SPECIAL REPORT: Regenerating interest in stem cell medicine (PART 1)

Stem cell technologies still hold potential to replace organs and tissues, but initial hype has been toned down

August 5, 2012
Randall C Willis
When the idea of embryonic stem cells first came up aboutthree decades ago, conversations ran rampant about thepotential—pluripotential, if you will—of this technology to cure all humandisease and assist us with replacement organs and tissues as those in our agingbodies failed over time. Despite a few early achievements, however, the hypequickly trailed off to be replaced by disappointment and anxiety.
 
 
"If you look back 20 years, the idea was to replacedefective human parts," says Zami Aberman, chairman and CEO of Israel-basedPluristem 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 BrainStormCell Therapeutics in Petach-Tikva, Israel, is that companies focusing on stemcell technologies picked therapeutic targets where they couldn't show aneconomic advantage.
 
 
"Many cell-based therapy companies have failed in the past10 years for two primary reasons: the lack of a profitable/sustainable businessmodel despite having approved products, and having products which offeredminimal 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 itslack of scalability, the only achievable business model involves orphanpopulations with no current efficacious therapy."
 
 
Furthermore, in places like the United States, controversiesover the use of human embryonic stem cells (hESCs) may have significantly slowedcommercial progress. Both Harel and Michael Hunt, CEO of Guildford, U.K.'sReNeuron suggest, however, that such controversies are not as big a problem inother regions of the world, and Harel is quick to point out that Israel inparticular boasts more stem cell companies per capita than the United States.
 
 
A new dawn
 
 
More recently, stem cell technologies—and regenerativemedicine, more broadly—have seen an upturn in their prospects as new stem cellsources have been identified, and both academic centers and cell specialistcompanies have changed their approaches to developing the next generation ofstem cell-based therapies.
 
 
"I see 'stem cells' as an umbrella term that too broadlyforms a catchall for different kinds of interventions," says Rob Brenner, presidentand CEO of AlloCure, based near Boston. "There are distinctions between thedifferent cells types—hESCs and mesenchymal stem cells (MSCs), for example—muchas there are different types of protein biologics, ranging from short peptidesto antibodies."
 
 
While not necessarily abandoning the desire to outrightreplace damaged tissues—and perhaps, one day, organs via tissue engineering—stemcell companies have tamped down earlier rhetoric on being "the" solution forhuman disease.
 
"Stem cells are by no means the ultimate panacea to humandisease," says Harel. "In fact, they do not necessarily address the cause ofthe disease, as in the case of infections or inflammatory processes, but ratherthe outcome of the disease.
 
 
"In the case of amyotrophic lateral sclerosis (ALS)," Harelnotes about an area of great interest to BrainStorm, "where there is neuronaland muscular atrophy and loss of function, stem cells hold promise forrestoring that function."
 
Aberman agrees: "We think it's important to take a step-by-stepapproach, viewing cells as tiny producers of cytokine cocktails that improvecell and tissue function," he says. "Without product on a shelf and some senseof quality control, however, it will remain hard to convince Big Pharma thatthere is a business here."
 
 
The renewed interest is reflected in the sheer number ofclinical trials currently underway around the world involving stem cells (see chart,"Current Clinical Trials in Regenerative Medicine"), in which academic andcorporate scientists are applying stem cells to a vast array of medicalconditions. Brenner, however, raises a warning flag on any thoughts of taking agrapeshot approach, and suggests that AlloCure made sure to put the diseasebefore the technology.
 
"From the outset, our scientists were thinking about an areaof significant unmet medical need—acute kidney injury—and tried to determinewhat was the best tool to interdict against this condition, which has noFDA-approved therapies. I think other companies approached the problem as atool looking for an indication," Brenner says.
 
 
ReNeuron followed a similar disease-centric path to therapydevelopment. The company was founded in 1997 on the basis of Chief ScientificOfficer John Sinden's work in central nervous system models, and as inBrainStorm's case, applies stem cells to reinvigorate or restore tissuefunction lost following injury such as stroke.
 
Regenerative medicine is also seeing its fair share ofgovernment investment. Despite the controversial period when the hESCs cameunder tight scrutiny and outright rejection for research funding in the UnitedStates, the U.S. National Institutes of Health (NIH) has consistently fundedregenerative medicine and stem cell research at levels below but in alignmentwith those for major therapeutic categories such as diabetes, neurodegenerativedisorders and cardiovascular disease (see chart, "NIH Expenditures (2008-2013)on Select Therapeutic Categories").
 
 
Likewise, regulatory agencies like the U.S. Food and DrugAdministration (FDA) and the European Medicines Agency (EMA) continue toactively engage the regenerative medicine community to facilitate thereview—and hopefully, timely approval—of new therapies as they are developed.
 
 
"Our recent Fast Track designation is reflective of theFDA's understanding of the importance of our treatment to a significant unmetmedical need," says Brenner. "As well, it is indicative of the FDA's beliefthat there is nothing inherently problematic or worrisome about MSCs."
 
Israel-based MacroCure received similar support from theFDA, says Nissim Mashiach, the company's CEO.
 
 
"We're currently enrolling patients in a Phase III study inthe United States with a commitment from the FDA to speed the product toapproval if it meets its clinical criteria," he says.
 
