Stem cell companies have languished long enough in micro-cap territory. The industry is now approaching highly visible Phase II and Phase III catalysts that will produce results never before seen in medicine. Managing Director and Senior Biotechnology Analyst Jason Kolbert of the Maxim Group has staked out a select group of nascent cell therapy companies positioned to reap huge gains for investors willing to diversify. In this interview with The Life Sciences Report, Kolbert reflects on the regenerative medicine space following the recent RegenMed Investor Day conference, and makes an enthusiastic case for his very best ideas.
The Life Sciences Report: Jason, I enjoyed the RegenMed Investor Day conference on April 17 in New York City, which was sponsored by the Alliance for Regenerative Medicine [ARM] and co-hosted by your firm, the Maxim Group, with Burrill & Company and Piper Jaffray. The conference was clearly oversold, and there appeared to be roughly twice the number of people originally expected. Could that meeting have been an inflection point at which investors decided that the stem cell field is worth looking at?
Jason Kolbert: Thank you very much, George. The answer is yes, I think it was a watershed event. I don't think this conference would have been possible two or three years ago. But today we have companies like Mesoblast Ltd. (OTCPK:MBLTY), which has a market cap of under $2 billion [$2B] with $332M on its balance sheet, and which is partnered with Teva Pharmaceutical Industries Ltd. (NYSE:TEVA) in a global, pivotal, 1,700-person trial in congestive heart failure [CHF]. The trial is getting ready to launch, so institutional clients covering Teva came to the RegenMed meeting. That's something we wouldn't have seen two or three years ago because clinical trials in cell therapies were not mature enough.
Companies are also maturing on the oncology/immunology side. Dendreon Corp. (NASDAQ:DNDN) seemed like an isolated example three years ago, but today it is not unusual to hear of a Phase II cell therapy trial. In fact, talk of pivotal trials in regenerative medicine is beginning to be commonplace. Whether it's wound-healing, with the work that Shire Plc (NASDAQ:SHPG) is doing, or the clinical trials in CHF that Mesoblast is doing, it's clear the space is maturing.
TLSR: Jason, I want to ask you about the U.S. Supreme Court case that was heard on April 15. The Association for Molecular Pathology v. Myriad Genetics Inc. is being litigated to determine if human genes are patentable. You'll recall that a year ago the High Court affirmed, in Mayo Collaborative Services v. Prometheus Laboratories Inc., that laws of nature are not patentable. But federal circuit panels have twice ruled that the DNA sequences, BRCA1 and BRCA2, which Myriad Genetics Inc. (NASDAQ:MYGN) has isolated can be patented. Do you have a take on this?
JK: I do. In the world of regenerative medicine, or even in oncology, how do you patent these products? Let's take a look at Dendreon and its product, Provenge [sipuleucel-T] for prostate cancer, which was approved at the end of April 2010. It was the first cellular immunotherapy, or therapeutic vaccine, approved by the U.S. Food and Drug Administration [FDA]. Provenge is a dendritic cell, but it's been highly processed. It has been modified to elicit a T-cell response that targets the prostate-specific antigen [PSA]. That processing does come with intellectual property [IP].
TLSR: I want to relate this to cell therapy, which could be thought of as a natural product.
JK: We can extend the analogy to what a company like Mesoblast is doing with mesenchymal precursor cells [MPCs]. It uses monoclonal antibodies to select the cell type, and then it goes through a very proprietary process through which it expands the cells. While the individual cell may exist in nature, the concentrated dose-the final product being delivered to patients-does not exist in nature.
A company can't necessarily patent a mesenchymal cell, but certainly the process, the method of use and, in some cases, the composition of the final product can be patented. Of course, there will be emerging patent battles among players in the space. If we compare what Osiris Therapeutics Inc. (NASDAQ:OSIR), Pluristem Therapeutics Inc. (NASDAQ:PSTI) and Mesoblast are doing, they all have different variations of an allogeneic product [using cells from the same species]. But there is enough proprietary IP in what they're doing that these products can be treated like traditional pharmaceuticals with regard to their proprietary natures.
TLSR: This question is highly theoretical, but let's assume that two companies come along and segregate or isolate the same mesenchymal stem cell [MSC] using different techniques, perhaps isolating the cell by targeting different antigens on the cell membrane. But they end up with the same cell. A company can certainly concentrate the cells for a certain dose or apply different excipients to the formulation, but assuming it is the same cell, what happens then?
