PERTH, Australia – Stem cell therapy company Mesoblast Ltd. saw its stock drop 15% on the news that its allogeneic mesenchymal cell therapy, rexlemestrocel-L (Revascor), failed to meet the primary endpoint of a reduction in hospitalizations in its phase III advanced chronic heart failure trial.

Clinical outcomes of the DREAM trial were evaluated in 537 advanced heart failure patients (206 with class II disease as defined by the New York Heart Association, and 331 with class III disease) randomized 1-to-1 to either a sham procedure or a transendocardial injection by catheter of rexlemestrocel-L (150 million cells). All patients were continued on maximal oral agents for heart failure and were followed for at least 12 months post-procedure.

“We evaluated whether rexlemestrocel-L could affect both morbidity or mortality in these high-risk patient populations,” Mesoblast CEO Silviu Itescu told analysts during a Dec. 15 conference call. “The primary endpoint in the trial was reduction of recurrent hospitalization. We did not see a difference between treated or control patients in this endpoint.”

But the secondary endpoints of ischemic major cardiac adverse events, defined as a stroke or a heart attack, were significantly reduced in the overall patient population by 60%, “which was highly significant compared to sham-controlled patients [p=0.002]. This reduction in ischemic events was seen regardless of class II or class III patients.

“Moreover, we saw a very significant 60% reduction in cardiovascular death in patients with class II heart failure, who represented 206 patients out of the 537 total patients.”

Silviu Itescu, CEO, Mesoblast Ltd.

Both the treated and control patients demonstrated relatively stable disease for the first 20 months, Itescu said. But after about 20 months, control class II patients deteriorated and resembled class III disease with mortality, while the class II patients who received the treatment did not progress to class III status.

“This suggested that rexlemestrocel-L reduced mortality, especially in early stage disease. The dramatic reduction in mortality we’ve seen suggests this treatment could change the paradigm,” Itescu said.

“There is an urgent need for new therapies that can reduce the high death rates in heart failure patients by different modes of action from existing drugs which reduce hospitalization rates but have not significantly reduced mortality rates,” he added.

The trial results show that rexlemestrocel-L significantly reduces cardiovascular mortality when used early in heart failure patients at risk of disease progression.

Mortality benefit should support path to approval

Mesoblast Chief Medical Officer Fred Grossman said that he expected the mortality benefit would support a potential path for approval of rexlemestrocel-L in patients with advanced chronic heart failure.

Mesoblast has had “multiple meetings with the FDA,” Itescu said, and it was clear that reduction in mortality is key. “Any therapy that has this degree of reduction in mortality in a well-conducted randomized placebo-controlled study of this size has to be taken seriously in its ability to change the natural course of the disease,” he added.

There was a significant benefit in the class II population but not so much in the class III population, he said, noting that Mesoblast would need to identify the optimal time to intervene.

Mesoblast has two distinct cell therapy products in development. Rexlemestrocel-L is being developed for local delivery into the myocardium for chronic heart failure and via intra disc for severe chronic low back pain.

Remestemcel-L is being developed for inflammatory conditions such as acute graft-vs.-host disease (GVHD) and acute respiratory distress syndrome (ARDS).

Mesoblast received a complete response from the FDA in October for remestemcel-L even though approval was highly anticipated after the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 9-1 that the stem cell therapy showed evidence of efficacy as a treatment for steroid-refractory acute GVHD in children. Remestemcel-L would be the first FDA-approved GVHD treatment for children younger than 12 and the first MSC product approved in the U.S.

Mesoblast also inked an exclusive global licensing deal with Novartis AG for the development, manufacture and commercialization of remestemcel-L, with an initial focus on ARDS, including that associated with COVID-19. That trial is ongoing.

Mesoblast shares on the Australian Securities Exchange (ASX:MSB) dropped more than 15% on the news, falling AU69 cents to AU$3.85 per share on market close Dec. 15.