 
According to ReNeuron's Hunt, however, simply choosing atherapeutic area where nothing else works may not be enough to ensure yourproduct is supported by payors.
"We need to set the bar high in our clinical trials to showmeaningful efficacy," he warns. "Is it an endpoint that will garner yourproduct reimbursement?"
 
 
Companies will need to be creative in how they design trialsto ensure that they provide evidence that is compelling to all stakeholders, headds.
 
 
"It's all well and good to have an effective product, but ifyou can't get it reimbursed by established payors, what was the point?" heasks.
 
 
Conversations between companies, regulators and payors arestarting to happen in the United Kingdom, he says, and ReNeuron is looking atthe pharmacoeconomics of what they are proposing. But it's still early, andnever an easy sell.
 
 
"I think we really have to keep playing the broader argumentof the need to develop treatments for chronic conditions that are currentlyundertreated—something of a pay- now-or-pay-later' approach," Hunt says.
 
Autologous vs.allogeneic
 
 
With the advent of new stem cell sources and a betterunderstanding of stem cell biology, there has been dramatic growth in thedevelopment of allogeneic products, threatening the tight grip that autologoustherapies once had on this field.
 
 
In fact, there are almost equal numbers of clinical trialscurrently underway or initiating that use either autologous or allogeneic cellsources (1209 vs. 1167, respectively, for those keeping score).
 
 
"Autologous stem cells are relatively easy to harvest andcan form many different cell types," says BrainStorm's Harel. "Moreimportantly, they do not present the risk of rejection, and have a minimal riskof forming tumors, as opposed to embryonic stem cells, which have a very highrisk of inducing tumors."
 
He also points to the 40-year safety record of bone marrowtransplantation.
 
 
Others, like Pluristem's Aberman, challenge this position ofsuperiority for autologous systems, pointing in particular to the variousimmune-privileged cells lines that are now available, which do not trigger animmune reaction in the host and therefore do not require immunosuppression whenused in allogeneic treatments. Pluristem, for example, relies on cells derivedfrom placental tissues.
 
 
Mashiach downplays the significance of tissue typing as alimitation in allogeneic cell therapies.
 
 
"We're using blood products that only require a simple bloodtest to match donor with host, bypassing the typical donor-recipient issues,"he says.
 
 
He then raises a concern about autologous systems that isechoed by Aberman.
 
"With autologous therapy," Mashiach says, "you're drawingcells from the patient himself, and that won't work when those cells aredamaged or non-functional."
 
AlloCure's Brenner also suggests that some medicalconditions don't give you the luxury of working with autologous cell therapies.
 
 
"An autologous approach just isn't realistic with acutekidney injury," he explains. "It is an acute condition that offers no lead timeto do the scale-up and return of cells to patients. Using MSCs, the allogeneicapproach fits within the conventional infrastructure as the cells don't triggeran immune response and have powerful anti-inflammatory properties."
 
 
With regard to safety, Brenner points out that more than5,000 patients worldwide have been treated with MSCs.
 
 
ReNeuron's Hunt is a bit more pragmatic about things, seeingit 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 allogeneicdebate," he says. "Allogeneic makes better sense for our area of interest, butthat is not to say that autologous doesn't have its place. Many companies havemade autologous much more financially viable, so one can't be too proscriptive.There may even be situations within a disease state where patient needs willdictate the choice between autologous and allogeneic therapies."
 
 
Off-the-shelf
 
 
Perhaps a more dramatic impact of the expansion inallogeneic options (and to a lesser extent, autologous via cord blood storage)is a significant shift in the possible business models for cell-basedtherapeutics firms from a focus on service to a focus on product.
Because allogeneic cell lines do not require the harvestingof tissues from the affected patient, but rather from a healthy donor, theyafford companies the opportunity to store them in a freezer for later use ormodification. In essence, when a new patient shows up in a hospital, theattending physician has the opportunity to merely place an order for cell-basedtreatment as they would for a more traditional small-molecule or biologic-basedtherapy.
 
 
"I think the growth of 'off-the-shelf' products is a sign ofindustry and technology maturation," says Mashiach. "Availability of cells isalways going to be an issue with autologous therapies. If you want to meet massdemands and market growth, you cannot be limited by your supply and donorpopulation."
 
 
And this change in model has definitely attracted theinterest of Big Pharma looking to fill its dwindling pipelines.
 
 
"We have engaged larger biopharmaceutical companies inconversation, and we get the sense that [the off-the-shelf] approach is easierfor 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 pharmain partnering discussions. It will take a bold company to make that leap, headds, but leap they must.
 
 
Hunt describes the ways in which ReNeuron's products matchedBig Pharma's needs, breaking it down to six criteria: Therapies targetingdiseases with significant patient populations or subgroups; diseases that areunaddressed by existing drugs/biologics; off-the-shelf products rather thancomplex procedures (e.g., complexmanipulation or re-derivation); readily scalable with favorable cost of goods;broad and robust data package and identifiable mode of action; comprehensive IPposition.
 
BrainStorm's Harel is quick to remind us, however, thatthere may still be limitations for these solutions and a role for autologoustherapies.
 
"Off-the-shelf, allogeneic cell-based therapies stillrequire 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'sown cells are manipulated and differentiated, the model is completelydifferent. It's actually personalized medicine."
 
 
Again, Hunt holds the middle ground, noting that companiesdeveloping autologous therapeutics have come a long way in developingrelatively inexpensive and scalable solutions, much like their allogeneiccounterparts.
 
STORY CONTINUES: Click here for PART 2
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