Balancing Risks and Rewards With Muscular Dystrophy Gene Therapy

John Brandsema, MD

Even before the FDA's approval of Sarepta Therapeutics' gene therapy product delandistrogene moxeparvovec-rokl (marketed as Elevidys), patients with Duchenne muscular dystrophy (DMD) had a range of different therapeutic options to choose from. Thus, this new product, although providing substantial hope to the community, has also made treatment decisions even more complicated.

CGTLive® recently spoke with John Brandsema, MD, a pediatric neurologist in the Division of Neurology at Children’s Hospital of Philadelphia, to learn more about how patients and families are navigating the landscape of care for DMD today. He spoke about the potential benefits and risks of the gene therapy product, and emphasized the importance of collecting more data, especially from older patients, to help with the decision-making process.

CGTLive: Can you give some background information about the current landscape of care for Duchenne muscular dystrophy?

John Brandsema, MD: We've striven for decades to improve the standard of care for DMD with a multidisciplinary approach, but it's really been a few years of innovation and new opportunities in this disease, starting with the approval of deflazacort and eteplirsen for exon 51 skipping about 5 years ago. We now have 4 exon skipping agents approved and also 2 new steroid alternatives approved with vamorolone and givinostat. As such, there is a new world of opportunity for our Duchenne patients in terms of combination therapy approaches with different agents that target both the genetic cause of the disease as well as muscle supportive treatments, with much more still in research trials and on the horizon.

How has the FDA’s approval of the gene therapy product Elevidys changed this treatment landscape?

This is a novel therapeutic approach that has a lot of hope associated with it for both provider teams and families. What we're able to do is give back what's missing in the muscle. These children are missing their dystrophin protein, and while we can't give back the full gene due to the size of dystrophin not being packageable in the current technology, we give back a "micro" or "mini" version of it that's designed to be as functional as possible. We hope that this transgene will express a protein that is both localized where it needs to be and also functions in the way that it needs to with other proteins in the muscle. It seems, from the early trials in this that there is at least a stabilization of this disease, if not an improvement in some of the young children that are treated. The challenge is that it is an irreversible decision, that we can't take it back once we've administered it to the body. If there is a safety event, which we've seen in terms of immune reactions in a small number of patients, with a very predictable timing after the dose, those immune-related safety events need to be treated in terms of a reactional approach; we can't reverse the therapy. This would be things like myocarditis, immune-mediated myositis, or hepatic inflammation. There's also been some cases in other programs of thrombotic microangiopathy early after the dose, although this has not been seen with Elevidys.

Basically, if you are antibody-negative for rh74, which is the delivery mechanism, and if you do not have a deletion that includes exons 8 and 9 of the dystrophin gene, you're potentially eligible for Elevidys. But this conversation is quite complicated with families because there's other multisystemic aspects of the disease that sometimes make people more vulnerable to safety events, and also the durability across the experience of Duchenne has not been demonstrated yet. It's really been the young children that have been studied the most extensively, and we're awaiting data from late, ambulatory and nonambulatory populations. There's been a very small number of subjects treated in the trials thus far. So while the label is broad and is for everyone, we don't necessarily have the data to back that up yet and that makes the conversation more nuanced. We also aren't sure about the durability of transgene expression. Muscle is a high turnover tissue, and therefore whether this is going to be a lifelong effect is still up in the air; although it does seem, from the early boys treated that there is a measurable difference in their trajectory years after the dose, up to 5 or 6 years at this point now.

This transcript has been edited for clarity.