Medical Device Daily

NEW ORLEANS — Osiris Therapeutics (Baltimore) unveiled positive clinical data on its adult stem cell product Provacel in heart attack patients. The report was issued earlier this week at the scientific sessions of the American College of Cardiology (Washington).

The findings showed that patients receiving the mesenchymal therapy had significantly lower rates of adverse events, such as cardiac arrhythmias, as well as significant improvements in heart, lung and overall condition. Those efficacy results not only exceeded expectations, but also proved to be the proverbial icing on the cake, given that the 53-patient study achieved its principal objective of establishing Provacel's safety in the cardiac setting.

"The magnitude of the efficacy and the across the board nature of the efficacy were surprising to us," Randal Mills, company president/CEO, told Medical Device Daily's sister publication BioWorld Today. "Across all the different ways we tested them, these patients did better in pulmonary function, arrhythmias, cardiac function and 6-minute walk tests. And the fact that this was a double-blinded, placebo-controlled trial, where the physicians didn't know and the patients didn't know what they were getting, really helps to reinforce the validity of the statistical significance."

Of note, he said the benefits were seen in patients receiving the best standard-of-care, so their improvements came on top of existing treatments.

Among specific data, only 9% of those who received Provacel experienced an arrhythmic event compared to 37% of those receiving placebo (p=0.025). In addition, half the arrhythmias in the placebo group involved the ventricle, which are associated with scar formation in the affected portion of the heart following a heart attack and can signal a poorer prognosis, compared to 14 percent in the Provacel group.

Also, Provacel's anti-arrhythmic effects lowered the frequency of premature ventricular contractions, with 11% of Provacel patients experiencing clinically significant premature ventricular contractions compared to 24 percent of placebo patients across all time points (p<0.001).

Other data showed that 42% of Provacel patients had an improved overall condition at six months compared to 11% of those on placebo (p=0.027). Also, Provacel patients with major anterior wall heart attacks had a statistically significant 24% improvement in ejection fraction at three months and a 25% improvement at six months over baseline (p<0.05), while similar patients receiving placebo did not have significant improvement.

Furthermore, Provacel patients had significantly improved lung function as measured by improvement in FEV1 percent predicted values: 17 point Provacel vs. 6 point placebo (p<0.05). Placebo patients required repeat hospitalization sooner, after an average of 66 days, compared to 120 days for those treated with Provacel, and more often.

Going forward, Osiris plans to test the therapy in a sicker population of patients to better characterize its effects, given that there were greater improvements over placebo in patients with lower ejection fractures or more severe sites of infarct.

Future studies are likely to begin before final results from this trial, though more precise details on study designs aren't yet known. Patient evaluation is continuing for two years following treatment.

"So when we're powering our next round of trials," Mills said, "we're going to want to target those areas where we see the greatest benefit, and clearly that's patients with more severe infarct."

The intravenously delivered stem cells, partnered with Boston Scientific (Natick, Massachusetts) in this cardiac setting, confer a systemic benefit because of that route of administration, and that could be advantageous relative to potentially competing therapies. Mesenchymal stem cells migrate directly to sites of inflammation, Mills said, explaining how their "general reparative effects took hold in other things."

There were no patient deaths, and no toxicity was observed with Provacel, which was found to be well tolerated at all the three dose levels evaluated in the study: 500,000, 1.6 million and 5 million cells per kilogram of body weight. In addition, it produced no serious adverse events, and there were 5.3 adverse events per patient in those on Provacel compared to seven for placebo patients.

Current cell therapies for heart disease include those derived from skeletal muscles to regenerate a heart's contractile muscle, Mills said, and bone marrow. Both are directly injected into a heart.

The co-development arrangement with Boston Scientific provides Osiris with development payments as well as a $50 million loan to be repaid through future revenues. If approved, Osiris would handle manufacturing and Boston Scientific would market it for cardiac use.

In addition to the cardiac program, Osiris has the stem cells in two Phase III trials for steroid refractory Graft vs. Host disease and Crohn's disease. Both indications have been granted fast track status by the FDA.

Those data are due next year, and an initial approval could follow soon after.

In another stem cell study, researchers reported that they replaced scarred heart tissue with healthy muscle by administering intracardiac injections of autologous skeletal myoblasts, which are stem cells form the skeletal muscle.

The myoblasts were harvested form the patient's own skeletal muscles, thus avoiding potential immune system and tissue compatibility issues. No anesthesia was required in the catheter procedure and the 23 patients in the study were discharged within 24 hours of the procedure.

The patients had poor heart function and congestive heart failure marked by progressive weakening and inability of the heart to pump.

The control group consisted of 11 patients on standard drug therapy; the treatment group was given varying doses of ASM cells, ranging from 20 million to 600 million. After six months, the ASM group showed marked improvement in quality of life and potential heart function improvement, while those in the control group worsened.

Nabil Dib, MD, lead investigator, reported FDA approval of a Phase II study of the method in 160 patients.

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