Mesoblast said today that it and the FDA have agreed on a clinical pathway toward a marketing application for the company’s allogeneic cell therapy product candidate Revascor in end-stage heart failure patients implanted with a left ventricular assist device (LVAD).

That pathway will include a confirmatory Phase III trial of Revascor in LVAD patients, whose results will form the basis for a BLA filing. The confirmatory trial’s primary endpoint will be reduction in major mucosal bleeding events, while key secondary endpoints will include demonstrating improvement in various parameters of cardiovascular function, Mesoblast said.

The confirmatory trial is planned to be conducted with the International Center for Health Outcomes and Innovation Research (InCHOIR) at the Icahn School of Medicine at Mount Sinai in New York, in line with a Memorandum of Understanding signed earlier this year.

“We will work closely with the FDA and InCHOIR to generate the confirmatory clinical data needed for full marketing approval of Revascor in the prevention of this life-threatening inflammatory complication of an LVAD implant in end-stage heart failure patients,” Mesoblast chief executive Silviu Itescu, MBBS, FRACP, said in a statement.

Speaking with GEN recently, Itescu said the agency had given Mesoblast “very positive feedback” about Revascor during a July meeting. A month earlier, the FDA had granted of an orphan drug designation to Revascor for prevention of post-implantation mucosal bleeding, including from the gastrointestinal (GI) tract, in end-stage chronic heart failure (CHF) patients who require an LVAD.

At the 2018 American Heart Association Scientific Sessions, NIH Cardiothoracic Surgical Trials Network investigators presented results from a 159-patient, placebo-controlled Phase IIb study (NCT02362646) of Revascor in end-stage heart failure.

76% reduction in GI bleeding

The results showed that a single intra-myocardial dose of the cell therapy candidate resulted in a 76% reduction in major GI bleeding events and 65% reduction in related hospitalizations in end-stage heart failure patients implanted with an LVAD. The FDA has agreed with Mesoblast that the reduction in bleeding was an important clinical outcome in patients implanted with an LVAD, with the company citing studies showing that up to 40% of patients are rehospitalized as a result of major GI bleeding.

Results also showed Revascor did not achieve statistically significant successful temporary weaning from LVAD support at 6 months compared to the control group (61% vs. 58%), an outcome Mesoblast said reflected blood clots in the devices. The Phase IIb trial was funded and sponsored by the NIH’s National Heart, Lung, and Blood Institute (NHLBI) and the Canadian Institutes for Health Research.

The FDA has confirmed to the company that data from the Phase IIb trial can support product marketing authorization through a BLA along with confirmatory clinical data, Mesoblast said.

Revascor—once known as MPC-150-IM and rexlemestrocel-L—consists of 150 million mesenchymal precursor cells (MPCs) administered by direct injection into the heart muscle in patients suffering from CHF and progressive loss of heart function.

“We believe that our cells, by switching off the inflammatory process are able to reverse the abnormal vasculature sufficiently that bleeding is reduced,” Itescu said.

Revascor is regulated under the FDA’s Regenerative Medicine Advanced Therapy designation, created through the 21st Century Cures Act to accelerate development of cell therapies intended to treat serious diseases and life-threatening conditions.

Revascor is also the subject of another Phase III trial (DREAM HF-1, NCT02032004), designed to assess the candidate in advanced heart failure. The trial has completed patient enrollment across 55 centers in North America, with 566 patients randomized to receive Revascor or placebo. The study will be completed when sufficient primary endpoint events have accrued, Mesoblast said earlier this year.

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