The pioneering status of regenerative medicine is forcing developers and regulators to write the rules as they go, resulting in a highly collaborative regulatory environment that builds the framework for all subsequent regenerative therapies. Speakers at the recent “World Stem Cells and Regenerative Medicine Congress” explored that situation, highlighting many of the therapies in clinical trials now and some of the lessons they have learned.
Dendreon paved the way through many of the regulatory hurdles, winning approval in April last year for the first autologous cellular immunotherapy. “That set a precedent approval pathway,” notes Tim Mayleben, president and CEO of Aastrom Biosciences.
Nonetheless, the dearth of approved cellular therapies continues to present challenges and opportunities. “There are no hard and fast rules, so working with the FDA requires a more collaborative process,” Mayleben said. “Approach with sound data and work with the regulators there as scientists and colleagues.”
“Cell therapies are, necessarily, establishing the regulatory guidelines as they go,” said Kristin Comella, CSO for BioHeart. “Because we have a less formal relationship with our clinical reviewer at the FDA, we can call or email a quick note to get guidance about a particular approach or other issue,” she said.
BioHeart’s MyoCell® is a case in point. It reportedly improves cardiac function by populating regions of scar tissue within a patient’s heart with myoblasts derived from a biopsy of a patient’s thigh muscle.
MyoCell is developed from muscle-derived stem cells and can only form muscle, Comella emphasized. Therefore, they are used to help congestive heart failure patients form muscle to improve cardiac function. “They are delivered with a catheter through the femoral artery directly to the heart, so there is no need to crack open the chest,” she continued.
It is one of the few stem cell therapies currently in Phase III trials in the U.S. “Yet, stem cell therapies fall under pharmaceutical procedures,” Comella says, “which requires demonstrating potency. That is an almost impossible challenge for live cells,” she explained.
That sort of challenge is one of the reasons MyoCell’s development process has been so lengthy. “We conducted our Phase I study for MyoCell in 2001, and have spent more than $100 million, yet we still don’t have a commercial product.”
She suggested that a commercialization pathway should be developed to deal with autologous therapies, which are based upon a patient’s own cells, and to facilitate process innovation during development without returning the project to animal trials.
Mayleben outlined the development of Aastrom’s lead product, known generically as ixmyelocel-T, an autologous, expanded multicellular therapy derived from bone marrow.
“It’s unique in that we start with the patient’s own bone marrow—the body’s reservoir of stem and progenitor cells. It is expanded, so while we start with a very small aspirate, we significantly expand the number of important CD90 and CD14 auto+ cells.” And, he continued, “it is multicellular, containing many different types of cells, rather than only selected single cells such as mesenchymal stem cells. Therefore, it has multifaceted mechanisms of action.
“Bone marrow has been used successfully for 30 years, so it is well-characterized, safe, and efficacious, but unpatentable,” Mayleben said. Aastrom has built upon that record by expanding and enriching the cells and developing a patentable version.
Aastrom anticipates beginning Phase III trials in no-option critical limb ischemia (CLI) patients during the third quarter of 2011. The company has fast-track designation for the CLI program and is completing negotiations with the FDA for a special protocol assessment for the Phase III program.
Phase I trials were conducted in Germany, which, Mayleben said, “historically has had broader acceptance of cellular therapies and easier rules to navigate for deriving clinical data for experimental therapies.” That data was presented to the FDA before beginning later-stage U.S. trials.
The use of autologous cells also streamlined development. As Mayleben explained using a bread-baking analogy, “We’re not scaling up from a one pound loaf to a 10,000 pound loaf. We’re making one loaf of bread over and over. The FDA recognizes that.
“The real challenge—a lot of what we have to do—is to educate the regulators about our particular manufacturing method,” Mayleben continued. That will be a challenge for the industry for the next decade, he predicted, until a body of knowledge accumulates.