Regenerative medicine pioneer Aastrom Biosciences Inc. enrolled the first patient in its Phase III REVIVE trial assessing the efficacy and safety of ixmyelocel-T in critical limb ischemia (CLI). The primary endpoint of the trial will be amputation-free survival at 12 months.

Ixmyelocel-T is a patient-specific multicellular therapy expanded from a patient's own bone marrow and delivered directly to damaged tissues.

The randomized, double-blind, placebo-controlled study will be conducted at 80 sites in the U.S. and will include 594 CLI patients with existing tissue loss due to ischemia who have no option for revascularization. Patients will be followed for 18 months, including 12 months from randomization for efficacy and an additional six months for safety.

Ann Arbor, Mich.-based Aastrom said the landmark study, which received a special protocol assessment (SPA) from the FDA, is the largest ever conducted in CLI. The REVIVE trial also was granted fast-track designation by the FDA.

"There are no good treatment options for these patients today," Tim Mayleben, Aastrom's president and CEO, told BioWorld Today. "The only treatment option is amputation, and that's not a good option."

William R. Hiatt, professor of medicine at the University of Colorado and president of CPC Clinical Research, a nonprofit academic research organization, is leading an independent steering committee of vascular medicine and clinical research experts who will offer oversight and clinical guidance during the trial. Members of the committee helped Aastrom in the process to achieve the SPA.

"When you're talking about investing tens of millions of dollars into a Phase III study, you want to have as much confidence as you can that, at the end, the FDA is going to be of the mindset that the protocol design and the statistical plan meet their requirements," Mayleben explained.

Aastrom filed the SPA in October 2010 and reached agreement with the FDA on the trial design in July 2011 . (See BioWorld Today, Oct. 21 , 2010.)

The company has confidence in the Phase III study, Mayleben added, after a Phase IIb study of ixmyelocel-T in CLI patients with no revascularization options demonstrated that patients in the treatment arm had a 62 percent reduction in risk relative to placebo in the primary endpoint of time to first occurrence of treatment failure. While the study was not powered to show statistical significance in the secondary endpoint of amputation-free survival, results from a subgroup of 45 patients with wounds at baseline showed a positive trend (21 percent in the ixmyelocel-T group vs. 44 percent for the control event rate). Those data were presented in November 2011 at the American Heart Association Scientific Sessions in Orlando, Fla.

Ixmyelocel-T is manufactured using Aastrom's automated, fully closed cell-processing system, starting with a small aspirate from the patient's own bone marrow. The company's technology then selectively expands mesenchymal cells, monocytes and alternatively activated macrophages – up to several hundred times more than the number found in the patient's bone marrow – while retaining many of the hematopoietic cells collected from the bone marrow sample. The bone marrow-derived product is subsequently delivered to the patient.

Because "our product is really a process," Aastrom also sought – and received – assurance that the FDA was comfortable with its manufacturing processes, Mayleben said. Those challenges met, the company hoped to begin the Phase III trial in the fourth quarter of 2011 , he added, but "lining up 80 sites across the United States, qualifying those sites and making sure those sites are ready to screen and enroll patients" wasn't completed until last month.

Aastrom expects Phase III enrollment to take about 18 months. With the endpoint occurring 12 months after the final patient is enrolled, Mayleben said top-line results would be reported in the fourth quarter of 2014.

In the meantime, Aastrom plans to complete a financing this quarter, though Mayleben was mum on details.

In the second quarter, Aastrom plans to report final results from two Phase I/II studies and to launch a randomized, double-blind, placebo-controlled Phase IIb of ixmyelocel-T in ischemic dilated cardiomyopathy.

Once the Phase III in CLI is complete and a biologics license application (BLA) is filed, Aastrom will seek to partner the cell therapy product for commercialization. The company already is meeting with potential commercialization partners – particularly ex-U.S., although some have expressed interest in the U.S. market, as well.

Although Mayleben was reluctant to acknowledge that regenerative medicine companies face a higher regulatory bar than other biotechs, he admitted the regenerative medicine space "is still plagued by the sins of the past" – the hype and so-far unrealized potential of stem cells. The FDA has approved only one cell therapy product for a medical indication – Dendreon's Provenge, which has struggled commercially. (See BioWorld Today, April 30, 2010, Aug. 5, 2011, and Nov. 4, 2011.)

Still, regenerative medicine is following the same successful, albeit arduous, track as antibodies, which took more than a decade to become fully accepted in biotechnology, noted Mayleben, who also addressed the topic during a regenerative medicine panel at the Biotech Showcase 2012 in San Francisco. (See BioWorld Today, Jan. 12, 2012.)

"My view is that we're on the right trajectory," he said. "Over the next three to five years, we're going to see a number of regenerative medicine and cell therapy companies get through final clinical trials and BLA submission and achieve commercial success."

Shares of Aastrom (NASDAQ:ASTM) gained 3 cents to close Thursday at $1.82.