Northbrook, Illinois-based Marathon Pharmaceuticals reports it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for the corticosteroid drug deflazacort as a treatment for Duchenne muscular dystrophy (DMD).
There is currently no FDA-approved treatment or cure for DMD, the most common and severe form of the disease — a congenital, chronic, degenerative muscle disorder that results in loss of ambulation, respiratory compromise and cardiac dysfunction.
Deflazacort has been granted Fast Track status, Orphan Drug designation, and Rare Pediatric Disease designation as a DMD treatment, and, if approved, it would become could be the first commercially available such treatment available in the U.S.
The past several months have been an emotional roller-coaster for people living with DMD and their families, with an FDA advisory panel voting not to approve Sarepta Pharmaceuticals’ investigational DMD drug eteplirsen in April, and the FDA’s rejection of BioMarin Pharmaceuticals’ investigational drug Kyndris earlier this year.
“This NDA submission starts a process that we hope will result in broad access to this medication for all of those living with Duchenne who need it,” said Jeff Aronin, Marathon Pharmaceuticals’ CEO, in a release. “We recognize the difficulty the Duchenne community has had in obtaining deflazacort and look forward to working closely with the FDA as they review our application.”
Marathon says its NDA filing is supported by a full preclinical and clinical study program, including results of two Marathon-licensed clinical efficacy trials involving more than 200 Duchenne patients ages 5 to 15. Data gathered in these studies show deflazacort treatment resulting in improvement in muscle strength and other functional outcomes in patients with DMD. In one of the randomized, double-blind, placebo-controlled and active comparator studies that followed 196 patients with DMD, deflazacort met its primary endpoint of improved muscle strength versus a placebo at 12 weeks.
Marathon also conducted seven clinical pharmacology and safety studies, and nine preclinical studies on deflazacort to provide evidence supporting either initiation of more clinical studies or marketing approval.
An expanded access program, Access DMD, is being operated by Marathon in the United States under FDA authorization to provide deflazacort — which is not currently approved in the U.S. for any indication — free of charge to patients with Duchenne while the NDA review process is ongoing. Patients, families, and physicians can learn more about ACCESS DMD, including a list of clinical sites participating in the program, by visiting http://www.AccessDMD.com or calling 1-844-800-4DMD (4363).
Various versions of deflazacort are available in several other countries where the drug is approved for treating certain disorders, including DMD in Canada.
A 2012 open access paper published in the journal Acta Myologica describes “The Canadian experience with long term deflazacort treatment in Duchenne muscular dystrophy.“ The co-authors, Laura C. Mcadam, Amanda L. Mayo, Benjamin A. Alman, and W. Douglas Biggar, variously affiliated with the University of Toronto; the Hospital for Sick Children; and Holland Bloorview Kids Rehabilitation Hospital, all in Toronto, Canada, note that deflazacort is the most commonly prescribed corticosteroid for treating Duchenne MD in Canada.
The researchers review long-term experience with deflazacort treatment at centers in Toronto and Montreal, observing that the drug — an oxazoline derivative of prednisolone with anti-inflammatory and immunosuppressive activity — has proved beneficial in both patient cohorts. It has been shown to prolong independent ambulation; improve and preserve cardiac and respiratory pulmonary function; delay onset of cardiomyopathy; reduce incidence of scoliosis; and improve survival. Compared to the corticosteroid prednisone, deflazacort has been shown in other diseases to cause fewer side effects; better preserve bone mass; and cause less weight gain, a better lipid profile, and less glucose intolerance.
Common side effects of deflazacort noted in their study include weight gain, decreased height, and formation of cataracts.
Marathon notes that less common but significant side effects of deflazacort include decrease in bone density (osteopenia) or bone fragility (osteoporosis) potentially leading to fractures; acne; irritation to the stomach lining; increased susceptibility to infection; sugar intolerance; and aggravation of diabetes, blood pressure elevation, and behavioral and mood changes. Other side effects common to both prednisone and deflazacort include behavior changes, increased appetite, cushingoid appearance, hirsutism, and gastric symptoms, and it remains unclear unclear how deflazacort affects bone health. However, the investigators conclude that overall, the Canadian experience supports use of deflazacort in treating boys with Duchenne MD.
A survey of members of the Canadian Pediatric Neuromuscular Group determined that in current care of pediatric DMD patients across Canada, deflazacort was the main corticosteroid prescribed, although two also occasionally prescribed prednisone.
“Duchenne muscular dystrophy is a devastating disease. Having broad access and clear guidance from the FDA on this treatment option, which has the potential to delay disease progression, would be an important step forward for our community,” said Pat Furlong, founding president and CEO of Parent Project Muscular Dystrophy, and whose two sons suffered from DMD and lost their battle with the disease in their teenage years. “We are committed to improving the care for people with this disease and are encouraged by this milestone and the critical efforts to persevere in the fight against Duchenne.”
DMD affects mainly boys and young men and is marked by progressive muscular weakening and wasting, leading ultimately to the inability to walk by the teen years or earlier, and severe respiratory and cardiac complications. Few patients live into their thirties.