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NeuroVoices: Emma Ciafaloni, MD, on the Vast Expansion of Innovative Approaches to Duchenne Muscular Dystrophy

The professor of neurology and pediatrics at the University of Rochester Medical Center provided insight on the emerging therapies and advancements for treating patients with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) was first described by the French neurologist Guillaume Benjamin Amand Duchenne in the 1860s, though it took until 1986 for researchers to identify a particular gene flaw that leads to the condition. The identification of the dystrophin gene by Louis Kunkel and Jerry Louis opened the door for disease-modifying therapies such as exon-skipping, stop codon readthrough, gene therapy, and CRISPR/cas9 mediated gene editing that focus in on dystrophin restoration.

Currently, there are 4 drugs approved in the United States for mutations amenable to skipping of exons 51, 53, and 45, which are applicable to about 30% of patients total with DMD. Each of these were approved through the accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases. At the recently concluded 2022 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) annual meeting, September 21-24, in Nashville, Tennessee, Emma Ciafaloni, MD, gave the Reiner Lecture to a crowd of a few hundred clinicians, highlighting new treatments for DMD.

In her talk, she summarized the expanding pipeline of agents for DMD, how each differs mechanistically, and whether any are more advantageous than another. Ciafaloni, a professor of neurology and pediatrics at the University of Rochester Medical Center, also discussed how to translate new treatments from trials to clinics, the need to improve clinical trial design and process, and how researchers can build on previous successes. Prior to her presentation, as part of a new NeuroVoices, Ciafaloni provided commentary on several topics regarding the DMD pipeline, including the differences and advantages each approach brings, as well as ways to overcome complexities with conducting clinical trials.

NeurologyLive®: What makes what makes each of these therapies unique and different from each other?

Emma Ciafaloni, MD: The exciting research development in the field of Duchenne muscular dystrophy is extraordinary. Many years after understanding the pathophysiology of Duchenne—which the gene wasn’t discovered until the late 1980s—all that knowledge is finally paying off and opening a window on therapeutic strategies that have to do with disease-modifying gene editing. There are many different approaches now, some like exon skipping, which are already used in the clinics. Some are different stages of development, such as gene therapy in phase three trials. I would be surprised if we didn’t have a gene therapy drug in the clinic in the near future. And then CRISPR, which has not been used yet in humans, but has made major milestones and proof of concept in animal models that are highly promising. These are all strategies that are advancing very rapidly, I think that the field is moving much faster than in the past because of the collaboration between pharma and academia, and the patients and the families. There are many clinical trials in Duchenne, and it's a very exciting time.

Also, there has never been a time before in muscular dystrophies in general, not just Duchenne, where there were so many different, new ideas, as well as old ideas that finally started working in humans. The second part of my talk briefly covered other treatments, ideas and strategies that are not directed to restoration of dystrophin. They're not genetic treatments, but they work more on the downstream pathology of muscle degeneration into Duchenne, like the fibrosis, inflammation, and regeneration. There are some interesting drugs out there, probably a few that are going to be approved soon. We're looking at probably a multifactorial type of treatment, it may be a combination treatment. It's never been a richer time in terms of treatments for Duchenne. Also, it's exciting because some of the lessons learn, for example, with the genetic treatments, are extremely helpful for the larger field of neuromuscular diseases and even neurology. The learning has been fantastic.

With spinal muscular atrophy leading the way, we're moving into more muscle-based diseases [with gene therapy], but the lessons learned are still very valuable. Additionally, we have seen this collaboration between different sponsors, pharmaceuticals, and academia’s to share the learning, because that's just going to help move things faster and better and in a safer way. That is a positive phenomenon that is unprecedented, and it's helping to accelerate the science in a safe and effective way.

Are there advantages in investing into one approach vs another?

There are still many questions that remain. All these genetic modification approaches have been exon skipping, or gene therapy replacement. They don't replace the full-length dystrophin because it's a very large gene. It's a biologically modified type of dystrophin, so there is no doubt that it will have a profound benefit, but I think that there is plenty of room for improvement. Obviously, gene therapy is not approved yet, so remains to be seen in terms of clinical improvement. But even in the exon skipping, I think that we're going to see much more exciting next generation, exon-skipping that people are currently working on very hard on. The field of science and medicine always evolves. What we have now is only going to be much better down the road in a few years. I have no doubt, and the community of Duchenne is working very hard to make even the drugs that we have now, better.

What are some of the challenges with Duchenne clinical trials right now? How has the field tried to overcome them?

Sometimes, for the more general neurologist or certainly for the general public, it's important to remember that when we talk about Duchenne muscular dystrophy, or many of our neuromuscular diseases that we discuss here at AANEM, these are also rare diseases. The definition from the FDA for a rare disease is less than 200,000 total patients in the United States. For Duchenne, for example, we're talking about maybe around 12,000 patients. This is not [multiple sclerosis], or Parkinson disease or Alzheimer disease. There are challenges in clinical trial designs that are unique, and they need to be understood. Some of the accelerated approval for some of these drugs is part of that challenge and difference. For example, especially with the genetic approach, some of these genetic approaches like exon skipping, only target a specific mutation in maybe 10% to 13% of patients. Now you're taking a subgroup of an ultra-rare disease that is only 10% of that population. Then you need to run clinical trials that are going to have a chance to prove a difference, and so, you restrict the inclusion criteria to a specific age. Then you're really challenged to find enough patients to do well in a placebo-controlled trial. It's important to keep that in mind that there is plenty of room for improvement in making our rare disease clinical trial design more effective, less time consuming for patients, and improving the approval path.

I also want to say that in Duchenne, the amount of data that has been produced in the past several years in terms of motor endpoints, natural history, the six-minute walk test, the North Star [Ambulatory Assessment], etc. These outcome measure prospective cohorts have been incredibly invaluable. This is just to recognize the incredible amount of work that researchers and families and patients have done in the past several years that is helping the field immensely. We are at a different time, it’s an exhilarating, exciting time. I think that the community of rare diseases like Duchenne have been incredibly, hard-working in a good, cohesive way to advance the field forward, which is very refreshing.

Transcript edited for clarity. Click here for more NeuroVoices.