Cell Therapy Shows 'Hope' for Duchenne Cardiomyopathy

Deborah Brauser

November 22, 2017

ANAHEIM, CA – "Minimally invasive" treatment with cardiosphere-derived cells (CDCs) may improve CV outcomes in boys and young men with cardiomyopathy secondary to Duchenne muscular dystrophy (DMD), new research suggests[1].

In the Halt Cardiomyopathy Progression in Duchenne (HOPE-Duchenne) trial, which included 25 patients with DMD, those randomly assigned to standard care plus an infusion of intracoronary allogeneic CDCs (CAP-1002, Capricor Therapeutics) had a 7% reduction in myocardial scars 1 year later, as measured by MRI. Those who received standard care alone had an increase in scars.

In addition, skeletal muscle function improved in those receiving the investigational therapy who had the most severe baseline performance of the upper limb (PUL) scores.

Although temporary atrial fibrillation (AF) was reported by five of the 13 patients receiving CDCs, this is common in young patients during cardiac catheterization, note the researchers.

Dr Ronald G Victor

Primary investigator Dr Ronald G Victor (Cedars-Sinai Heart Institute, Los Angeles, CA) told theheart.org | Medscape Cardiology that although the trial was small, he's excited about the signal of effectiveness shown for a patient population that has few treatment options.

"It's been so frustrating with all of the positive mouse studies; the mouse has been cured umpteen times. But it's been painful for the scientists and community to see what looks like a blockbuster to show no benefit in a clinical trial," said Victor. 

For the current study, "this is just the first step, but it's aptly named 'Hope.' We don't want to provide false hope, but I think there is some realistic hope here."

He presented the findings at the American Heart Association (AHA) 2017 Scientific Sessions.

After the presentation, official discussant and former US Food and Drug Administration (FDA) commissioner Dr Robert Califf (Verily Life Sciences, San Francisco, CA) patted Victor on the back, smiled warmly, and said: "Let's just hope this does as well in a bigger trial."

To theheart.org | Medscape Cardiology, Califf reiterated the importance of finding effective treatment for such "an excruciating disease."

"Now that we understand more about the etiology of the disease, we have a target; but we haven't found effective therapies yet," he said. For the current study, "I would say there's a flicker of hope, but I would urge caution against excitement because we don't want to raise expectations. The answer will come from a larger trial."

X-Linked Genetic Disorder

DMD is an X-linked genetic disorder affecting both skeletal and cardiac muscle and affects about one in 3600 boys, note the investigators. Average life expectancy is around 25 years, and most patients with DMD are unable to walk by the age of 12.

In addition, "DMD-associated heart failure exhibits loss of functional heart muscle and replacement by scar," they add.

"The need is great because there is no current treatment to address heart failure in these patients," coinvestigator Dr Eduardo Marban (Cedars-Sinai) said in a press release.

In mouse studies, intramyocardial CDCs have shown a reversal of "key pathophysiological hallmarks of Duchenne cardiomyopathy," while also improving global heart function, the researchers report.

"Unexpectedly, CDCs also increased exercise capacity, improved survival, and enhanced isolated skeletal muscle function" in the mouse models.

Because in-human heart-failure studies have suggested efficacy from CDCs, the investigators created the open-label, phase 1/2A HOPE-Duchenne trial. Marban developed the CDC technology used in the study, which used CDCs from donated heart muscle.

"This was a safety trial with multiple exploratory efficacy end points," Victor told meeting attendees.

12-Month Scar Reduction

The investigators enrolled 25 boys and young men aged 12 to 22 years (mean age 17.8 years) who had a myocardial scar greater than 4 segments (as measured by MRI) and were on a stable regimen of corticosteroids. Among the participants, 68% were dependent upon wheelchairs.

All were randomly assigned to standard care plus the intervention (treatment group, n=13) or standard care only (control group, n=12).

The treatment group received a one-time infusion of intracoronary 75 M cells into the three major coronary arteries. Standard care consisted of continued use of prescription medications.  

The efficacy end points included cardiac MRI scans and PUL test scores.

While myocardial scars increased in the control group from baseline to 12 months, the treatment group had a trend for reduction at 6 months (P=0.09) and a significant reduction at 12 months (P=0.03). At 12 months, the group difference in change score was 11.9%.

