Crystal Proud, MD: Standard of care for our boys with Duchenne muscular dystrophy includes the institution of corticosteroid administration. Typically, when we start to see them change in their function around age 4 to 6 years, we start them on an oral corticosteroid regimen with either prednisone or deflazacort, and this has been demonstrated to prolong ambulation. With that we tend to see a reduction in the need for scoliosis surgery, and it may have positive benefits on the pulmonary function and perhaps cardiac function as well. Institution of oral corticosteroids is considered standard of care for our patients with Duchenne muscular dystrophy.
Oral corticosteroids, as with any medication, have accompanying potential for adverse effects, so we have to monitor for that. One potential adverse effect is impact to bone health, so we monitor bone health through a combination of ways, including x-rays to look at bone density, most typically the DEXA [dual-energy x-ray absorptiometry]. We also measure vitamin D levels on an annual basis, trying to optimize those levels in addition to utilizing calcium and vitamin D supplementation to maintain bone health. Corticosteroids can increase appetite, and this is where we utilize the help of our dietitians to try to optimize the nutritional health of our patients, attempting to help them avoid becoming overweight, which can be very challenging, especially in boys who have limitations of their mobility. There are some other potential adverse effects of corticosteroids that we have to keep in mind as well, and this is routinely evaluated by the neuromuscular specialist at each visit.
Emma Ciafaloni, MD: Among the treatment of Duchenne muscular dystrophy, eteplirsen belongs to a group of novel medications. This has been fairly recently approved by the FDA, and they’re gene-modifying treatments. They allow skipping of the mutated region of the gene, so that the gene can be back in-frame and able to actually produce some dystrophin. It’s not gene transfer, but it’s a gene-modifying treatment that belongs to the group of exon skipping medications and basically has been proven to improve production of dystrophin. Eteplirsen is applicable to only about 13% of patients who have the correct mutation that can actually be amenable to skipping of exon 51. This is not a medication for all Duchenne patients, but only for a portion with certain mutations.
The mechanism of action is this is a morpholino antisense oligonucleotide that attaches to a certain region of the messenger RNA in the dystrophin gene and allows the transcription of some dystrophin protein. You are basically skipping the missing portion of the gene to allow for transcription of some dystrophin. Rather than producing zero dystrophin, with this medication there is partial production of dystrophin protein. This particular drug is given once a week through an IV intravenous infusion, usually at the beginning when the medication is initiated in a patient. the first infusions are given in an infusion center in the hospital as an outpatient, and then once it’s established that a patient is tolerating the medication well and generally this is the medication that has quite a safe adverse-effect profile, then many patients receive the infusion weekly at home with just a nurse coming to the home.
Amy D. Harper, MD: With each new diagnosis of Duchenne, the first step is always to understand the genetics because that is really going to pinpoint the best genetically based therapy for that patient. With eteplirsen, this medication is going to skip exon 51 and essentially is going to take that piece out, so you can take an out-of-frame mutation and transfer it to an in-frame mutation. Making it a milder disease is the idea. But you must have the right genetics, so it must benefit that child to remove that particular gene. If your gene changes such that it won’t make a difference, then this is not the medication for that particular child. Sometimes there is a duplication in the DMD gene, and this would not be the appropriate therapy for duplication. If your deletion was in the wrong area, then it’s not going to be a benefit to you to skip exon 51. What they were able to show, in terms of efficacy, is that there was 2.8-fold increase in the dystrophin. Typical adverse events in the studies included headaches, abdominal pain, nausea, and vomiting—those are the most common adverse effects in that category of medications.
Golodirsen is an exon 53 skipping treatment, so you have to have a mutation that is amenable to exon 53 skipping. If you take that 1 out, does it take the reading frame into end frame? Knowing the genetics ahead of time is important with that. Golodirsen did get FDA approval through an accelerated process, and I think we’ll continue to see medications of this type get accelerated approval just because they have gone through rigorous trials and are beginning to show more benefit.
Crystal Proud, MD: Golodirsen has recently achieved FDA approval, and this is a unique medication because it really is geared toward a specific DNA change. We were talking previously about the puzzle pieces that make up the dystrophin gene. Many of our patients have missing puzzle pieces that lead to a disruption of that reading frame when that protein is trying to be created in the transcription translational process. Golodirsen is geared to helping to facilitate correction of that reading frame by allowing what’s called exon skipping. In particular, allowing exon skipping for what we consider to be a 53 skippable DNA change. This is allowing for exon skipping 53, leading to an improvement in that reading frame to create dystrophin protein. In the clinical trials it was demonstrated to lead to a clinically significant improvement in the dystrophin production, as was examined by muscle biopsies. This allowed for the FDA approval of that medication. It is an intravenous medication administered on a weekly basis to patients who are amenable to exon 53 skipping.