The pricey evolutionary tradeoff for walking on two legs is the curse of lower back pain. Jason Kolbert of the Maxim Group understands the power of stem cells as disease-modifying therapies for degenerative disc disease of the spine, a leading-edge, multibillion-dollar indication. Kolbert explores the opportunities that cell therapies offer investors in this interview with The Life Sciences Report, and puts a personal spin on their regenerative promise.
The Life Sciences Report: Jason, I wanted to ask you some questions about degenerative disc disease (DDD) and the use of cell therapy to manage the problem. Some people have said that the spine is a hostile environment. Why is it hostile?
Jason Kolbert: It is a unique environment versus other areas of the body because of the relative dearth of vasculature. In critical limb ischemia (CLI), congestive heart failure (CHF), stroke and other diseases there is a significant amount of blood flow and a lot of metabolic movement to the affected areas. The spine is hostile because it does not have the same level of blood flow and metabolic activity as other tissues.
TLSR: Could that minimal amount of metabolic processing in the disc space mean that cells have a longer time to work if placed directly into lesions?
JK: It’s the opposite of that. When we inject cells into the intervertebral space, we want those living cells to be enriched with a good blood supply because they must react to the local environment. It is important for the cells to survive long enough in the diseased space to exert their therapeutic effects. In the hostile spinal environment, one could argue that cells either have to be more robust or that they must exert their effects in a shorter period of time because of their shorter life expectancy. That’s been one of the problems in using cell therapy in the spine.
TLSR: Briefly, tell me about DDD.
JK: The intervertebral space contains a cartilaginous disc that, under normal and healthy conditions, cushions two neighboring vertebrae and enables normal, pain-free articulation of the spine in the upright human. However, with advancing age there is a progressive loss of the proteoglycan material that confers these stress-mitigating properties on the disc.
Let me address two types of treatment, and I don’t want them to be confused. In dealing with herniated, bulging and generally degenerated discs, we want to stop the pain by stopping the inflammation and hopefully, in a best-case situation, healing the diseased tissue. In a spinal fusion, a direct connection between two vertebrae is made, stopping their ability to move and rub against each other, and thus stopping the potential for nerve encroachment and pain. The two are often linked—that is, disc disease often precedes a fusion (especially if the fusion is not accident- or cancer-related).
TLSR: Endpoints are how we measure efficacy. What is an acceptable endpoint for degenerative disc disease? Clearly, we want the patient to be pain-free, but is that enough?
JK: We, as analysts, are asked that question a lot. Pain can be a subjective endpoint, so whenever we don’t have to use it—and can use a qualitative endpoint instead—we prefer to avoid it. That said, from the U.S. Food and Drug Administration’s (FDA’s) point of view, reduction of pain is an acceptable endpoint and does represent the standard by which it has and will likely continue to approve drugs for DDD.
Secondary endpoints are important as well, and evidence of those may be observed via MRI or radiographic imaging. This is where we get into a lot of nuance. Mesoblast Ltd. (MSB:ASE; MBLTY:OTCPK) ran preclinical studies with its human mesenchymal precursor cells (MPCs) in ovine (sheep) models. Sheep are quadrupeds, resting and walking on four legs. Gravity does not exert the same vertical or upright force on a quadruped as it does on a bipedal mammal like a human. In Mesoblast’s ovine studies there was beautiful radiographic evidence of restoration of vertebral height.
Now researchers want to know if restoration of vertical height should or could be a primary endpoint for Mesoblast’s DDD trial in humans. We don’t think it should because of the inherent differences between two-legged and four-legged mammals. It simply doesn’t make sense to use radiographic imaging of vertical height a primary endpoint, but it could be a secondary endpoint. We also think it may take more time to show radiographic changes versus changes in pain patterns. In terms of a clinical trial and product development strategy, it makes more sense to use pain as the primary endpoint. That is what we expect Mesoblast, and other companies that follow them, to do.
TLSR: Lack of–or diminished–pain is certainly going to be enough from a patient’s perspective. But obviously researchers want to be able to tie in radiographic and/or MRI changes in the same way imaging evidence is used in cancer drug development. Correct?
