stem cell therapy that originates from cord blood mesenchymal stem cells. Key to Pluristem’s intellectual property are a series of patents on three dimensional bioreactors that allow for mass production of these cells. Interestingly, it is unclear to us who holds the intellectual property on the cells themselves. For example, Osiris holds the patents to many types of mesenchymal stem cells, ViaCell holds patents on some of the placental and cord blood mesenchymal cells, Celgene also holds patents on some of the cord blood and Wharton’s Jelly mesenchymal stem cells. Nevertheless, Pluristem has been pushing forward in development treatments, initially for post bone marrow transplant hematopoietic engraftment, and more recently for treatment of the terrible condition critical limb ischemia, which causes amputations in approximately 150,000 patients per year in the USA. Currently Pluristem planning to conduct its Phase II/III trials for critical limb ischemia in the second part of 2011. Given the success of the company in its clinical development programs, the CEO Zami Aberman recently announced that they will be working on their own towards commercialization. This is in contrast to other deals that we have seen in the recent past, such as the $1.7 billion deal between Pharma company Cephalon and the Australian stem cell company Mesoblast.
The ability to general large number of mesenchymal stem cells is a very important feature that gives the company a competitive edge over others in the space. Specifically, the use of bioreactor technologies allows for much higher production yields and a lower cost of production. Although the patent situation is somewhat uncertain for Pluristem, at the end of the day, numerous jurisdictions do not allow patenting of cells, so it may be feasible that the bioreactor patents that Pluristem has may be sufficient to protect the company as it is growing.
Mr. Aberman stated in a recent interview with Reuters “We do not need to raise money and we have sufficient capital to move the company to the end of Phase III studies,” Pluristem, which raised about $38 million in a public offering last month, plans to start a Phase II/III trial in both Europe and the United States to treat critical limb ischemia (CLI) in the second half of the year. He continued “We have been approached by a variety of pharmaceutical companies interested in cooperating not only on CLI but (also) for additional indications like inflammatory bowel disease, multiple sclerosis and orthopedic indication. However currently we are focusing on finding a marketing partner once our pivotal trials are underway. ”
In contrast to other companies that are working in this space and require processing of the patient’s own bone marrow as a source of stem cells, the Pluristem approach revolves around the concept of universal donor stem cells that are stockpiled and ready for use.
“The fact that we can do the treatment on demand because we have an off-the-shelf product is crucial, since CLI patients require immediate treatment,” Aberman said.
There have been previous studies performed in critical limb ischemia using mesenchymal stem cells. Mesenchymal stem cells can be used either autologous or allogeneically (meaning from another donor). Below we will list some of them.
For example, In 2010 Lasala et al reported combination cell therapy including EPCs and mesenchymal stem cells (a source of pericytes progenitors and angiogenic regulators) may represent a preferential stimuli for the development of blood vessels. In this phase I clinical trial, patients with LI were infused with a cell product consisting of autologous bone marrow-derived mononuclear and mesenchymal stem cells. After 10 2 months of follow-up, efficacy assessment demonstrated improvements in walking time, ankle brachial pressure, and quality of life. Concomitantly, angiographic and 99mTc-TF perfusion scintigraphy scores confirmed increased perfusion in the treated limbs. These results show that the use of a combination cell therapy appears to safe, and feasible in patients with CLI (Lasala, G.P., et al., Combination stem cell therapy for the treatment of severe limb ischemia: safety and efficacy analysis. Angiology, 2010. 61(6): p. 551-6.).
It was previously demonstrated in a rat model of critical limb ischemia that MSC are superior to bone marrow mononuclear cells in terms of angiogenic potency and limb preservation. This was suggested to be in part based on the ability of MSC to withstand the ischemic environment better than bone marrow mononuclear cells, as well as their ability to differentiate not only into endothelium but also smooth muscle (Iwase, T., et al., Comparison of angiogenic potency between mesenchymal stem cells and mononuclear cells in a rat model of hindlimb ischemia. Cardiovascular research, 2005. 66(3): p. 543-51). A comparison between bone marrow mononuclear cells and bone marrow MSC was made in 41 patients with CLI who had type II diabetes. The ulcer healing rate of the BMMSC group was significantly higher than that of BMMNCs at 6 weeks after injection (P=0.022), and reached 100% 4 weeks earlier than BMMNC group. After 24 weeks of follow-up, the improvements in limb perfusion induced by the BMMSCs transplantation were more significant than those by BMMNCs in terms of painless walking time (P=0.040), ankle-brachial index (ABI) (P=0.017), transcutaneous oxygen pressure (TcO(2)) (P=0.001), and magnetic resonance angiography (MRA) analysis (P=0.018). There was no significant difference between the groups in terms of pain relief and amputation and there was no serious adverse events related to both cell injections. The authors concluded that BMMSCs therapy may be better tolerated and more effective than BMMNCs for increasing lower limb perfusion and promoting foot ulcer healing in diabetic patients with CLI (Lu, D., et al., Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: A double-blind, randomized, controlled trial. Diabetes research and clinical practice, 2011).
