Chantal Coles PhD NMDRC provides a Research Update…

On September 19th last year the U.S Food and Drug Administration (FDA) approved the first drug for the treatment of Duchenne Muscular Dystrophy, called EXONDYS 51™.

This drug, formally known as Eteplirsen, is a gene modifying agent that bypasses a stop codon of the dystrophin, forming a truncated or incomplete version of the dystrophin which would normally be non-functional. The result of such a therapy aims to render a functional version of the dystrophin protein to reduce the severity of DMD to a less debilitating form, similar to that of Becker Muscular Dystrophy.

Last week the U.S media released news that a 12 year old DMD boy from Ohio was about to commence treatment of EXONDYS 51™, the first to trial the drug following FDA approval. Whilst this is an exciting and promising time for the DMD community, we need to remain cautious about the potential of this drug as the clinical benefits have yet to be determined. Here is what you need to know about EXONDYS 51™ in order to maintain an open mind and not be too hopeful of a drug that although approved by the FDA, is still in its early stages.

• EXONDYS 51™ was approved under the accelerated approval pathway whereby promising new drugs are made available to patients offering an advantage over current drug treatments.
• It is important to note the drug is made available whilst clinical trials are still being conducted by the drug companies to determine a clinical benefit. The decision went against FDA advisory committee due the lack of quality of scientific evidence but was later overruled by Janet Woodcock, Director of FDA’s Drug Division.
• An appeal to this was raised but the commissioner of the FDA, Robert Califf, denied the appeal and accepted her decision. The scientific evidence from clinical trials showed patients receiving the drug showed an improvement in the 6-minute walk test (6MWT) over 36 months of treatment and after three years of treatment only 16.7% patients lost ambulation compared with 46.2%.
• However, the advisory committee wasn’t convinced due to the small number of patients used in the study.

This was advice made to the drug company, Sarepta Therapeutics, by the FDA previous to release of the findings.
• Currently, Sarepta are required to undertake a two-year randomised control study to assess clinical benefit. This includes determining the levels of dystrophin in skeletal muscle in EXONDYS 51™ treated patients.
• To date, they have shown dystrophin levels in muscle biopsies of patients receiving EXONDYS 51™ increased from 0.28% to 0.93%.
• Whether this increase in dystrophin is enough to slow-functional decline in DMD patients is to yet to be determined.
• Sarepta Therapeutics must provide such evidence in studies in the years to come to prevent the FDA from withdrawing EXONDYS 51™ as a treatment for DMD.
• EXONDYS 51™ is suitable to only 13% of DMD patients amenable to exon 51 skipping.
• EXONDYS 51™ was renamed from Eteplirsen and is developed by the drug company Sarepta Therapeutics of Cambridge, Massachusetts.
• EXONDYS 51™is administered at 30mg/kg per bodyweight once weekly as a 35-60 minutes intravenous infusion.
• EXONDYS 51™is well tolerated by most patients, some DMD patients have shown adverse reactions including balance disorder (38%), vomiting (38%) and contact dermatitis (25%) and to a lesser incidence (≥ 10%) contusion, excoriation, arthralgia, rash, catheter site pain and upper respiratory tract infection. Transient erythema, facial flushing and elevated have been reported on days of EXONDYS 51™infusion.
• EXONDYS 51™ is estimated to cost US $300 000/patient/year.
• EXONDYS 51™ is currently not available for use in Australia.