JK: I would stop you right there. I would not mix cancer and DDD trials. They’re very different. For cancer, the gold standard is to delay mortality—to increase overall survival. In degenerative disc disease, the primary endpoint that the FDA will use is reduction in pain. However, if pain reduction in a specified period of time is supported by qualitative data such as improvement shown in radiographic imaging evidence, that would be the Holy Grail of spinal disease.
TLSR: I’ve dwelled on imaging evidence because pain is very subjective. In the management of chronic or intractable pain, clinicians might give patients a written test every three months to measure their pain-reaction threshold.
JK: That is a great point. As I previously mentioned, as an analyst, I am nervous when pain is a primary endpoint because I want to know how pain was measured and how the trials were run. Were they double-blinded? Were they placebo-controlled? Trial design has to be scrutinized.
However, the reality is that in a disease like DDD, pain reduction is the standard primary endpoint. Can you take someone who’s had degenerative disc disease over a period of 15 to 40 years and reverse the damage? That would be asking cells to do a lot. A trial should not fail if a patient becomes pain-free but doesn’t demonstrate the imaging changes we’d love to see. The reality is, if you can alleviate the suffering from degenerative disc disease and avoid the progression to spinal fusion, then the value you bring to the patient–and the reduction in costs to the system–are huge.
TLSR: One more question about trial design in DDD: In cancer trials we are bound, in most instances, to begin with standard of care—older, approved treatments—before progressing to an experimental drug. In the meantime, patients have become more resistant to any therapy. Can you relate that to Mesoblast’s human studies?
JK: Yes. Mesoblast did something very interesting in its phase 2 human clinical trial for DDD. It recruited steroid-refractory patients—people who had already failed steroids for their pain. Therefore, the fact that cells showed a good result in these patients is very significant. We think the long-term use of steroids does nothing toward healing disc disease. Cell therapy opens up an entire new treatment paradigm in back pain.
TLSR: Does cell therapy have to be superior to current therapies, steroids in particular? Isn’t it enough that cells won’t cause steroid necrosis in the spine?
JK: Mesoblast went around the current therapy issue entirely by enrolling steroid-refractory patients in its trial. If it can demonstrate that cell therapy works in patients who have failed steroids, the company is dealing in a niche market, essentially an unmet medical need. That’s huge.
Going forward, once Mesoblast has FDA approval, how would it extend the label for frontline usage? That’s the question. Would it have to run a control arm against steroids and show noninferiority? That’s more likely than being required to show superiority, particularly if it occurs in a sequence where it has already shown utility in steroid-refractory patients. That is the brilliance of the Mesoblast strategy.
“Delivering the cells is relatively simple and quick, not too dissimilar to an epidural steroid injection.” —Silvio Itescu of Mesoblast Ltd.
Provided a pivotal trial replicates the phase 2 data I would expect to see NeoFuse (immunoselected, culture-expanded, nucleated, allogeneic MPCs), Mesoblast’s spinal fusion cell therapy, approved and on the market as early as 2016. NeoFuse represents a highly cost-effective alternative to open spinal surgery for patients, and would target patients whose discs have degenerated too far for any hope of repair, where fusion is the only viable option to eliminate pain. In other words, cell therapy creates a new alternative for treating DDD patients. Surgery is always an option and is reserved for when less-invasive options have failed.
TLSR: Let’s go to how the cells work. Is engraftment of cells necessary for therapeutic effect?
JK: This is misunderstood by most people in the space, who believe engraftment relates to autologous cells (derived from the same patient to which they will be administered) versus allogeneic cells (from a same-species donor). The fact is that engraftment is not occurring with Mesoblast’s allogeneic cells, but neither is engraftment occurring with most autologous cell therapies.
When we talk about indications in which cell therapies might be useful, such as degenerative disc disease, cardiovascular disease or critical limb ischemia, we’re talking about cells acting like microfactories, producing therapeutic proteins or cytokines for a period of time before going away. It’s not a question of autologous or allogeneic. This is a key point. We don’t believe that engraftment is part of the cell therapy paradigm for the most part. It’s a question of the cell’s ability to react with potency to the local environment, and not a question of one cell type versus another.
