Cell-based therapies, enzyme inhibitors at vanguard of muscular dystrophy treatment

Key takeaways:

• New therapies for muscular dystrophy must go beyond traditional corticosteroid administration.
• Treatments that combine different mechanisms of action may expedite the process of finding effective therapies.

ORLANDO, Fla. — Cell-based therapies and enzyme inhibitors currently in development are likely to become the next-generation treatments for ambulatory and non-ambulatory forms of muscular dystrophy, according to a speaker.

“The approved therapies in Duchenne are corticosteroid agents,” Dimah Saade, MD, clinical assistant professor in the division of neurology in the Stead Family department of pediatrics at the University of Iowa’s Carver College of Medicine, said during her presentation at the American Neurological Association annual meeting. “There are treatment strategies aimed at enhancing or restoring dystrophin expression.”

Duchenne muscular dystrophy is a rare pediatric disease, yet it is the most common dystrophy found in childhood, which affects an estimated one in 5,000 live male births. There is no cure, and treatment options are limited, Saade said.

New drugs like givinostat (Duvyzat, Italfarmaco) — a histone deacetylase inhibitor that was approved by the FDA in March to improve muscle regeneration — have yet to prove efficacy beyond disease modification, she said.

Current novel therapeutics, Saade continued, include EDG-5506, an oral agent and selective fast myosin inhibitor which targets skeletal muscle and attempts to arrest mechanical stress injuries that may result in membrane injury.

Two major studies measuring the impact of cell-based therapies, HOPE-Duchenne and HOPE-2, investigated the safety and efficacy of cells taken from healthy human hearts and administered to a pediatric DMD population with concurrent cardiac issues.

HOPE-Duchenne is a phase 1/2 study including mostly nonambulatory children with cardiac fibrosis. Results showed that an intracardiac injection was linked to a clinically significant decline in arm function and improvement on cardiac MRI at 12 months. HOPE-2 is a phase 2 examination of an intravenous cardiosphere-derived therapy for late-stage DMD that demonstrated a significant change (1.8 points) in the Performance of Upper Limb scale score at 12 months after repeated IV administration.

Clinical trials such as the phase 2 ARCH and Grand Canyon trials for Becker muscular dystrophy, as well as phase 2 studies Lynx and Fox for Duchenne and a phase 2/3 study of an enzyme inhibitor to address sorbitol dehydrogenase deficiency, are also ongoing.

Additionally, Saade revealed that a phase 3, randomized, double-blind clinical trial of oral ribitol for Limb Girdle Muscular Dystrophy 21 is under way, and includes ambulatory and nonambulatory patients aged 12 to 60 years. This study will evaluate changes from baseline in the North Star assessment for the condition at 36 months, with results expected in 2025.

Once better treatments are approved, an arduous prior authorization insurance process will likely to follow, Saade noted. Starter drug packages or patient assistance programs may be offered as the authorizations cycle through every 6 to 12 months for all one-time treatments.

“Ultimately, there may be incremental benefit in combining treatments with different mechanisms of action,” she said. “Every precise diagnosis and understanding of the underlying disease is an essential first step in hopes of arriving at treatment.”

References:

Taylor M, et al. Neurology. 2019;doi:10.1212/WNL.00000000006950.

McDonald CM, et al. Lancet. 2022;doi:10.1016/S0140-6736(22)00012-5.