"A decreased scar is counter to the natural history of DMD," Victor pointed out.

The CDC group also showed improved regional systolic wall thickening, especially in the inferior wall (P=0.04 at 6 months, P=0.09 at 12 months). Although there was a similar trend in the anterior wall, it was not significant.

Onward to HOPE-2

PUL scores were greater at week 6 and at months 3, 6, and 12 in the treatment vs standard-care group, but the differences were not significant.

However, among the participants with middle and distal PUL scores less than 55 at baseline, signifying more advanced disease, 89% of those receiving CDCs had a sustained or improved score at 12 months vs no one in the control group (P=0.007).

Serious adverse events (AEs) at the end of the study included urinary-tract infection, fever/confusion, and ventricular fibrillation in the treatment group and femur fracture in the control group.

There were also "AEs consistent with an intracoronary infusion procedure," said Victor. In addition to transient AF in five members of the treatment group, all 13 members had periprocedural cardiac troponin elevation (vs two control-group members).

"This is the first trial to test cell therapy to treat heart disease" in this patient population, said Victor in the press release.

He added that the investigators are now planning the new HOPE-2 phase 2 trial, which will assess patients receiving CDCs via intravenous drip over several months. He said that, pending FDA approval, this study should begin enrollment in early 2018.

More Work Needed

After the presentation, Califf told attendees that the researchers should be congratulated on looking at such a tough disease for which "therapies are desperately needed. Even with the recent approvals, nothing is showing a dramatic improvement at this point."

However, this safety trial was so short and had so few participants that it was more of "a notion of a safety trial," he noted. That said, "I would agree that the data looked pretty good on the safety side."

He added that he appreciated the reporting of the increased signal for AF and the troponin elevation, and although this was a signal of harm, it wasn't of clinical harm.

"I just wish I could figure out how this therapy works, though," said Califf. "We have a lot of work to do and it's a tough area. Anything that can be done to sort out mechanisms better so that we can point therapy in the right direction would be good."

He noted that a small criticism is that all data for such a small study should have been presented, instead of bar graphs in some cases.

Also, he wasn't completely impressed with a P value of 0.03. "I don't know what to make of P values that hover around 0.05. I don't think 0.09 is that different from 0.03, but I'll grant that everything's moving in the right direction."

Overall, he noted that the pipeline is filling up with various treatments, but not in the direction of this population.

"It's my understanding that most of the therapies are aimed at younger patients, with the hope of keeping people as functional as possible for as long as possible," he said. "So I'm glad to see a treatment aimed at more advanced disease."

Standing Behind Past Decision

During his talk, Califf alluded to past conflict over another drug for this disorder.

In September 2016, the approval of eteplirsen (Exondys 51, Sarepta Therapeutics) for DMD by the US Food and Drug Administration (FDA) was extremely controversial, with some specialists saying the evidence did not support the drug's efficacy and others upset at the developmental program model used. As then-FDA commissioner, Califf was asked to weigh in on the decision made by Dr Janet Woodcock, the director of the FDA Center for Drug Evaluation and Research.

He answered with a 126-page memo that outlined why he supported Woodcock's decision to approve the drug under the accelerated approval pathway and that he deferred to her judgment.

Asked about that decision after Victor's presentation, Califf told theheart.org | Medscape Cardiology that although "there was a lot of struggle" over the approval, he still stands by it.

"I think we made a good decision," he said. "Hopefully things will play out in the postmarket phase and more will be learned about [the drug's] effectiveness."

The study was funded by a grant from the California Institute for Regenerative Medicine to Capricor. Support or guidance was provided by Coalition Duchenne, CureDuchenne, and Parent Project Muscular Dystrophy. The CDC used in HOPE were provided by Capricor Therapeutics. Victor has been a consultant to Capricor but was not paid by the company for this study. He has also been a site primary investigator (PI) for Catabasis Pharmaceuticals; received a research grant from Coalition Duchenne; and was a steering committee chair, global PI, and site PI for Eli Lilly. Disclosures for the coauthors are listed in the abstract. Califf reported no relevant financial disclosures.

Follow Deborah Brauser on Twitter: @MedscapeDeb. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.