September 15, 2011 (Vol. 31, No. 16)

Companies Find It Easier to Navigate Regulatory Requirements in Asia and Europe

American companies focused on stem cell treatments and technology platforms have met with success in finding partnerships and revenues overseas in the past decade. And it’s not for the reason many people might think, namely the controversy over U.S. federal funding of human embryonic stem cell (hESC) research.

Two other factors better explain why U.S. stem cell companies have been looking beyond their borders to Asia, according to Bernard Siegel, founder and full-time executive director of the nonprofit Genetics Policy Institute (GPI).

One is the attractiveness of Asian countries as markets for stem cell treatments. That reflects both high population concentrations as well as the willingness by national governments to invest in stem cell research as well as companies commercializing such treatments and encourage additional research by outside parties. The other is Asia’s lower regulatory hurdles when compared to the U.S.

“It’s easier to move toward the translational process and get clinical trials cranked up in Asia than in the United States,” Siegel pointed out. “I think that’s one aspect of it.”

U.S. companies can do that and more in Europe as well, if one company’s experience is any indication. Cytori Therapeutics  has won both initial and expanded indication approval in Europe for its Celution® system family of medical devices and instruments, which is not yet available in the U.S. Celution extracts and separates stem and regenerative cells from a patient’s own adipose tissue.

“As we moved through the European market we found that a head-start was really important relative to the U.S. or other places,” Cytori president Marc H. Hedrick, M.D., told GEN.

Japan’s Position

The initial European approval allowed Cytori to expand into Japan where, Dr. Hedrick noted, the company obtained its first clinical experience. The company capitalized on the fact that doctors in Japan can, with a prescription, import technologies approved elsewhere.

“And it just so happened that we had a relationship with one of the preeminent surgeons in Japan. In fact, our first 20 patients had breast cancer reconstructions performed in Japan at his university hospital,” Dr. Hedrick recalled.

“At the same time, we identified someone to lead the charge in Japan, that we were very fortunate to get, who was also a business leader at Baxter in Japan. One thing led to another, and we now have the majority of our revenues from Japan. It was all tied back to that original regulatory approval in Europe that allowed us to get into that market very quickly,” Dr. Hedrick added.

Japan’s share of Cytori’s sales tumbled during the first quarter to 30% from 72% a year earlier due to the March 11 Tohoku earthquake and resulting tsunami. Japan is where Cytori, which maintains a Tokyo office, found two investors among some of the country’s corporate giants.

Last year Astellas agreed to buy $10 million of Cytori stock, and in 2008, Olympus, a medical device company, led a $17 million private placement financing. Two years prior, Olympus made an $11 million milestone payment to Cytori for obtaining CE Mark approval for the original Celution system.

“They provided a significant amount of capital to Cytori, and that was another reason why it made sense to focus on the Japanese market,” Dr. Hedrick said.

Other Countries in Asia

Neuralstem is also involved in partnerships with Asian companies, with deals initially focused on research. While Neuralstem established a wholly owned subsidiary in China last year, it has yet to come to terms with commercial or regulatory collaborators.

By year-end the firm plans to start a clinical trial in China focused on transplantation of cells into the brain to treat stroke. The trial would take place at Beijing’s BaYi Brain Hospital, which has been working with Neuralstem to prepare a clinical protocol for treatment of motor deficits due to ischemic stroke.

In Japan, the company came to terms with the wholly owned subsidiary of Sumitomo, Summit Pharmaceuticals, to market development and licensing rights for NSI-189, Neuralstem’s lead small molecule neurogenic compound. It is currently in an FDA-approved Phase I trial for major depression. The company has said it intends to take NSI-189 through Phase II trials before seeking a partner for worldwide rights.

Neuralstem has also entered into collaborations in Taiwan, including one with China Medical University & Hospital, to advance development of its human spinal cord neural stem cell therapies for amyotrophic lateral sclerosis. It is also working with the hospital to commence a clinical trial focused on treating stroke.

Additionally, the company is planning a clinical trial for later this year in India, to assess the ability of its cell therapy to treat spinal cord injury. The Indian market is so large that companies like Neuralstem need to find a technological partner first to ensure access to the best neurosurgeons it can find, according to Richard Garr, CEO.

“We’re happy to do the proof of principle human studies ourselves before we look for a commercial and regulatory partner.”

Neuralstem notes that it has done most of its proof of principle collaborations with American universities such as the University of California, San Diego and the University of Michigan.

