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By Marie Powers

News Editor

The first sites are screening patients in the pivotal U.S. phase III trial of ECCS-50, the adipose-derived regenerative cell (ADRC) therapy developed by Cytori Therapeutics (San Diego), in the lead indication of scleroderma. The trial, dubbed STAR (Scleroderma Treatment With Celution Processed Adipose Derived Regenerative Cells), will evaluate the efficacy and safety of an autologous graft consisting of ADRCs processed with the company's Celution system to treat hand dysfunction caused by scleroderma.

The randomized, double-blind, controlled trial is expected to enroll 80 patients, who will receive a single dose of ECCS-50 or placebo. The primary endpoint is improvement in hand function, measured at 24 weeks using the validated Cochin Hand Function Scale, according to Cortellis Clinical Trials Intelligence. However, the company plans to follow patients in STAR for at least a year and use those data in its filing with the FDA.

The inclusion of more than a dozen secondary endpoints will provide a broader picture of the effectiveness of ECCS-50 on disease modification, according to Marc Hedrick, president and CEO of San Diego-based Cytori. They include measures such as finger circumference, grip and pinch strength, improvement of blood vessel morphology in the nail bed and digital ulcer count, as well as markers for Raynaud's syndrome and quality of life indicators.

STAR and its design were predicated on promising data from a phase II pilot trial, SCLERADEC-I (Assessment of the Subcutaneous Reinjection of Human Autologous Adipose-derived Stromal Vascular Fraction [Celution System] in the Hands of Patients Suffering From Systemic Sclerosis), which enrolled 12 patients at a single site in France, evaluating safety and tolerability at two and six months as well as improvement in the Cochin functional index. Findings from the trial, published last year in Annals of Rheumatic Diseases, suggested the treatment was safe and potentially effective in improving certain hand symptoms in patients with scleroderma.

Subsequent follow-up of the SCLERADEC-I patients at 12 months showed the beneficial effect of ECCS-50 therapy in scleroderma persisted beyond 12 months. Those data were accepted for publication and are in press, according to Hedrick.

Cytori has confronted several important challenges in bringing ECCS-50 to late-stage development in scleroderma, not the least of which was the decision by the FDA's Center for Biologics Evaluation and Research (CBER) to regulate the therapy as a device rather than a drug.

"While we have orphan drug designation in Europe, we don't have that in the U.S.," Hedrick told Medical Device Daily.

Cytori has engaged in frequent meetings with the agency to evaluate the Celution system. Last month, the company received follow-on investigational device approval from the FDA for recent updates to the system, including enhanced software code to improve the efficiency of the bedside therapeutic manufacturing process for ECCS-50.

Although CBER decided to regulate the cellular therapeutic generated by the Celution cell manufacturing system under the device pathway, the FDA nevertheless agreed to accept the preliminary data package from SCLERADEC-I as the basis to initiate the U.S. phase III.

Cytori expects the first patients in STAR to be treated this month, with most sites active by October. Enrollment could take approximately one year.

'We're not suggesting this is a cure'

In the EU, where ECCS-50 received orphan drug designation in April for the treatment of scleroderma, Cytori received a green light from the French government to conduct the randomized, double-blind, placebo-controlled SCLERADEC-II study that would enroll 40 patients at five sites and could serve as the basis for a marketing authorization application to the EMA.

"That trial will likely finish ahead of the U.S. trial," Hedrick said. "If those data are available, and it's a shorter time point, we would take that directly to the EMA, which could be a very rapid turnaround time." Findings from STAR could be used to supplement the SCLERADEC-II data package in Europe, he added.

The European trial also includes a crossover arm to cryopreserved cells, allowing Cytori to gather data on potential use of these cells for follow-on treatment. Cytori's therapeutic approach involves the removal of adipose tissue from a patient, with those cells processed and formulated into ECCS-50.

"We could take a few extra cells and cryopreserve an additional dose or more for those patients so that, if they do need to be re-treated downstream, the therapy would be available in a very simple logistical approach," Hedrick said. "We'll be able to study that in this trial and potentially get approval for the cryopreserved version of the therapeutic, as well."

Scleroderma is a chronic, progressive condition, and "the hand complication is the biggest unsolved problem right now," he pointed out. Because ECCS-50 appears to work on a multimechanistic level, addressing the related ischemia and inflammation, "we have high hopes for this indication," Hedrick said. So far, data suggest that a single initial dose offers clinical benefit, possibly augmented by a repeat dose at one to three years.

"We're not suggesting this is a cure for the hand-related condition, but if we can start showing substantial benefit for these patients, out beyond one year, this would provide dramatic improvement in their lifestyles," he said.

Cytori plans to look for a partner to commercialize its cell therapy in scleroderma in Europe and the Middle East. "We're in active discussions right now," Hedrick said, noting that the process has gained a sense of urgency from "an interesting named patient opportunity" in Europe that could allow the company to pre-launch the product in conjunction with the SCLERADEC-II trial rollout in Europe. "We think it's wise to find a partner who has experience in that area," he added.

The U.S. is a different story. Twenty sites are approved for the STAR trial, representing the majority of scleroderma centers of excellence in the U.S.

"We're very much dedicated to going direct to market in the U.S." Hedrick said. "In the meantime, we're working on the reimbursement and commercialization pathways, in parallel to the trial."

In addition to the scleroderma work, Cytori is rapidly advancing ECCO-50 in osteoarthritis of the knee (OAK). Demand for the phase IIa/b trial was so high that it was fully enrolled six months ahead of schedule. The company envisions cell therapy in OAK as a means to bridge the treatment gap between nonsteroidal medications or lifestyle modifications and last-resort knee replacement surgery.

"We're in scramble mode to be ready for phase III," Hedrick acknowledged.

An investigator-sponsored phase III of the cell therapy in male urinary incontinence also is preparing to launch in Japan, supported by the Japanese government. Provided the 45-patient trial succeeds, the company would likely receive approval in the indication in Japan, "and if it works in men, it's a pretty short development path to evaluate whether the treatment works for female incontinence," Hedrick said.

Although the company completed two phase II studies in a fourth indication of heart failure, "strategically, we've pulled back on our investments in the cardiac area," Hedrick admitted. Although Cytori still has faith in its therapy in the heart failure indication, "the amount of capital required to bring a cardiovascular therapy all the way through the space probably doesn't warrant the investment, given where the company is in its life cycle," he said. "We have a number of other indications that we can bring to market much more quickly."

The decision to put the heart failure indication "in the parking lot for now" had nothing to do with Cytori's voluntary hold on enrollment in the ATHENA and ATHENA II trials, according to Hedrick. The hold was based on the company's safety review of reported cerebrovascular events, when the same undisclosed symptom, which later resolved, occurred in three patients.

Enrollment resumed several months later. Interim six-month data from the trials have been submitted for presentation at the American Heart Association Scientific Sessions in Orlando in November. The company recently received and is analyzing the 12-month data.

Cytori, which reported quarterly results after Thursday's market close, disclosed cash and debt balances of approximately $23.8 million and $17.7 million, respectively, as of June 30. The company had second quarter and year-to-date operating cash burn of $4.8 million and $9.8 million, respectively, compared to $9.2 million and $18.1 million for the same periods in 2014.

Shares (NASDAQ:CYTX) closed Friday at 41 cents, off a penny.

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