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SPECIAL REPORT: Regenerating interest in stem cell medicine (PART 1)
August 2012
by Randall C. Willis  |  Email the author
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When the idea of embryonic stem cells first came up about three decades ago, conversations ran rampant about the potential—pluripotential, if you will—of this technology to cure all human disease and assist us with replacement organs and tissues as those in our aging bodies failed over time. Despite a few early achievements, however, the hype quickly trailed off to be replaced by disappointment and anxiety.  
 
"If you look back 20 years, the idea was to replace defective human parts," says Zami Aberman, chairman and CEO of Israel-based Pluristem Therapeutics. "A lot of promises were made, but nothing happened. There were some early successes, but a true industry didn't develop."  
 
Part of the challenge, adds Adrian Harel, CEO of BrainStorm Cell Therapeutics in Petach-Tikva, Israel, is that companies focusing on stem cell technologies picked therapeutic targets where they couldn't show an economic advantage.  
 
"Many cell-based therapy companies have failed in the past 10 years for two primary reasons: the lack of a profitable/sustainable business model despite having approved products, and having products which offered minimal benefits over existing, less expensive competing products," Harel explains. "Given the high cost of autologous therapy due to the need for some type of ex-vivo manipulation, in addition to its lack of scalability, the only achievable business model involves orphan populations with no current efficacious therapy."  
 
Furthermore, in places like the United States, controversies over the use of human embryonic stem cells (hESCs) may have significantly slowed commercial progress. Both Harel and Michael Hunt, CEO of Guildford, U.K.'s ReNeuron suggest, however, that such controversies are not as big a problem in other regions of the world, and Harel is quick to point out that Israel in particular boasts more stem cell companies per capita than the United States.  
 
A new dawn  
 
More recently, stem cell technologies—and regenerative medicine, more broadly—have seen an upturn in their prospects as new stem cell sources have been identified, and both academic centers and cell specialist companies have changed their approaches to developing the next generation of stem cell-based therapies.  
 
"I see 'stem cells' as an umbrella term that too broadly forms a catchall for different kinds of interventions," says Rob Brenner, president and CEO of AlloCure, based near Boston. "There are distinctions between the different cells types—hESCs and mesenchymal stem cells (MSCs), for example—much as there are different types of protein biologics, ranging from short peptides to antibodies."  
 
While not necessarily abandoning the desire to outright replace damaged tissues—and perhaps, one day, organs via tissue engineering—stem cell companies have tamped down earlier rhetoric on being "the" solution for human disease.
 
"Stem cells are by no means the ultimate panacea to human disease," says Harel. "In fact, they do not necessarily address the cause of the disease, as in the case of infections or inflammatory processes, but rather the outcome of the disease.  
 
"In the case of amyotrophic lateral sclerosis (ALS)," Harel notes about an area of great interest to BrainStorm, "where there is neuronal and muscular atrophy and loss of function, stem cells hold promise for restoring that function."
 
Aberman agrees: "We think it's important to take a step-by-step approach, viewing cells as tiny producers of cytokine cocktails that improve cell and tissue function," he says. "Without product on a shelf and some sense of quality control, however, it will remain hard to convince Big Pharma that there is a business here."  
 
The renewed interest is reflected in the sheer number of clinical trials currently underway around the world involving stem cells (see chart, "Current Clinical Trials in Regenerative Medicine"), in which academic and corporate scientists are applying stem cells to a vast array of medical conditions. Brenner, however, raises a warning flag on any thoughts of taking a grapeshot approach, and suggests that AlloCure made sure to put the disease before the technology.
 
"From the outset, our scientists were thinking about an area of significant unmet medical need—acute kidney injury—and tried to determine what was the best tool to interdict against this condition, which has no FDA-approved therapies. I think other companies approached the problem as a tool looking for an indication," Brenner says.  
 
ReNeuron followed a similar disease-centric path to therapy development. The company was founded in 1997 on the basis of Chief Scientific Officer John Sinden's work in central nervous system models, and as in BrainStorm's case, applies stem cells to reinvigorate or restore tissue function lost following injury such as stroke.
 
Regenerative medicine is also seeing its fair share of government investment. Despite the controversial period when the hESCs came under tight scrutiny and outright rejection for research funding in the United States, the U.S. National Institutes of Health (NIH) has consistently funded regenerative medicine and stem cell research at levels below but in alignment with those for major therapeutic categories such as diabetes, neurodegenerative disorders and cardiovascular disease (see chart, "NIH Expenditures (2008-2013) on Select Therapeutic Categories").  
 
Likewise, regulatory agencies like the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) continue to actively engage the regenerative medicine community to facilitate the review—and hopefully, timely approval—of new therapies as they are developed.  
 
"Our recent Fast Track designation is reflective of the FDA's understanding of the importance of our treatment to a significant unmet medical need," says Brenner. "As well, it is indicative of the FDA's belief that there is nothing inherently problematic or worrisome about MSCs."
 
Israel-based MacroCure received similar support from the FDA, says Nissim Mashiach, the company's CEO.  
 
"We're currently enrolling patients in a Phase III study in the United States with a commitment from the FDA to speed the product to approval if it meets its clinical criteria," he says.  
 
According to ReNeuron's Hunt, however, simply choosing a therapeutic area where nothing else works may not be enough to ensure your product is supported by payors. "We need to set the bar high in our clinical trials to show meaningful efficacy," he warns. "Is it an endpoint that will garner your product reimbursement?"  
 