TLSR: You are, in essence, saying that there is a paracrine or druglike effect with these microfactories, and then the cells leave. That implies that retreatment will be necessary in the future. In my mind, that could be a limiting factor in the use of allogeneic materials, such as Mesoblast’s cells. I find it interesting that these DDD studies involve a single administration of cells, not multiple doses over time. Is there still an overhang of potential danger in the readministration of these allogeneic cells? The immune system could mount a huge immune response or defense against their reintroduction into a patient.
JK: The answer is no. We have seen no tangible evidence that the readministration of allogeneic cells puts you at risk for any type of anaphylaxis.
We spent a lot of time with Mesoblast and Athersys Inc. (ATHX:NASDAQ) looking at the historical examples and the number of treated patients. We found zero evidence of immune response. We’re aware of the recent events with Pluristem Therapeutics Inc. (PSTI:NASDAQ), which uses full-term maternal placenta-derived adherent stromal cells. The FDA placed a hold on the company’s 74-patient phase 2 study for intermittent claudication/peripheral artery disease due to a serious allergic response that required hospitalization of one patient in the trial. We believe that is a Pluristem-specific issue.
Let’s delve into the immune reaction topic because it is also key. Manufacturing is critical. What are you actually doing to the cells? After they are harvested from the body, do you purify them? Do you enrich them? Do you expand them? Even autologous cell companies are manipulating cells in some way. They may qualify as minimally manipulated, but they’re still manipulated, whether an allogeneic cell or an autologous cell. Therein lies the opportunity to create the basis for an immune reaction. If a cell has been exposed to a particular serum or a contaminant in the manufacturing process, or if it has been roughly treated or exposed to turbulent flow, that contaminant or process may impact cell vitality and create an immune reaction.
You were at the Alliance for Regenerative Medicine Investor Day conference back in April. I was a panelist, and Maxim Group was one of the co-hosts. When NeoStem Inc. (NBS:NYSE.MKT) was finishing up its presentation, it suggested that autologous cells were safe. By inference the company suggested that allogeneic cells were not. We believe that is an example of misdirection, because reality tells us that it’s a question of manufacturing.
The questions are: Does a company have a robust manufacturing process with proper controls? Does the company know, in fact, that the process is safe? In its animal work, Mesoblast went so far as to manufacture both autologous and allogeneic cells to see if there was any difference in immune response. If there were a difference, it could be clearly traced back to the cell itself. And the company found no difference—no immunotoxicity. Mesoblast was validating the robustness of its manufacturing process. So long as a company has that, it will be OK. No one should use Pluristem’s hiccup and the FDA’s clinical hold as evidence that allogeneic is not safe.
TLSR: In other words, an immune reaction might be attributed to an artifact introduced into the patient, not the cells themselves.
JK: Correct. It may be an artifact introduced by the manufacturing process that Pluristem has to track down and correct.
We believe that other autologous companies face the same risks in their manufacturing processes. If we look at Baxter International Inc. (BAX:NYSE), with its autologous CD34+ mesenchymal stem cells from peripheral blood, or at NeoStem with its CD34+ bone marrow-derived autologous cells, these companies are enriching the cells using columns in the manufacturing process. The cells are separated, sorted and flow through the column. They interact with the column and the resulting fraction is enriched for a specific cell marker. The cell product, as such, has been manipulated. Each step is an opportunity for something to go wrong, such as the introduction of a contaminant. Starting with an autologous cell does not mean that the final product is safe.
I will grant that there are probably fewer manufacturing steps in an autologous setting, but the individualized handling, lack of automation and quality control are all limited by comparison to the advantages of a well-defined allogeneic process. If there is any manipulation whatsoever, the risk of anaphylaxis exists.
TLSR: I’d like to talk about administration of cells. Is each company developing its own methods and cannula systems to administer the cells, or will there be an all-purpose device to administer cells for intervertebral disc disease?
JK: I believe companies will develop their own devices. In fact, BioRestorative Therapies Inc. (BRTX:OTCBB) has developed a very interesting cannula that seems to work extremely well and is very unique. Companies are trying not to change the traditional methodology of the pain treatment paradigm for disc disease. So cells will be introduced in the same way that steroids are introduced. However, cells are not steroids, and it makes sense that a specialized cannula is needed.