JK: That's a great point. Cytori Therapeutics Inc. (NASDAQ:CYTX) is isolating autologous cells [derived from the patient] from a stromal vascular fraction of adipose [fat] tissue using a collagenase enzyme to produce a proprietary product. Is it possible that someone else, through a different method, could produce a similar product, if not one that is virtually identical? The answer is yes, that's absolutely possible. There is probably more than one way to isolate a stromal vascular fraction. Enzymatic digestion with centrifugation, as in Cytori's case, is one way. Direct sonification, using no enzymes, is another technique that some clinicians today are utilizing, under practice-of-medicine rules.
It ultimately comes down to which process is faster and cheaper, which process has gone through a regulatory approval process, and as such can have a label and can make certain claims.
Let's take a moment and think about the regulatory process. This allows the company to make its product claims, to describe the therapeutic benefit of the product. A company must run a clinical study to demonstrate that its product is equivalent in terms of claims. As is true for biologics, the pathway for generic versions is not simple. Many companies will not be able to accomplish what Mesoblast has, for instance. It is conducting a $130M, two-year pivotal trial, and in doing so, creating a hurdle for the competition. Mesoblast is saying, in effect, "If you want to bring an allogeneic cell therapy forward for CHF, you're going to have to do a 1,700-person clinical trial."
Once a company has a label and a claim, as well as supporting IP, it then has a real commercial product. Of course, there will always be investigators and even clinicians who will treat patients with cells themselves [in the autologous world]. Cytori's process actually enables these doctors to try cells with a proven process.
TLSR: Most times the list of claims in a patent is very long, and will include things like mechanism of action, targets, production, et al. If you can make those claims specific enough, you are building a wall around that therapeutic.
JK: That's exactly right. Having specific claims backed up by clinical data and supported with IP builds a wall. That's what makes longevity for a product.
TLSR: One general concern is that I never hear anyone suggest a potential problem with re-administration of allogeneic cells to the same patient. In an eight-week period, a patient can develop antibodies to cell surface antigens, and there is the potential for an anaphylactoid response. I'm guessing that so far it hasn't been a problem. How do we deal with this?
JK: Most of those who raise red flags about retreatment with allogeneic cells are the autologous players. I absolutely agree that a person's own cells are safe. However, there are increases in time, processing, patient inconvenience and cost associated with an autologous product versus an allo product. Allo products are "off the shelf" and therefore relatively cheap, and can be administered when needed, like a drug taken off the shelf. I understand why autologous makers might maximize allogeneic risk.
The reality, based on my conversations with allogeneic companies, is that they have not seen immune reactions and, in fact, have demonstrated that their products demonstrate a degree of immune privilege.
At the end of the day, I personally believe that, whether autologous or allogeneic, cells go to the target area, exert their local effects and leave. In other words, even autologous cells are not necessarily integrating into the heart or other tissues and organs. The cells are acting as microdrug factories that show up, do the job, impact the surrounding [local] environment and leave.
TLSR: Let me turn that question around a bit and go to the topic of autologous therapies. I wonder if there's much thought given to the fact that the disease phenotype we're treating with autologous materials has been caused by the genotype contained in the same cells that we're giving back to these patients. In my mind this would certainly be a concern in cardiovascular and neurodegenerative diseases, which are surely heritable.
JK: That's a great question. Let me rephrase it: Is the condition of the patient a factor in the state of his or her own cells? Clearly, if we talk about Mesoblast, Pluristem or Osiris, we're talking about allogeneic cells that come from young, healthy donors. These are not people who are 60 or 70 years old, who have diabetes or multiple comorbidities. There are arguments both ways. Clearly, the autologous companies try to maximize the allogeneic immune risks that you asserted in the previous question, and the allogeneic companies try to maximize the host comorbidity, cell-vitality argument. To the question about the risk of administering same-genotype cells that could produce the same disease phenotype, the allo companies will say that this is where they shine versus the auto companies, where this is a risk.
One consideration that does seem to be emerging is that cells sourced from adipose tissue, as in the Cytori model, seem to be healthier than cells sourced from marrow. A company like Cytori may have a strategic advantage by using an adipose-sourced cell. But this has not been proven to be a factor in a clinical trial, and it's only through clinical trials that we're going to be able to answer this argument.
TLSR: If we could talk about some companies, that could be great. Would you talk about your best ideas?
JK: Of course. I want to make a few comments first on how we come to these ideas. After the ARM meeting we updated and republished our cardiology overview report. This was a wonderful exercise because it forced me to think logically on not just whether I like a company, but what the logic flow tells me. I wanted to make a few important arguments to help me sort out the space.
