Just last year, the FDA approved Exondys 51 (eteplirsen) for DMD, over the recommendations of FDA scientists and an external scientific advisory committee. Read more.
Duchenne Muscular Dystrophy (DMD) is a progressive disease that strikes young boys. It is universally fatal, but advances in the understanding of its genetic and molecular underpinnings offer hope that gene therapies might one day help, said a researcher at the AMCP Managed Care & Specialty Pharmacy Annual Meeting, in Denver, during the March 29 session, “Duchenne Muscular Dystrophy: Advances and Controversies.”
Just last year, the FDA approved Exondys 51 (eteplirsen) for DMD, over the recommendations of FDA scientists and an external scientific advisory committee. Eteplirsen does an end-run around the gene mutation that causes DMD, bypassing a stop codon in the gene to allow production of a less-flawed version of the dystrophin protein. It only helps 10% to 15% of patients, but clinical testing was, controversially, limited to 12 patients.
The hope is that other gene therapies might one day offer dramatic relief. Until then, incremental clinical advances will continue to improve some patients’ lives.
“There have been dramatic changes in its natural history based largely on multidisciplinary care,” said Dennis J. Matthews, MD, of the University of Colorado School of Medicine in Aurora, Colorado. “What’s really changed over the past 15 or 20 years is the institution of steroids. Steroids have significantly increased the life expectancy and delayed the loss of ambulation.”
“The other areas that have changed significantly are cardiac, pulmonary and nutritional support,” Matthews said. Cardiac nerve conduction defects and cardiomyopathy are common; angiotensin-converting enzyme (ACT) inhibitor therapy or angiotensin receptor-blocking therapy are frequently prescribed.
With the institution of “really good cardiac management,” these advances have changed the natural history of DMD. But it remains a devastating, invariably fatal disease.
Because it is caused by gene mutations on the X chromosome, girls and women can be carriers but patients are boys. The DMD gene mutations disrupt normal production of dystrophin, a structural muscle protein that enhances muscle fiber stability.
Symptoms are usually apparent by age 5 years and include developmental delays in speech and walking, abnormal gait, frequent falling, and difficulty climbing stairs.
“The classic case is a little boy between 3 and 5 years old with a delay in walking and an abnormal gait pattern, with a wide walking base and a very significant enlargement of calf muscles,” Matthews said. “These boys usually have a speech delay, and if you ask them to get up off the ground, you’ll see that they have an abnormal way of doing that.”
Diagnosis was long made on the basis of muscle biopsy but now involves a simple blood draw and X-chromosome gene mutation test. Seventy percent of boys with DMD have a deletion mutation and the other 30% instead have duplication, translocation, or premature stop-codon gene mutations.
“We’re becoming very good at identifying the gene defects, leading to lots of opportunities to develop a lot of treatment modalities,” he noted.
Gene therapies and interventions
Early research and development is underway for gene therapies and other molecular interventions. Approaches being explored include “fixing the gene” through gene therapy or stem cells, Matthews said. It may also prove possible to substitute mutated genes, or to target the downstream effects of the gene using myostatin inhibitors, antiinflammatories, or protease inhibitors.
But because DMD is a rare and heterogeneous disease, clinical research is challenging. Based on an intensive case-finding effort in Colorado, prevalence is about 1.6 cases per 10,000 boys.
Families have advocated for more research.
Caregivers must commit to very long-term routine stretching exercises, although it now appears that a subset of affected boys are resistant to the benefits of these exercises. Some boys wear night splints or use other prosthetics to maintain a range of mobility for longer periods of time.
Prolonging function and lifespan are the goals of therapy.
“It is possible to strengthen dystrophic muscles, so we try to do that,” Matthews said.
Eventually, however, patients are rendered completely unable to move without assistance.
“Ambulation usually ceases around age 10 to 12 years,” he noted. “The boys have leg asymmetries and they fall. There’s a technique to measure this clinically and anticipate when the boys will lose ambulation.”
The biggest clinical advance in the treatment of DMD was the institution over recent decades of steroid therapy, Matthews emphasized. Steroid therapy with prednisone (0.75 mg/kg per day) or deflazacort (1 mg/kg/day) can improve patients’ overall function and delay their loss of movement.
“We’re not exactly sure how steroids work,” Matthews noted. “We used to stop steroids once the boys went into the wheelchair but now we’re finding that it protects the upper body-pulmonary and cardiac function and we very rarely cease the drugs based on mobility and function.”
Steroid therapy can bring complications, however, including excessive weight gain, behavioral issues, hypertension, glycosuria and bone fractures.
Research efforts are underway to identify minimal effective steroid dose and optimal dosing frequencies, and a move has emerged in recent years to dose only on weekends, he said.
Half of patients develop progressive spinal scoliosis, usually by age 12 to 15 years, although that is becoming a less frequent problem. Special wheelchairs have been designed to slow that process, he noted. Spinal fusion can also slow the progression of scoliosis.
Steroids are helping boys stay active and stronger until older ages than before steroid therapy, and that is helping to drive down scoliosis rates, Matthews explained. Steroids also delay the need for assisted breathing, although noninvasive positive-pressure nighttime ventilation-and eventually, full-time ventilation assistance-are prescribed.
Mucociliary clearance is an issue for boys with DMD; they need help coughing and cough assistance with mechanical vibration is often necessary.
One area of real hope for neuromuscular diseases including DMD is molecular genetics.
“We’ve seen tremendous advances in molecular genetics and have identified over 100 neuromuscular diseases,” he said. “I believe that treatment is likely within our lifetime.”