One of the things that caught my eye is that BioRestorative Therapies is doing work with cells from brown fat. It’s an interesting argument, and a different cell source than Mesoblast’s. But the company has developed a lot of anecdotal data in humans that suggests its cells are like Mesoblast cells—robust and with potential therapeutic value in bulging and herniated disc disease.
TLSR: What is your impression of BioRestorative versus Mesoblast?
JK: BioRestorative is an interesting little company with mountains of anecdotal data that suggest its cells and delivery device may actually work. Having looked at Mesoblast’s data in DDD and in spinal fusion, it looks like it works too. The question is: If BioRestorative follows Mesoblast, where will that leave it if Mesoblast is the first mover? Only the management teams are in the position to answer.
“We believe we can effectively and safely treat patients using a nonsurgical, minimally invasive procedure that can be performed routinely in a physician’s office.” —Mark Weinreb of BioRestorative Therapies Inc.
Suffice to say that 5–10 years from now, I believe there will be competing cell therapies for disc disease. There will be an optimum cell type and delivery methodology for each disease or situation. But that thinking is too sophisticated for where the industry is today. It comes down to this: Right now the outlook for cell therapy is binary—either it works or it doesn’t work. I believe the evidence is clear—cell therapy can work, in the right indication, at the right “dose,” with the right cell type and in the right trial. Mesoblast has the resources in place to address these issues and will, I believe, end up with a positive outcome. Once the market accepts the reality—once we have an approved blockbuster cell therapy—the natural next question will be how we make the therapy better. My bet is that there will be multiple competing products, each with respective pros and cons.
TLSR: The anesthesiologists, the interventional neurologists and the neurosurgeons who treat spinal disease are already injecting drugs like steroids into intervertebral spaces. Are payers going to look at these cell therapies as just another drug going into a patient’s intervertebral space and ultimately want to pay on that basis?
JK: That’s exactly the right question. The payers are going to ask why should they pay for cell therapy at, let’s assume, the $10,000 per dose level if that will give the patient the same level of pain relief that could be achieved with a steroid at $100 per dose. That is going to be an issue. It’s going to be important for companies like Mesoblast and BioRestorative Therapies to generate data suggesting not only that cell therapy works, but also that it works in patients where steroids don’t—and that cell therapy does what steroids can’t, which is to arrest disease progression. Steroids treat the symptoms and not the underlying problem, and there is good reason to believe that cell therapy can not only alleviate pain, but also help arrest disease progression. The value of that is huge.
As far as the cost of spinal fusion. . .now we’re talking tens of thousands of dollars, and fusion often doesn’t even stop the pain. Sometimes a fusion of two vertebrae creates problems in adjacent vertebrae. Most clinicians and patients see fusion as a last resort. Clearly the treatment armamentarium needs a new resource. To the extent that a company like Mesoblast or BioRestorative can show data that changes the paradigm, payers will see value.
TLSR: Jason, you have addressed the issue that companies like Mesoblast and BioRestorative Therapies are trying not to change the way clinicians perform procedures. Clearly, administration of cells is not technique-sensitive relative to what clinicians are already doing. Uptake should be pretty rapid if these therapies are proven efficacious, shouldn’t it?
JK: You’ve hit the nail on the head. If you ask the neurosurgeon or the pain specialist to learn a new modality or technique for administration of an agent, you’re talking about a steeper learning curve, and a longer time to penetrate the marketplace. If clinicians don’t have to change their procedures in any way, shape or form, you’re talking rapid uptake.
I think the latter will be the case with cell therapies in degenerative disc disease and even spinal fusion, which might also be accomplished with cells. In fact, in the case of spinal fusion, cell therapy may actually make the orthopedic surgeon’s life easier because a step is eliminated. The surgeon is not performing an autologous bone graft from the hip, which can be very painful for the patient. If you can keep the paradigm identical—or even eliminate a step—we think there is a huge win for the patient, the clinician and the product developers.
Eliminating a step is where we believe allogeneic therapy wins. First, it tends to have lower cost of goods versus autologous, and second, it is patient friendly. You don’t have to harvest cells or tissues from the patients—not from their bone marrow, not from their fat, not from their peripheral blood. An allogeneic therapy is off-the-shelf and ready to use. That’s true even when we look at CHF or STEMI (ST-segment elevation acute myocardial infarction)-based CHF treatment, where Athersys is working.