The ability to use universal donor cells in the context of critical limb ischemia is advantageous in that the bone marrow of patients does not need to be punctured. Usually patients with critical limb ischemia have numerous co-morbidities that makes bone marrow aspiration extremely difficult. Additionally, it is almost impossible to performed secondary transplants. In the area of critical limb ischemia, it may be important to perform multiple injections for additional therapeutic effects. Another advantage of universal donor cells is that many times the bone marrow of patients with critical limb ischemia are insufficient in ability to produce cytokines or stimulate angiogenesis in vitro or in vivo. The administration of selected cells that are purified for maximal potency possesses a therapeutic advantage. Disadvantages of the Pluristem approach include the possibility of knock-off technologies due to the lack of a patent on composition of matter on the cells. Worse yet, companies such as Celgene and now PerkinElmers possess intellectual property on cells derived from the placental matrix. It will be interesting to see how these patents play out in terms of enforceability.
Pluristem to develop stem cell therapy on its own: CEO
Pluristem to take part in EU stem cell study
(Shiri Habib-Valdhorn, Globes [online], Israel business news) Broadly speaking there are two types of adult stem cell therapies: Those that involve the use of the patient’s own stem cells, called autologous, and those that involve use of another patient’s cells, called allogeneic. There are pros and cons to both approaches.
In the autologous approach the main advantage is that because the cells come from the same patient, there is no issue of immunological rejection or fear of contamination from another person’s infectious agents. The drawbacks with autologous approaches include: a) the fact that stem cell extraction, manipulation, and re-administration requires expensive and laborious procedures, as well as the need for equipment that is not commonly available at most hospitals; b) patients with a variety of disease conditions often have defective stem cells that work suboptimally as compared to stem cells from healthy patients; and c) many times the procedure for extracting the patient’s own stem cells involves painful procedures such as bone marrow aspiration, or potentially dangerous procedures such as stem cell mobilization. This allows the procedure to be performed only for a limited number of times.
The allogeneic stem cell therapy approach has the advantage of using cells that have been generated in large quantities for a specific function and biological activity. This means that the cells used are of a certain quality standard. Additionally, the allogeneic approach does not require complex cell manipulation procedures since the cells are shipped frozen to the point of care. Allogeneic cells can be administered on multiple occasions to the patient if needed. The downside of allogeneic cell therapy is the potential for immunological rejection, as well as patient sensitization. The sensitization of the patient to allogeneic cells may not allow for future use of the stem cells, as well as preclude the patient from bone marrow transplantation.
Pluristem Therapeutics Ltd. (Nasdaq:PSTI; DAX: PJT) is an Israeli company that trades on NASDAQ which is focused on generating allogeneic, “off the shelf” cellular products from placental cells using a proprietary bioreactor device. Originally Pluristem was working on using these stem cells to accelerate bone marrow engraftment after transplantation.
The process of bone marrow transplantation involves administration of chemotherapy and/or radiation to patients with blood malignancies in order to destroy the abnormal cells of the recipient, followed by injection of healthy donor blood making cells (hematopoietic stem cells) in order to provide to the recipient a new immune system. While this procedure has saved thousands of lives, one of the major drawbacks is that the donor cells sometimes take weeks, if not months, to start producing new blood cells. The use of donor cord blood has also been tried in this context experimentally, however, cord blood takes even longer than bone marrow to “engraft” in the recipient. Pluristem believed that its cells produce various growth factors that accelerate the process of engraftment.
In 2009 Pluristem began using its cells for the treatment of critical limb ischemia. This disease is a manifestation of advanced peripheral artery disease characterized by non-ceasing pain, ulcers, and a high rate of amputation. Given that the Pluristem cells produce high amounts of various growth factors, the concept is that administration of these cells into the muscles of patients with critical limb ischemia will result in production of new blood vessels, which will provide increased circulation to the legs of these patients. Other companies such as Medistem Inc are also using allogeneic cells, albeit from different sources (menstrual blood endometrial regenerative cells), for the treatment of this condition.
Recently Pluristem was chosen as one of 19 companies from 12 countries that will participate in a placenta stem cell study financed by EU Seventh Framework Progamme for Research and Development.
The study will be conducted concurrently at 12 European medical centers to examine the effect of placenta stem cell treatments on several kinds of heart cells that are damaged by high blood glucose levels caused by diabetes. The study will examine whether placenta stem cell-based anti-inflammatory agents can prevent or delay the onset of diastolic heart failure (DHF) among diabetics.
This is a new indication for Pluristem’s PLX (PLacental eXpanded) cell therapy product. The company will be allotted $150,000 from the Seventh Framework Progamme for R&D to cover the cost of the research and to develop the stem cells for the program.
Pluristem chairman and CEO Zami Aberman said, “There has been a growing interest in the potential of PLX cells to treat a variety of clinical indications following the release of the PLX-PAD clinical study interim results, which demonstrated safety and shows a trend of efficacy. The decision to use our PLX cells in this DHF study is further verification of the uniqueness of Pluristem’s PLX cells as an off-the-shelf product that requires no tissue matching prior to administration. There is a significant unmet medical need for the treatment of DHF, not only in Europe but also globally, and Pluristem’s placenta-derived cell therapy may provide patients and physicians with an effective and safe treatment option for this disease.”
The use of mesenchymal stem cells for treatment of cardiac diseases has previously been reported by Medistem Inc and Osiris Therapeutics.