Companies will need to be creative in how they design trials to ensure that they provide evidence that is compelling to all stakeholders, he adds.  
 
"It's all well and good to have an effective product, but if you can't get it reimbursed by established payors, what was the point?" he asks.  
 
Conversations between companies, regulators and payors are starting to happen in the United Kingdom, he says, and ReNeuron is looking at the pharmacoeconomics of what they are proposing. But it's still early, and never an easy sell.  
 
"I think we really have to keep playing the broader argument of the need to develop treatments for chronic conditions that are currently undertreated—something of a pay- now-or-pay-later' approach," Hunt says.
 
Autologous vs. allogeneic  
 
With the advent of new stem cell sources and a better understanding of stem cell biology, there has been dramatic growth in the development of allogeneic products, threatening the tight grip that autologous therapies once had on this field.  
 
In fact, there are almost equal numbers of clinical trials currently underway or initiating that use either autologous or allogeneic cell sources (1209 vs. 1167, respectively, for those keeping score).  
 
"Autologous stem cells are relatively easy to harvest and can form many different cell types," says BrainStorm's Harel. "More importantly, they do not present the risk of rejection, and have a minimal risk of forming tumors, as opposed to embryonic stem cells, which have a very high risk of inducing tumors."
 
He also points to the 40-year safety record of bone marrow transplantation.  
 
Others, like Pluristem's Aberman, challenge this position of superiority for autologous systems, pointing in particular to the various immune-privileged cells lines that are now available, which do not trigger an immune reaction in the host and therefore do not require immunosuppression when used in allogeneic treatments. Pluristem, for example, relies on cells derived from placental tissues.  
 
Mashiach downplays the significance of tissue typing as a limitation in allogeneic cell therapies.  
 
"We're using blood products that only require a simple blood test to match donor with host, bypassing the typical donor-recipient issues," he says.  
 
He then raises a concern about autologous systems that is echoed by Aberman.
 
"With autologous therapy," Mashiach says, "you're drawing cells from the patient himself, and that won't work when those cells are damaged or non-functional."   AlloCure's Brenner also suggests that some medical conditions don't give you the luxury of working with autologous cell therapies.  
 
"An autologous approach just isn't realistic with acute kidney injury," he explains. "It is an acute condition that offers no lead time to do the scale-up and return of cells to patients. Using MSCs, the allogeneic approach fits within the conventional infrastructure as the cells don't trigger an immune response and have powerful anti-inflammatory properties."  
 
With regard to safety, Brenner points out that more than 5,000 patients worldwide have been treated with MSCs.  
 
ReNeuron's Hunt is a bit more pragmatic about things, seeing it as less of an "us-versus-them" discussion, and more as an "us-and/or-them" conversation.  
 
"We've tried to avoid the autologous versus allogeneic debate," he says. "Allogeneic makes better sense for our area of interest, but that is not to say that autologous doesn't have its place. Many companies have made autologous much more financially viable, so one can't be too proscriptive. There may even be situations within a disease state where patient needs will dictate the choice between autologous and allogeneic therapies."  
 
Off-the-shelf  
 
Perhaps a more dramatic impact of the expansion in allogeneic options (and to a lesser extent, autologous via cord blood storage) is a significant shift in the possible business models for cell-based therapeutics firms from a focus on service to a focus on product. Because allogeneic cell lines do not require the harvesting of tissues from the affected patient, but rather from a healthy donor, they afford companies the opportunity to store them in a freezer for later use or modification. In essence, when a new patient shows up in a hospital, the attending physician has the opportunity to merely place an order for cell-based treatment as they would for a more traditional small-molecule or biologic-based therapy.  
 
"I think the growth of 'off-the-shelf' products is a sign of industry and technology maturation," says Mashiach. "Availability of cells is always going to be an issue with autologous therapies. If you want to meet mass demands and market growth, you cannot be limited by your supply and donor population."  
 
And this change in model has definitely attracted the interest of Big Pharma looking to fill its dwindling pipelines.  
 
"We have engaged larger biopharmaceutical companies in conversation, and we get the sense that [the off-the-shelf] approach is easier for them to accept as a better fit for them," says Brenner.  
 
Hunt puts it more succinctly: The closer you can get to "cell therapy in a pill," the better it will be with respect to engaging pharma in partnering discussions. It will take a bold company to make that leap, he adds, but leap they must.  
 
Hunt describes the ways in which ReNeuron's products matched Big Pharma's needs, breaking it down to six criteria: Therapies targeting diseases with significant patient populations or subgroups; diseases that are unaddressed by existing drugs/biologics; off-the-shelf products rather than complex procedures (e.g., complex manipulation or re-derivation); readily scalable with favorable cost of goods; broad and robust data package and identifiable mode of action; comprehensive IP position.
 
BrainStorm's Harel is quick to remind us, however, that there may still be limitations for these solutions and a role for autologous therapies.
 
"Off-the-shelf, allogeneic cell-based therapies still require matching and immunosuppression, as is the case with other transplants, and will therefore never be as straightforward as drug treatment," he warns. "In the case of autologous cell-based therapy such as ours, where the patient's own cells are manipulated and differentiated, the model is completely different. It's actually personalized medicine."  
 
Again, Hunt holds the middle ground, noting that companies developing autologous therapeutics have come a long way in developing relatively inexpensive and scalable solutions, much like their allogeneic counterparts.
 
STORY CONTINUES: Click here for PART 2
 
Code: E081229

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