For instance, in the catheterization laboratory, when a stent is being placed, allogeneic therapy would be readily available without harvesting anything from the sick patient, and the patient would not have to return for a second procedure. You want to limit the number of interventions you make to a patient who has heart disease. As investors scrutinize companies, it’s very important to recognize which score best on the standard SWOT (strengths, weaknesses, opportunities and threats) analysis.
TLSR: Have we seen response related to dose of cells?
JK: The answer is yes, but the reasons are not obvious. When we look at small molecules, we expect to see a linear response. You give dose one at 5 mg, dose two at 10 mg, dose three at 15 mg and dose four at 20 mg, and expect to see increasing efficacy and maybe increasing adverse events until a maximum tolerated dose and efficacy plateau is reached.
Cell therapy, on the other hand, doesn’t follow a linear curve. You have to put in enough cells to hit critical mass, but you could use too many cells, with the result being lower efficacy. Let me explain. Let’s say there are three doses of cells, 5 million (5M), 10M and 20M. It may be that 5M cells are not enough to exert the therapeutic benefit because we did not reach critical mass. But it could be that 20M cells are ineffective because too many cells end up competing for resources in a confined space and/or in a hostile environment. You could overload that space, with the result being that the cells don’t survive long enough to exert a therapeutic effect. You could ultimately determine that 10M cells are optimal. By the time researchers get to phase 3, they should have a really good handle on the right dose for a given indication.
TLSR: Jason, these cell therapy companies have not moved like biotech companies over the past year. Why are they not participating in what has been a broader biotech rally?
JK: There is inefficiency in the micro-cap space. Not only is there inefficiency, but there aren’t many analysts who follow cell therapy. Most analysts don’t really understand it.
When we look at the larger-cap companies that are heavily followed by institutions on both the buyside (institutional money management) and sellside (investment bank-driven research), there is much greater efficiency in the trading of shares. I’ll give you a great example. At Maxim we recently launched coverage of Teva Pharmaceutical Industries Ltd. (TEVA:NASDAQ). When I was at the Teva research and development conference, I counted about 400 analysts in the room. Most of them were on the buyside. As for the sellside, I don’t believe we’ve ever seen an analyst who covers Teva write extensively about its partnership with Mesoblast. It’s very clear that there is a very large inefficiency in the marketplace.
The challenge for many stem cell companies is how good data will change the company. Mesoblast is moving into pivotal trials for spinal fusion and degenerative disc disease, and also into a large, 1,700-patient trial in CHF that is being paid for by Teva—to the tune of $130M. I think it’s very important that investors step back and ask themselves what is real and what’s not real.
TLSR: Teva owns 20% of Mesoblast, and that equity is now worth $300–350M to Teva. Even with Teva’s sponsorship, Mesoblast is down 18% over the past 52 weeks.
JK: Let me add a few things. Mesoblast is primarily domiciled in Australia, and its shares are very thinly traded in the U.S. Even with a $1.8B market cap and $330M in cash on its balance sheet, it is not well followed.
We’re not going to get real institutional ownership in cell therapy stocks until they have data and proof of concept. If you’re a fund manager with $10 billion ($10B) under management, you can’t afford to buy a micro-cap company or even a big-cap company that is thinly traded in the U.S. Companies like Mesoblast need to establish a more significant U.S presence that will lead to better share liquidity, which will then allow institutional ownership. Then I believe institutions will say, “OK, if I own Mesoblast, what else might work?” They will start scouring the landscape to find companies like Osiris Therapeutics Inc. (OSIR:NASDAQ), Athersys or Pluristem, which are allogeneic counterparts to Mesoblast. The fund managers can then ask, “Are these stocks cheaper alternatives?”
TLSR: By the way, how is your ankle?
JK: Thank you for asking. I’m not just an analyst; I’m also a patient of Dr. Steven Victor, founder and CEO of IntelliCell BioSciences Inc. (SVFC:OTCPK). As you remember, I rotated my ankle this past winter with extensive damage to the ligaments. I was evaluated at the emergency room and had an orthopedic specialist follow up. The original prognosis was 3–6 months of recovery with minimal physical stress, such as running. Dr. Victor treated my ankle and for me, an n=1, the results were amazing.
