With its Center for Regenerative Medicine having produced only one program ready for clinical testing in the last four years, the NIH is rethinking its strategy for translating stem cell therapies. When the NIH holds a stem cell workshop next month to map out its path forward, many stakeholders hope the message will be that the NIH should focus less on drug development and more on standardizing procedures and protocols.

Clinical progress of stem cell therapies has yet to gain momentum because there are many drug development hurdles caused by the fact that this type of treatment has so many differences from other more common therapeutic modalities.

For example, unlike small molecules, which can be manufactured, characterized and purified to well-defined and uniform standards, "with autologous therapy, the patient is the source of the product, so you're not in control of the manufacturing of the product; you're just transplanting it," said Douglas Losordo, CMO of stem cell company NeoStem Inc. "There's no playbook for much of this right now."

The NIH created the Center for Regenerative Medicine (NIH CRM) in part to help address those differences.

According to James Anderson, director for program coordination, planning and strategic initiatives at the NIH, the impetus for launching the center dates to 2009, when Francis Collins said that an intramural research program was needed to overcome the hurdles in stem cell research.

However, the emphasis shifted to include drug development activities, and in 2010 the NIH CRM was established by the NIH Common Fund to help drive in-house programs to the clinic.

"There was not a lot of stem cell work oriented at overcoming obstacles to cell therapy. There was lots of biology work, but it wasn't patient oriented. NIH wanted to establish a program using its own clinical facilities, focused on getting cell therapy to patients that would ultimately help inform the field," Anderson said.

From inception through 2013, CRM received $16 million in funding from the NIH Common Fund.

For the first two years, the center used its pilot funds to stimulate intramural interest in working on basic stem cell biology with seminars, workshops with the FDA and meetings with biotechs. The next step, Anderson said, was for investigators to advance their programs to the clinic within a defined period of time.

Four years on, the program has not spawned the clinical programs the center had hoped for, and "only one project was ready for the launching pad," Anderson said. "We don't have enough different synergistic projects moving forward."

In late March, NIH CRM director Mahendra Rao stepped down, and the institute announced it would hold workshops in May to define what it should accomplish, identify priorities and map out the time line for the next few years.

"We're stepping back and asking the question again-where can we have a broad impact that will help the community move forward?" Anderson asked.

Role-play

Rao-who has joined The New York Stem Cell Foundation (NYSCF) as VP of regenerative medicine-told SciBX that the time is ripe for re-examining what roles the NIH, not-for-profit organizations, academia and industry should play in the field.

"Different people are trying to play too many roles. Some institutions are trying to do everything and are dropping the ball," he said. According to Rao, the private sector and not-for-profit organizations are best placed to create new stem cell therapies and move them to the clinic. He said that the NIH should focus on identifying the procedural steps needed to take a product to the clinic, such as standardizing how to write patient consent forms.

Anderson agreed that the NIH's role could include solving technical and regulatory challenges such as what cell culture matrix to use, what experimental steps are needed to get to the clinic, what protocols to use to differentiate and isolate cells, what biomarkers to use and how to image the cells when they are reintroduced into animals or humans.

"People are thinking about one-off 'my-lab' experiments rather than what are the overall obstacles in the field," he said.

Susan Solomon, cofounder and CEO of NYSCF, also thought that the NIH should rethink its role in the field. "The role of government typically is not to do breakthrough work but to scale up research done in the private and philanthropic sector," she said.

For example, Solomon said, NYSCF could benefit from help with scaling up its program to create living bone from induced pluripotent stem (iPS) cells. In 2013, NYSCF scientists found a way to generate vascularized bone but could only produce bone that was the length of a fingertip.1 To use the technology to replace craniofacial damage, a hip joint or a leg bone, the system would need considerable scaling.

A government organization could have the resources and capabilities to help reach the necessary scale, said Solomon, because companies are still cautious about investing in this field.