This was the first question I considered: homogeneous or heterogeneous? In other words, is it better to give a concentrated dose of one cell type, or is it better to have a mixture of cells? I can't answer this. No one can answer it emphatically without clinical data.
If you believe that an effect is driven solely by the trophic capacity of a single cell type [the robustness of that cell as a local drug factory], then you're in the homogeneous camp. If that turns out to be true, it's my opinion that allo wins. If allo wins, that tells me that Mesoblast, Pluristem and even Osiris are potentially big winners in this space.
But if we separate those companies, Mesoblast is the leader in the space because it has approximately $332M in cash [as of the last reported, year-end 2012 results and including a Q1/12 raise]. It has a great partner in Teva, which is paying for not only its Phase III trial for CHF but also an expanded Phase II trial with an increase the patient numbers to give it even greater significance. That trial is evaluating patients who experience an ST-elevated myocardial infarction, which then results in CHF [STEMI-induced CHF]. Given the cash balance and the strength of Teva as a partner, it is going to be hard to beat Mesoblast.
Now, what if it is that the elements of a heterogeneous population-the multiple cell types-provide maximal efficacy? This is the opposite of a homogeneous population of cells, which depends on the trophic capacity of one cell type. If that turns out to be true, it means that companies such as Cytori are potential big winners. Why? Well, Cytori uses a patient's own cells, a heterogeneous mixture of cells, rapidly processed on site from that patient's own adipose tissue.
Personally, as an analyst and a scientist, I tend to believe that allogeneic looks good [based on the total picture], and that homogeneous therapy probably will give patients enough of an effect to be approved. Of course, clinical data is what will matter. But so will patient convenience, cost of goods and availability. When I look at some of Mesoblast's data, particularly in rheumatoid arthritis [RA], what I see is the capacity of a mesenchymal precursor cell to change the way it functions based on its environment. In other words, when that cell is in an ischemic environment, it can produce cytokines that promote neoangiogenesis [new blood vessel formation]. When that cell is in an inflammatory environment, like an arthritic knee, it can down-regulate that inflammation. It can influence the status of T regulatory cells and T effector cells. The right cells can act a bit like chameleons-and I'm not saying that they change their cell types, because that would be an argument about pluripotent cells [stem cells with the ability to differentiate into other cell types, like an MSC cell that becomes a neuron, an astrocyte or an oligodendrocyte]. Instead, these cells are influenced by their local environment and modify their responses based on what is needed. Based on that data, it seems that while there may be certain efficacy advantages to a heterogeneous population of cells, you may get the majority of those advantages with the right homogeneous cell population.
TLSR: Jason, bring these thoughts together for me. How will the winners be determined?
JK: I use the SWOT analysis-strengths, weaknesses, opportunities and threats. It's about the cost of goods sold [COGS], patient convenience and cells being readily available-like the pills-in-a-bottle pharma or drug model, which becomes critical when we talk about reaching a large market. When we talk about cardiovascular disease, the last thing we want to do, because the market is so large, is a highly personalized, expensive approach. Here's where Cytori shines, because it provides basically the best of both worlds. It has an autologous process with allogeneic-like COGS. That is going to be important as investors and analysts look at Mesoblast and watch Pluristem and Cytori as examples. Those are some of the leaders.
Data is the real driver for biotechnology companies. Let's take a look at who might have data ahead. We are going to see data on ulcerative colitis from its trial with partner Pfizer Inc. (NYSE:PFE), and we're going to see data from its unpartnered Phase II ischemic stroke trial.
Of course, Mesoblast just reported strong data, not in the cardiovascular space but in degenerative intervertebral disc disease or DDD. It showed a high efficacy rate with an associated p-value, or a statistically significant result, which demonstrates it's not just luck. This, combined with a small trial [the size of the trial impacts the ease or difficulty by which a statistically significant result can be demonstrated, which it wasn't originally powered to show] tells me that these cells are really working. In addition, the result is further supported by two earlier trials in a related but different indication, spinal fusion. The two trials reported at the end of last year showed the cell therapy worked just as well as autologous bone graft to successfully fuse a spine.
We're beginning to see multiple indications open up among these companies: Mesoblast in CHF, orthopedics, systemic indications such as rheumatoid arthritis and diabetes, as well as a local indications such as wet macular degeneration; and Cytori in chronic myocardial ischemia. I think these are clearly the leaders in the regenerative medicine space, and they're going to be exciting for investors to watch.