Truly, the treatment was as close to minimally manipulated cell therapy as one can get. A stromal vascular fraction was extracted from my belly fat. The harvest was 750M cells; 50M were injected locally into my ankle, with 700M administered systemically. Dr. Victor believes that the systemic administration of cells in conjunction with the local administration creates two modalities of repair. The local repair process accelerates and is supported by the systemic impact, which address generalized inflammation.
I will tell you, my ankle was close to 100% within 10 days of treatment. I had a fantastic season of skiing this past winter, and have been water skiing all summer long. Ankle strength is critical in water skiing.
Clearly, I personally believe cell therapy works. I believe it’s viable. I know that from my personal experience, and while I’m only one patient, the results were dramatic. I think cell therapy represents the future of medicine.
TLSR: The therapy that you had administered did not have to be approved by the FDA. There is anexemption for minimally manipulated biological tissues. No premarket approval (PMA) or even 510(k) clearance is necessary. Correct?
JK: That is exactly correct. In the case of IntelliCell BioSciences, cells are extracted from adipose tissue, but there is no collagenase (collagen enzyme) added to digest it. The company essentially appliessonification (ultrasound) and separates out the stem cells. Within an hour it reintroduces the cells to the patient. Because cells are so minimally manipulated and because the entire process is done onsite, in the room adjacent to the patient, it likely qualifies under the FDA exemption that allows physicians to treat patients at their discretion as a “practice of medicine” issue.
Plastic surgery centers around the world are discarding patients’ fat. But we would say that there is gold—your stem cells—in that fat. I know that Dr. Victor has treated more than 300 patients, and he’s had some amazing successes. These are not FDA-controlled trials. They’re not blinded. They’re not randomized. He is one of many clinicians finding ways to harvest stem cells and treat patients with them, with amazing results. But I want to be very clear: I’m not promoting the use of stem cells without clinical trials. Clinical trials are the only pathway for the industry to commercialize the value of this technology. That said, the evidence is building that our bodies possess the ability to heal with a little bit of coaxing from good science.
TLSR: I have one last question. What’s to stop an anesthesiologist or neurosurgeon or orthopedist who treats back pain from extracting a stromal vascular fraction and treating their patients? How is that going to affect Mesoblast and others who have gone the long route with the great expense of clinical trials?
JK: There is nothing to stop people from doing that. But the caveat is that once a product is approved and has a label, things change. Imagine that two patients are treated, one with the Mesoblast product and one with the do-it-yourselfer. Let’s say something goes wrong with the do-it-yourselfer, and that patient’s pain is not ameliorated. It gets worse, and a fusion is required. The patient calls a lawyer, and the lawyer sues the doctor. The lawyer asks the doctor why he used an “unapproved do-in-yourself” therapy versus the FDA-approved product. That’s not a position I would want to be in as a treating clinician.
Once there is an approved therapeutic project, the do-it-yourselfers tend to go away. Therefore, we don’t see these as a fundamental threat to companies like Mesoblast or Cytori Therapeutics Inc. (CYTX:NASDAQ) because once clinical trials are completed and the product is approved, clinicians will use it.
TLSR: As always, it’s a pleasure speaking with you.
JK: It’s a pleasure to talk with you. Thank you.
Jason Kolbert has worked extensively in the healthcare sector as product manager for a leading pharmaceutical company, a fund manager and as an equity analyst. Prior to joining Maxim Group, where he is managing director, Kolbert spent seven years at Susquehanna International Group, where he managed a healthcare fund and founded SIG’s biotechnology team. Previously, Kolbert served as the healthcare strategist for Salomon Smith Barney. He is often quoted in the media and is a sought-out expert in the biotechnology field 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, New Paltz, and a master’s degree in business administration from the University of New Haven.
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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:Athersys Inc., NeoStem Inc., BioRestorative Therapies Inc. 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: NeoStem Inc. I personally am or my family is paid by the following companies mentioned in this interview: None. 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.
4) The following companies are investment banking clients of Maxim Group: Athersys Inc., Cytori Therapeutics Inc. Maxim Group or its affiliates have received compensation from the following companies in the past 12 months: Mesoblast Ltd., Athersys Inc., Pluristem Therapeutics Inc., Cytori Therapeutics Inc.
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