Treatments in Development for DMD


Crystal Proud, MD: Viltolarsen is another medication that may be applicable to our patients impacted by 53 skippable genetic mutations in the dystrophin gene. It is a medication that allows for a reading frame to be corrected for those 53 amenable patients. This leads ultimately to improvement in dystrophin production, and hopefully improvements in muscle function as we see increases in dystrophin production. The mechanism of action is such that it permits skipping of that exon 53 and allows for a reinstitution of the reading frame to produce dystrophin protein. When that dystrophin protein is improved in the amount that is produced, that ultimately we hope would lead to improvement in that muscle strength and muscle function.

Emma Ciafaloni, MD: This is a medication that is under review by the FDA under accelerated approval. It’s also an exon skipping drug that belongs to the same group as eteplirsen and golodirsen; they’re exon skipping medications. They’re meant to modify the gene mutation to allow skipping the mutated area of the gene to allow for production of dystrophin protein. This particular medication is for skipping mutations that are amenable to skipping of exon 53. It’s not approved, but we are expecting a potential approval I believe in the summer of this year. This drug will be applicable to about 10% of patients who have a mutation that is amenable to skipping of exon 53. It will be also a once-a-week intravenous infusion, but again it’s important to remember that this drug is not for all patients with Duchenne but only for those with Duchenne who have specific mutations that are amenable to skipping of exon 53. We’re really awaiting for this potential drug to add to our list of medication for Duchenne muscular dystrophy.

Amy D. Harper, MD: Viltolarsen is another treatment that is for patients who have the DMD gene changes that are amenable to exon 53 skipping. The initial trials looked at a low and a high dose for this particular medication in ambulatory boys and has just recently been published in JAMA. What they saw was that there was an improvement in the functional scales for the boys who were part of the studies that we do: what’s called a time to motor function, which looks at how quickly you stand up from the floor or how many steps you can take in a 6-minute walk. One of the things the study did show is an increase in the dystrophin levels and some of those increases for both the low- and high-dose cohorts were at 6%. Essentially golodirsen and viltolarsen are both for patients who skip exon 53. They differ in the structure of their molecules, so 1 is smaller than the other, and they seem to result in an increase in the dystrophin protein.

Emma Ciafaloni, MD: Viltolarsen has been studied in 2 doses, 40 and 80 mg/kg, to find best dose. The preliminary results on the phase 2 study showed that the drug was relatively safe with really no major emerging significant adverse effects. They also were able to demonstrate that there was in fact skipping, so that’s the mechanism of action. Using RT-PCR [reverse transcription polymerase chain reaction], they were able to demonstrate that there was skipping at the messenger RNA level. They also were able to demonstrate production of the dystrophin protein when studied by Western blotting, and the preliminary results were encouraging because it showed about 5% to 6% production of dystrophin. They were able to demonstrate that the dystrophin protein was localizing where it was supposed to localize at the level of the muscle membrane. These are very encouraging results, and we’re really looking forward to more data to show us that this is a potential medication for Duchenne muscular dystrophy.

Amy D. Harper, MD: With the viltolarsen trials, they have not seen any serious adverse events. It was well tolerated, and typical adverse effects included headaches, nausea, vomiting, and abdominal pain. Respiratory symptoms are common in boys who are on chronic steroids or children in general, so respiratory symptoms or respiratory illnesses were also noted as additional events.

Emma Ciafaloni, MD: It’s an IV infusion, and it has to be given once a week, again with the same model. Based on the safety that we know so far, it can be safely administered as an outpatient setting, so even in an infusion center or at home. In terms of safety, so far I have not seen any emerging serious adverse effects. In general with this group of medications, antisense oligonucleotides and morpholinos, you always have to be aware of the potential kidney toxicity and just keep an eye on that. Although so far, the results have been quite encouraging. This drug is really for patients who have mutation that are amenable to exon 53 skipping. As I said before, this comprises about 10% of all the patients with Duchenne. The preliminary clinical trials were done on children with Duchenne muscular dystrophy who were ambulatory, and I believe they were between the ages of 4 and 10 years. Usually, clinical trials are always done on children of about that age and ambulatory. You can also start showing clinical effectiveness, which usually is measured based on a 6-minute-walk test and the North Star Ambulatory Assessment, so motor function that has to do with walking, doing stairs, and getting up from the floor. I think there are preliminary data that suggest also some clinical benefit, meaning that all the motor skills were going in the right direction when compared with the natural history, which is obviously worsening all those motor skills over time. In terms of safety, from the preliminary results that have been presented so far, there haven’t been any emerging serious adverse effects that I know of.

Amy D. Harper, MD: Based on the data that were presented, there seems to be a difference in the amounts of dystrophin that is produced. We are looking at numbers, from 1% with golodirsen to about 6% with viltolarsen.

Emma Ciafaloni, MD: Both drugs are targeted to the same type of patients—patients who have mutations that are amenable to exon 53 skipping. They are similar in that way, and they will target the same subgroup of Duchenne patients. At the end of the day, once more final results and more data become publicly available, they will both target that group. It remains to be seen. They will compare the safety profile and the efficacy profile, and it will be very nice to have 2 options.

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