I don't want to leave our discussion on cell therapy without at least touching on cancer. Let's discuss ImmunoCellular Therapeutics Ltd. (NYSEMKT:IMUC). This small company is one of my favorites. Its Phase II trial in glioblastoma multiforme is now completely enrolled, and we're waiting for data. What does that mean? It means that the active arm and the control arm have now been treated. If people are living longer in the treated therapy group-statistically and meaningfully longer-then it's transformative for this company.
This is a dendritic cell therapy, very similar to Dendreon's Provenge. But it is different in two key ways. One, the cells can be cryopreserved, so in one apheresis setting, you can make multiple doses. Thus, the COGS is a fraction of what it is for Provenge. It is also different because it targets multiple antigens-six actually-that are expressed by a tumor, whereas Provenge only targets the prostate-specific antigen. Coupled with the unmet medical need in glioblastoma and the orphan nature of that indication, this could be a very exciting story.
TLSR: Let me ask a couple of specific questions about these companies. Cytori has a machine called the Celution System, which processes a liposuction aspirate into cells in a syringe in 60-80 minutes. I don't understand the business model. The Celution System costs $100,000, or the company leases it. Does Cytori charge a license fee for each batch of cells processed?
JK: I don't believe that Cytori has clarified its business plan, specifically. We know the plan is not selling capital equipment. Every time the machine is used, a consumables package must be purchased. So the question is, if you are processing a lipoaspirate for chronic myocardial ischemia [CMI], is that a different consumable package with a different price point than, say, a package for breast reconstruction or burns? I think the answer is yes, that different packages will go with each application, and there will be different margins.
But because the Cytori process is so cost-effective, I believe it is going to be able to have biotech-like margins, at a very attractive price point that will be priced on a per-use basis for the machine. I don't know if there will be a license fee associated with each use of the machine, or whether a fee will be built into the consumable products. I tend to believe the latter. But every time a product is manufactured, there will be a charge associated with it.
TLSR: Going to Mesoblast, since the company is just starting its 1,700-patient Phase III trial in CHF, it's three years away from any good data on that indication. I'm thinking that one of the big value drivers for the company right now is intervertebral disc disease. I wonder if there's evidence that mesenchymal precursor cells can add vertical dimension to these diseased cartilaginous discs. I understand how the injected cells might reduce the inflammatory process and therefore reduce pain, but what about actually restoring the surfaces of these disks? Theoretically, if you can increase the vertical dimension on these discs by adding cartilage, it could reduce nerve encroachment. What is the treatment theory?
JK: The answer is complex. In the data that Mesoblast announced, it showed a statistically significant result in terms of the pain score. In the ovine [sheep] model-and we want to be fair because that's a quadruped versus bipedal humans, where gravity has a different effect-the therapy showed a restoration of vertebral height. If the Mesoblast MPCs show a restoration of vertebral height in humans, many orthopedic surgeons have told me that would be the Holy Grail. It may take more than six or 12 months for a human result to be seen. These patients are going to be followed at six-month intervals for the next three years.
We don't know whether we're going to see the restoration of vertebral height produced in humans. But let's think about what we do know. In the Mesoblast trial, I think it's important for investors to recognize that the patients who were treated were refractory to steroids. In other words they have already failed treatment with steroids. Repeated steroid injections can actually start to damage the disk.
TLSR: Steroid necrosis.
JK: Yes. So the fact that there is a reduction in pain at six months is an important sign-and remember, from a regulatory standpoint, pain reduction is an approvable endpoint.
What you're really asking me is whether these cells are disease-modifying. Will they change the course of the patient's disease? Unlike the ovine model, where you're inducing disc disease and it's therefore acute, the people in the trial have developed a degenerative disc over a long period of time-30, 40 or 50 years. It is unlikely that can be reversed in three or six months. It may take time. Repeated doses may be needed. But I do believe that the pain result from this trial bodes extremely well for what we're going to see as we follow these patients out to the next time interval. I'm hopeful.
TLSR: We saw StemCells Inc. (NASDAQ:STEM) CEO Martin McGlynn at the RegenMed conference talking about his company, which is dealing with spinal cord injury and lysosomal storage disorders with its HuCNS-SC adult stem cells of embryonic origin. Do you follow this company?