“We haven’t gone overseas because we can’t do it here in the U.S.,” Garr remarked. “We went overseas because we believe those are their own independent markets.” Garr points out that commercialization efforts for each country are independent of each other.

“The other reason” to move into Asian countries, he added, “is because if you don’t, someone else will. And then you end up in a fight trying to protect it.”

Neuralstem broke into Asia in 2008, when Korean conglomerate CJ CheilJedang bought $2.5 million worth of Neuralstem stock. CJ has an exclusive option to Neuralstem’s spinal cord cell products for five Asian nations: South Korea, Vietnam, Indonesia, Malaysia, and Singapore.

CJ would have the responsibility to take the products through regulatory approvals and commercialization in their markets. Garr expects CJ to decide what its first clinical trial will be and where, later this year.

Another U.S. stem cell company that has teamed up with a Korean company is Advanced Cell Technology (ACT). In 2008, ACT joined with CHA Biotech to form a joint venture aimed at developing ACT’s hESC-based hemangioblast (HG) platform for the treatment of blood and cardiovascular diseases.

On July 21, the companies announced that their venture, Stem Cell & Regenerative Medicine International (SCRMI), exclusively licensed the rights to the HG program to ACT for the U.S. and Canada and to CHA Biotech for Korea and Japan.

“The partnership itself had research scientists working on trying to get things ready for starting human trials. ACT has hired substantially all the scientists that were working on the joint venture”—10 SCRMI employees in all, Gary Rabin, ACT’s interim chairman and CEO, told GEN.

Rabin said the first IND will be filed for using the HG platform to generate renewable sources of transfusable blood platelets. The platelets could unlock a significant opportunity for ACT, namely in the military wound-care market.

Last year, Robert Lanza, M.D., ACT’s CSO, and Kwang-Soo Kim, Ph.D., of Harvard University’s McLean Hospital and the CHA Stem Cell Institute, won a $1.9 million NIH director’s opportunity award to explore the potential of induced pluripotent stem cells (iPSCs) as a source of universal red blood cells and platelets for transfusion.

Another Asian market ACT is keeping an eye on is China. In March, the company reported that China’s State Intellectual Property Office allowed its patent application to provide broad intellectual property protection for the manufacturing and pharmaceutical preparations of retinal pigment epithelial (RPE) cells from hESCs for degenerative retinal disease.

ACT has initiated a Phase I study with the RPE therapy in the U.S. Additionally, ACT has launched human trials for Stargardt macular dystrophy and advanced dry age-related macular degeneration. Data from those trials is expected to be published this fall, after the first three patients are tested in both trials.

Working in Europe

In Europe, Cytori won expanded approval for Celution last year. The sanction included new indications such as breast reconstruction, repair of soft tissue defects, as well as the facilitation of healing certain types of wounds such as those resulting from Crohn disease.

“We’re relatively close, we think, to getting approval for cardiac disease,” Dr. Hedrick added. “and we’re actually beginning to get reimbursement and working toward our own diagnosis-related group payments for the technology in Europe. So that series of decisions, predicated all on the early regulatory approval of the device, has really pushed us down the road of being very active in Europe.”

Cytori sees more potential partnerships among global medical device companies across Europe, particularly in Switzerland, where the company has an office in Zug. Neuralstem is collaborating with Albert-Ludwigs-University in Freiburg, Germany, on a treatment for Huntington disease. It also plans on undertaking a chronic spinal cord injury trial using spinal cord cells being developed at the Czech Institute of Experimental Medicine.

The ability of the European market to grow as a stem cell mecca will hinge, Siegel said, on the outcome of a pending court case that—while different on specifics—parallels the U.S. debate over hESC funding.

Later this year, the Court of Justice of the European Union is expected to decide whether to side with its advocate general, who termed stem cell patents “contrary to ethics and public policy,” or with Oliver Brüstle, Ph.D., who since 2004 has fought to maintain a 1997 patent covering methods for deriving neural cells from hESCs, despite a challenge from Greenpeace. Dr. Brüstle is director of the Institute of Reconstructive Neurobiology at the University of Bonn.

A decision against Dr. Brüstle would cement Asia’s place on the hESC end of stem cell research and commercialization. The U.S. remains schizophrenic, with President Barack Obama’s administration scrambling to approve new hESC lines, while the Sherley v. Sebelius court case and the nation’s political divide keep federal funding from being a certainty.

Yet all of that doesn’t necessarily hurt U.S. stem cell companies. As the past few years have demonstrated, they are perfectly capable of following the money and partners in pursuit of the science and show no signs of pulling back from their overseas activity.

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