The Lancet Publishes Landmark Trial of Duchenne Muscular Dystrophy Therapy

An investigational cell therapy preserved heart and muscle function in boys and young men with Duchenne muscular dystrophy, according to Phase III clinical trial results from Cedars-Sinai Health Sciences University investigators and colleagues published in The Lancet.

The therapy, called deramiocel, is the first treatment shown to preserve heart function in Duchenne muscular dystrophy, a rare inherited disease that progressively weakens muscles throughout the body. Heart failure caused by Duchenne commonly leads to early death.

"After more than two decades of hard work, we have demonstrated that deramiocel can slow or even halt not only the loss of upper limb function, but also progression of heart failure in boys and young men with Duchenne," said Eduardo Marbán, MD, PhD, executive director of the Smidt Heart Institute at Cedars-Sinai and senior author of the study. Deramiocel is based on Marbán's discoveries.

Duchenne muscular dystrophy primarily affects boys because it is caused by a mutation on the X chromosome. Children born with this mutation develop muscle weakness throughout the body, including in the heart. As they grow older, these children have difficulty running, jumping, pedaling a bicycle and doing other activities, and eventually lose the ability to walk. There is no known cure.

Positive Findings

The randomized, double-blind study, called the HOPE-3 trial, compared deramiocel to placebo in 106 participants ages 10 to 22 with advanced disease. Every three months for one year, participants received an IV drip of either deramiocel or a placebo.

Results showed that the therapy slowed weakening of skeletal muscles by 54% and slowed heart dysfunction by 91%. In patients diagnosed with a condition called cardiomyopathy, which impedes the heart's ability to pump blood, those who received deramiocel showed full preservation or slight improvement of heart function.

"The benefits we observed could mean important improvements in quality of life in people with advanced Duchenne," said Craig McDonald, MD, distinguished professor of Physical Medicine & Rehabilitation and Pediatrics at UC Davis Health and national principal investigator of HOPE-3. "If young people maintain their upper limb function, it will help preserve their ability to do normal activities, such as feeding themselves. The heart benefits could reduce mortality."

Decades in the Making

The potential therapy takes a different approach from other therapies that have been studied for Duchenne. Deramiocel is made from cells taken from healthy hearts donated for transplantation but unable to be used as such and that would otherwise be discarded. The work began in 2004, when Marbán first isolated a population of heart progenitor cells called cardiosphere-derived cells. The first clinical studies of cardiosphere-derived cells were performed at Cedars-Sinai, on patients who had survived heart attacks.

Results published in 2012 showed that the cell infusions regenerated heart muscle damaged by heart attack. Ever since, Marbán's team has been studying the broader therapeutic potential of these cells. The investigators have made several important discoveries, such as that cardiosphere-derived cells secrete packets of RNA molecules that help cells repair the body's tissues.

In 2011, Catherine Jayasuriya, the mother of a child with Duchenne and a patient advocate, influenced Marbán to turn his focus from studying how cardiosphere-derived cells could repair the heart after a heart attack to studying their potential for Duchenne muscular dystrophy. Jayasuriya's fundraising provided the seed funding needed for Marbán's laboratory to launch initial investigations. The biotechnology company Capricor Therapeutics licensed Marbán's technology and continued the work by running clinical trials studying the safety and efficacy of deramiocel.

"This is the first Phase III trial to show that a cell therapy is effective against a genetic disease, or any type of heart disease," said Marbán, the Mark S. Siegel Family Foundation Distinguished Professor.

Investigators plan to continue studying the therapeutic effects of deramiocel, including whether it can be used to treat other diseases with major unmet medical needs.

"These results represent an important advance for cell-based therapy, one driven by relentless scientific pursuit made by Dr. Marbán and team," said Shlomo Melmed, MB, ChB, executive vice president of Academic Affairs and dean of the Medical Faculty at Cedars-Sinai.

Authors: A complete list of HOPE-3 investigators can be found in the supplementary appendix of the study.

Funding: The HOPE-3 trial was funded by Capricor Therapeutics Inc.

Disclosures: Eduardo Marbán, MD, PhD, is an inventor of patents licensed by Capricor Therapeutics Inc. and holds founder's equity in the company.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn moreabout the university.