Small Heart Failure Studies Show Positive Trends for Cell Therapy

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NEW YORK, NYUpdated results from 2 small randomized studies provide promising signs that patients with cardiomyopathy and even advanced heart failure may benefit from cell therapy. The findings, involving catheter-directed endocardial delivery of bone marrow stem cells, were presented January 23, 2013, at the Eighth International Conference on Cell Therapy for Cardiovascular Disease.

In a phase 2a trial of moderate to severe heart failure, researchers led by Emerson C. Perin, MD, PhD, of the Texas Heart Institute (Houston, TX), enrolled 60 patients with ischemic or nonischemic disease. Patients were randomized based on date of enrollment to transendocardial injection with 1 of 3 doses—25, 75, or 150 million cells—of Revascor (Mesoblast, Melbourne, Australia) or standard care (n = 5 for each group) at 6 sites.

Revascor consists of mesenchymal precursor cells, which release cytokines that promote tissue regeneration and angiogenesis. The cells are harvested from healthy young adult donors and expanded in a proprietary process before injection.

Efficacy Signals for the Highest Dose

Kenneth M. Borow, MD, also of the Texas Heart Institute, provided an update on efficacy data from the cohort, who had been diagnosed on average 9 years earlier.

Dr. Borow explained that the investigators had adopted a heart failure-specific endpoint, known as HF-MACE, consisting of multiple decompensated heart failure events and cardiac death. Mean follow-up of about 15 months showed comparable numbers for HF-MACE and several individual components between controls and the 2 lower-dose groups. But there were no events in the highest-dose group, indicating a trend toward superiority vs. controls (table 1).

Table 1. Interim Analysis: Outcomes by Cell Dose

 

15-Month Follow-up

25 Million

75 Million

150 Million

Control

Cardiac Death, n

0

1

0

1

Hospitalization for Decompensated HF, n

2

4

0

3

Successfully Resuscitated V-Fib, n

1

0

0

0

HF-MACE

20%

33%

0

27%

Abbreviation: V-fib, ventricular fibrillation.

Kaplan-Meier analysis after a minimum follow-up of 24 months showed an incidence of HF-MACE of 33% for controls, 27% for the 25 million cell group, 33% for the 75 million cell group, and 0 for the 150 million cell group. According to Dr. Borow, that translates to a significant difference between the highest-dose group and the 3 other groups since there was no overlap in the 95% confidence intervals for the respective hazard ratios.

Meanwhile, improvements in LV end-systolic and -diastolic volumes vs. baseline began to emerge for the highest dose at 6 months (-7.3 mL, P = 0.015 and -9.7 mL, P = 0.020, respectively) and widened at 9 months, although the latter values were not significant due to reduced follow-up, Dr. Borow said. Despite this reverse remodeling, however, no change was seen in LVEF at either 6 or 12 months (P = 0.387 and P = 0.725, respectively).

In addition, although at 6 months there was no difference in the change in 6-minute walk test distances from baseline among any of the groups, by 12 months a trend appeared favoring the highest-dose group vs. controls (50.8 m vs. -1.6 m; P = 0.062).

Dr. Borow observed that by 1 year, data on functional exercise capacity, LV remodeling, and appropriate clinical outcomes were all pointing in a positive direction, warranting further study in a larger population of chronic heart failure patients.

According to Dr. Perin, the allogeneic therapy was generally well tolerated. Six of the 45 treated patients (13%) developed donor-specific antibodies, but only 2, both from the highest-dose group, had anti-HLA antibodies that persisted beyond 1 month. No clinical signs or symptoms were associated with the presence of anti-donor antibodies.

Special Stem Cell Brew for Cardiomyopathy

In another presentation, Jay H. Traverse, MD, of the Minneapolis Heart Institute (Minneapolis, MN), reported early data on use of an enhanced version of a patient’s own bone marrow to treat dilated cardiomyopathy.

For the phase 2a trial, 22 patients with a low ejection fraction (≤ 30%) and no revascularization options at 3 centers were stratified by ischemic or nonischemic etiology. Then they were randomized 2:1 to standard care or catheter-directed injection of a mix of autologous stem cells into the left ventricle (n = 9/3 controls for ischemic, n = 6/4 controls for nonischemic). Control patients were allowed to cross over to stem cell treatment after a minimum of 6 months.

Called Ixmyelocel-T (Aastrom, Ann Arbor, MI), the proprietary cell therapy consists of patients’ bone marrow aspirate cultured to enrich multiple cell types (eg, mesenchymal, CD14+ monocytes, and macrophages) that facilitate tissue remodeling and angiogenesis while reducing other types that increase the risk of rejection.

No procedural complications were seen. At 12-month follow-up, treated patients had fewer and later MACE (composite of cardiac death or arrest, MI, sustained ventricular arrhythmia, pulmonary edema, acute heart failure, unstable angina, and major bleeding within 1 week of the procedure) than controls, although the difference was not significant (log-rank P = 0.2062).

Interestingly, treated patients in the ischemic cohort fared better compared with controls in terms of mean events (0.22 ± 0.147 vs. 1.67 ± 1.202) than did those in the nonischemic cohort (0.83 ± 0.401 vs. 1.00 ± 0.577). In addition, patients with ischemic disease were more likely to see improvements over baseline with respect to New York Heart Association (NYHA) class, 6-minute walk test distance, and ejection fraction than either those with nonischemic disease or controls, although the differences were not significant (table 2).

Table 2. Improvement from Baseline at 12 Months

 

 

Ischemic Dilated Cardiomyopathy

Nonischemic Dilated
Cardiomyopathy

Combined Controls

> 1 NYHA Class

100%

40%

0

Six-Minute Walk Test

67%

50%

20%

Ejection Fraction

20%

40%

50%

 
Given the positive trends seen in this study, Dr. Traverse said, a larger phase 2b trial for the same patient population is slated to begin in early 2013.

 

 


 

Sources:1. Perin EC, Borow KM. Clinical outcomes and surrogate efficacy data for a phase II dose-escalation study of allogeneic mesenchymal precursor cells in patients with chronic heart failure of ischemic and nonischemic etiology. Presented at: Eighth International Conference on Cell Therapy for Cardiovascular Disease; January 23, 2013; New York, NY.

 

2. Traverse JH. Administration of Ixmyelocel-T in dilated cardiomyopathy: Results of the phase 2a Catheter-DCM study. Presented at: Eighth International Conference on Cell Therapy for Cardiovascular Disease; January 23, 2013; New York, NY.

 

 

 

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Disclosures
  • The heart failure study was sponsored by Mesoblast.
  • Dr. Perin reports receiving consulting fees from Mesoblast.
  • Dr. Borow makes no statement regarding conflicts of interest.
  • The Catheter-DCM study was sponsored by Aastrom Biosciences.
  • Dr. Traverse reports no relevant conflicts of interest.

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