JK: I do. I admire the work that Martin McGlynn has done and, specifically, the investigators at the company-Dr. Stephen Huhn and Dr. Ann Tsukamoto. This company operates at the next level of cell therapy. When I talk about mesenchymal cells and the trophic effects, it's exciting. But when I talk about potentially pluripotent cells and the ability for cells to remyelinate a demyelinating disorder like Batten disease, or to impact dry macular degeneration, or to impact the outcome in spinal paralysis ... we're talking about the next level of science.
While it's been painstakingly meticulous, with the science and evolution of the field taking a long time, the way that StemCells is going about its clinical trials and developing its product and its cell line has been brilliant. I think it is a true leader in the field. When we look central nervous system [CNS] disorders, we should look at companies like StemCells-and the way it is accomplishing its science-as the right way to do things.
TLSR: As you are aware, the StemCells' scientific model is different from other companies, where cells are used in a drug-like model for their paracrine effects. StemCells has shown, on autopsy, durable engraftment of the human neurons that have been implanted in the brains of children with lysosomal storage disorders. It is very interesting work.
JK: That's exactly right. And it's a very different business model as well. If you're paralyzed and you've lost all sensation, you could potentially regain some sensation or maybe even regain some control [bladder control, for example] if treated with a StemCells product. That would have a huge impact on a patient's quality of life. This company is doing pioneering work.
Investors will see a lot of breakthroughs from companies like StemCells Inc. I don't follow Advanced Cell Technology Inc. (ACTC.OB), but it is doing interesting work in dry age-related macular degeneration. We recently published a very comprehensive CNS overview report in the amyotrophic lateral sclerosis space [Lou Gehrig's disease], and on the companies working to develop therapies for these patients. It is going to be an exciting couple of years as these companies start to show efficacy and proof of concept in CNS disorders.
TLSR: There have been some concerns with embryonic stem cells that could cause problems such as teratoma formation.
JK: The real risk that people have focused on is either teratoma, the uncontrolled growth of the cells, or cyst formation. In some of its early stem cell therapy trials, Geron Corp. (NASDAQ:GERN) showed some cyst formation in animals, but it has since overcome that. We know that former Geron CEO Tom Okarma, who is now part of BioTime Inc. (NYSEMKT:BTX), is in the process of resurrecting the Geron technology as part of a new company.
But in the case of StemCells Inc., we haven't seen any of those issues. That's why we're excited. We believe that StemCells is successfully translating animal clinical doses to the human-equivalent dose. That shows a high confidence level, in that the company has not seen uncontrolled cell proliferation, whether it's cyst or teratoma formation. We think that's a differentiating characteristic of StemCells' technology.
TLSR: I've enjoyed talking with you very much, Jason. Thank you for the time.
JK: Terrific. Thank you. It was my pleasure.
This interview was conducted by George S. Mack of The Life Sciences Report.
Maxim Group Managing Director and Senior Biotechnology Analyst Jason Kolbert has worked extensively in the healthcare sector as product manager for a leading pharmaceutical company, as a fund manager and as an equity analyst. Prior to joining Maxim Group, he spent seven years at Susquehanna International Group LLP, where he managed a healthcare fund and later founded SIG's sellside biotechnology team. Previously, Kolbert served as the healthcare strategist for Salomon Smith Barney. He has been quoted in Barron's and featured in the media [CNBC]. Prior to beginning his Wall Street career, Kolbert served as a product manager for Schering-Plough in Osaka, Japan. He received a bachelor's degree in chemistry from State University of New York at New Paltz, and a master's degree in business administration from the University of New Haven.
1) George S. Mack conducted this interview for The Life Sciences Report and provides services to The Life Sciences Report as an independent contractor. He or his family own shares of the following companies mentioned in this interview: None.
2) The following companies mentioned in the interview are sponsors of The Life Sciences Report: Streetwise Reports does not accept stock in exchange for its services or as sponsorship payment.
3) Jason Kolbert: I or my family own shares of the following companies mentioned in this interview: None. I personally or my family am paid by the following companies mentioned in this interview: None. My company has a financial relationship with the following companies mentioned in this interview: Maxim Group expects to receive or intends to seek compensation for investment banking services from Mesoblast Ltd., Pluristem Therapeutics Inc., Cytori Therapeutics Inc., Dendreon Corp., ImmunoCellular Therapeutics Inc. and StemCells Inc. in the next three months. Maxim Group received compensation for investment banking services from Cytori Therapeutics Inc. in the past 12 months. I was not paid by Streetwise Reports for participating in this interview. Comments and opinions expressed are my own comments and opinions. I had the opportunity to review the interview for accuracy as of the date of the interview and am responsible for the content of the interview.
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