Date: 2015-09-29
Type of information: Presentation of results at a congress
phase: 2
Announcement: presentation of results at the 19th Annual Scientific Meeting of the Heart Failure Society of America
Company: Mesoblast (Australia)
Product: mesenchymal precursor cells (MPCs)
Action
mechanism: stem cell therapy
Disease: end-stage or class IV New York Heart Association (NYHA) heart failure
Therapeutic area: Cardiovascular diseases
Country: USA
Trial
details: The multi-center, randomized, placebo-controlled trial compared outcomes in 30 endstage or NYHA class IV heart failure patients requiring LVAD mechanical support who received either a single low dose injection into damaged heart muscle of allogeneic, or off-the-shelf, MPCs or a placebo injection. (NCT01442129)
Latest
news: * On September 29, 2015, Mesoblast announced that additional Phase 2 trial results of its lead product candidate for the treatment of chronic heart failure (CHF) were presented at the 19th Annual Scientific Meeting of the Heart Failure Society of America in National Harbor, MD, USA held from 26-29 September. The results showed that Mesoblast's mesenchymal precursor cell (MPC) therapy had the greatest cardioprotective effect in the subset of patients with more advanced heart failure. A post-hoc analysis was performed in 30 patients from the Phase 2 trial who had been randomized to receive either placebo or a single administration of 150 million MPCs (MPC-150-IM). The results suggest that patients with advanced heart failure may be an optimal target population for treatment with Mesoblast's MPC therapy. The objective of the analysis was to evaluate the efficacy of MPC-150-IM in patients with advanced heart failure, as defined by substantial baseline left ventricular (LV) contractile abnormality (LV end systolic volume, LVESV, greater than 100 ml). LVESV greater than 100 ml is more than three standard deviations above normal LVESV and is a predictor of poor long-term outcomes in patients with CHF. A further sensitivity analysis across every decile in baseline LVESV between 70 ml and 120 ml confirmed the findings seen in the stratification using a LVESV greater than 100 ml. Cardiac remodeling by echocardiography at baseline and 6 months, time-to-first heart failure-related major adverse cardiovascular event (HF-MACE) by Kaplan-Meier analysis and incidence of total (recurrent) HF-MACE over 36 months were assessed. Key findings were: - control patients with baseline LVESV greater than 100 ml had the greatest deterioration (adverse remodeling) over 6 months in terms of worsening in both LVESV and left ventricular end diastolic volume (LVEDV), and loss of left ventricular ejection fraction (LVEF) Key conclusions are: - baseline LVESV greater than 100 ml identified a rapidly deteriorating sub-group of CHF patients with LV systolic dysfunction who experience a high rate of adverse outcomes An ongoing Phase 3 trial, using a time-to-first-event analysis of HF-MACE as the primary endpoint, is being conducted in 1,165 patients by Mesoblast's development and commercial partner, Teva Pharmaceutical Industries, across multiple sites in North America to investigate the use of MPC-150-IM in patients with advanced CHF. The Phase 3 trial is enriched for patients with high baseline levels of NT-proBNP and a heart failure hospitalization within the last nine months, two inclusion criteria known to predict adverse outcomes in CHF. This enrichment is expected to result in the majority of enrolled patients having LV systolic dysfunction, baseline LVESV greater than 100 ml and high rates of HF-MACE. Following recent discussions with the FDA, an interim analysis will be performed when 50% of the HF-MACE have occurred which will include a test for superiority allowing for the possibility of stopping of the trial early based on overwhelming efficacy. * On June 25, 2014, the australian regenerative medicine company Mesoblast announced that trial results evaluating a low dose of Mesoblast\'s proprietary mesenchymal precursor cells (MPCs) in patients with end-stage or class IV New York Heart Association (NYHA) heart failure who receive a left ventricular assist device (LVAD) have been published in the June issue of the American Heart Association journal Circulation. The trial was sponsored and funded by the United States National Institutes of Health (NIH) and coordinated by the NIH-funded Cardiothoracic Surgical Trials Network (CTSN). The trial investigators concluded that administration of a low MPC dose appeared to be safe and there was a potential signal of efficacy. The trial results showed that a single low dose MPC injection was associated with increased ability to maintain circulation without LVAD support, reduced early mortality, and reduced rehospitalization rates compared with control injections. At the trial\'s 90-day primary endpoint for safety and exploratory efficacy, a single lowdose injection of MPCs (25 million cells) into the damaged heart muscle resulted in: • decreased rate of immunization and allosensitization (10% vs 30% in controls)
- over a 6 month follow-up period, the 150 million MPC dose resulted in placebo-corrected significant reductions in LVESV of 57 ml (p equals 0.007) and LVEDV of 54 ml (p equals 0.004), and an increase in LVEF of 8.1 absolute percentage points (p equals 0.068) in patients with baseline LVESV greater than 100 ml
- all of the HF-MACE seen over 36 months in the Phase 2 trial occurred in control patients with baseline LVESV greater than 100 ml; the annualized HF-MACE rate was 24% in this group, with an overall 71% HF-MACE rate over 36 months
- in contrast, no HF-MACE were seen over the entire 36 months in 150 million MPC-treated patients with baseline LVESV greater than 100 ml (p equals 0.0007 when analyzed by Kaplan-Meier time-to-first-event analysis and p is less than 0.0001 by incidence analysis for total/recurrent HF-MACE, 0 versus 11 events).
- in these patients, a single administration of 150 million MPCs resulted in a significant cardioprotective effect and prevention of any HF-MACE over 36 months of follow up
- patients with baseline LVESV greater than 100 ml may be an optimal target group for the potential cardioprotective benefits of MPC therapy.
• increased proportion of patients successfully weaned from their LVAD mechanical support (50% vs 20% in controls)
• decreased mortality rate (0% vs 30% in controls).
Over 12 months of follow-up, MPC treatment resulted in:
• no cell-related immune responses or adverse events
• longer duration of successful LVAD wean than in controls at each time point evaluated
• increased proportion of patients tolerating one or more LVAD weans (85% versus 40% in controls)
• longer median time to first re-hospitalization (91 days vs 51 days in controls)
• decreased number of patients re-hospitalized over one year (22% vs 38% in controls)
• decreased rehospitalization rate from major gastrointestinal bleeding episodes (event rate/patient-year 0.55 vs 0.93 in controls)
• similar survival rates to controls.
The CTSN investigators stated that the results were promising and are planning next studies to evaluate the potential for higher or additional MPC doses to enhance the ability to wean LVAD recipients off mechanical support.
The article is ; \"Mesenchymal Precursor Cells as Adjunctive Therapy in Recipients of Contemporary Left Ventricular Assist Devices\". Deborah D. Ascheim, Annetine C. Gelijns, Daniel Goldstein, Lemuel A. Moye, Nicholas Smedira, Sangjin Lee, Charles T. Klodell, Anita Szady, Michael K. Parides, Neal O. Jeffries, Donna Skerrett, Doris A. Taylor, J. Eduardo Rame, Carmelo Milano, Joseph G. Rogers, Janine Lynch, Todd Dewey, Eric Eichhorn, Benjamin Sun, David Feldman, Robert Simari, Patrick T. O’Gara, Wendy C. Taddei-Peters, Marissa A. Miller, Yoshifumi Naka, Emilia Bagiella, Eric A. Rose, and Y. Joseph Woo. Circulation. 2014;129:2287-2296, doi:10.1161/CIRCULATIONAHA.113.007412.