Jason Gardner, head of GlaxoSmithKline plc's Regenerative Medicine Discovery Performance Unit, told SciBX that the field could benefit from a consortium model with industry and academia, driven by the NIH, similar to the Accelerated Medicines Partnership.2

Interactions with industry should come as early as possible, he said. For example, industry could advise academics on what types of data would be important and could give input to dose-response design and dosing frequency.

"These are hard trials to get right. That interface is important," he said.

Anderson agreed that the NIH could act as a facilitator. "The unique thing that NIH can do is convene the interested parties and figure out how we can approach this together," he said.

Gardner said that standardization of protocols and characterization of cells for safety, consistency, scalability and reproducibility are challenges that need to be addressed.

"This is a good pause point in terms of the expectations of certain groups for the translatability [of stem cell therapies]," he said.

In addition, he said that "it would benefit the field tremendously if there were more global harmonization." Different regulations between the U.S., Europe and the U.K. add further complexity.

Rao said that the U.S. and other countries should watch Japan, who changed its regulations about clinical trials related to stem cells to accelerate translation.

The new law, passed by the House of Councillors of Japan's parliament in late 2013, allows products to receive conditional approval for marketing if they are shown to be safe, without requiring demonstration of efficacy in Phase II clinical trials. Full approval would be granted after comprehensive studies confirm safety and efficacy in a wider population.

"This could turn out to be very important as a fundamental change for Japanese investigators and might get emulated by other countries," he said.

Risk reduction

Although companies have adopted various stem cell technologies in their screening efforts, few have gone down the therapeutic path. According to Solomon, the NIH should help solve logistical problems in translating innovations to the clinic, whereas not-for-profit organizations should focus on derisking early stage research.

"Private philanthropy can do the high-risk, high-return research with no preliminary data and with no certainty that it will work," she said. "Commercially, it doesn't make sense to take that risk. The failure rate of new drugs is too high to add this kind of risk around the technology."

NYSCF has about 45 internal scientists and funds another 60 scientists in external academic labs, with a total budget of about $22 million.

Elona Baum, general counsel and VP of business development at the California Institute for Regenerative Medicine (CIRM), also thinks that the risk in the field is still too high for some large pharmaceutical companies. She said that the CIRM contributes to derisking by funding preclinical work in addition to Phase I and II proof-of-concept studies.

Baum noted that the stem cell space has seen a trickle of deal activity this year. In January, Capricor Therapeutics Inc. partnered with  Johnson & Johnson's Janssen Biotech Inc. subsidiary to develop Capricor's cell therapy programs for cardiologic applications. The deal included lead compound CAP-1002. The allogeneic, cardiosphere-derived stem cells are in Phase I/II testing to treat myocardial infarction (MI).

Also in January, Sangamo BioSciences Inc. partnered with Biogen Idec Inc. to use Sangamo's zinc finger nuclease technology to develop cell therapies to treat b-thalassemia and sickle cell disease.

Both Sangamo's and Capriocor's projects had received funding from the CIRM prior to the partnerships.

Although those deals have not opened any floodgates, Baum said that she has had discussions with five different pharma R&D heads and expects to see another one or two stem cell deals this year.

Fishburn, C.S. SciBX 7(17); doi:10.1038/scibx.2014.478
Published online May 1, 2014

REFERENCES

1.   de Peppo, G.M. et al. Proc. Natl. Acad. Sci. USA 110, 8680-8685 (2013)

2.   Fishburn, C.S. SciBX 7(8); doi:10.1038/scibx.2014.215

COMPANIES AND INSTITUTIONS

Biogen Idec Inc. (NASDAQ:BIIB), Weston, Mass.

California Institute for Regenerative Medicine, San Francisco, Calif.

Capricor Therapeutics Inc. (OTCQB:CAPR), Beverly Hills, Calif.

GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K.

Johnson & Johnson (NYSE:JNJ), New Brunswick, N.J.

National Institutes of Health, Bethesda, Md.

NeoStem Inc. (NASDAQ:NBS), New York, N.Y.

The New York Stem Cell Foundation, New York, N.Y.

Sangamo BioSciences Inc. (NASDAQ:SGMO), Richmond, Calif.