Emma Ciafaloni, MD, on the vast expansion of innovative approaches to Duchenne muscular dystrophy

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

Currently, there are 4 drugs approved in the United States for mutations likely to skip exons 51, 53, and 45, which apply to approximately 30% of total DMD patients. Each of them has been approved through the fast track, which provides for the approval of drugs that treat serious or life-threatening conditions. At the recently concluded 2022 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) Annual Meeting, September 21-24 in Nashville, Tennessee, Emma Ciafaloni, MD, delivered 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 some are more beneficial than another. Ciafaloni, 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 the design and process of clinical trials, and how researchers can s build on past successes. Prior to his presentation, as part of a new NeuroVoices, Ciafaloni provided commentary on several topics regarding the DMD pipeline, including the differences and benefits that each approach brings, as well as ways to overcome the complexities involved in driving. of clinical trials.

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

Emma Ciafaloni, MD: The exciting development of research in the field of Duchenne muscular dystrophy is extraordinary. Many years after understanding the pathophysiology of Duchenne – whose gene was only discovered at the end of the 1980s – all this knowledge is finally bearing fruit and opening a window on therapeutic strategies linked to gene editing. disease modifiers. There are now many different approaches, some like exon skipping, which are already being used in clinics. Some are in various 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 hasn’t been used in humans yet, but has passed important milestones and proof of concept in very promising animal models. These are all very fast moving strategies, I think the field is moving much faster than in the past because of the collaboration between pharma and academia, and patients and families. There are many clinical trials at Duchenne, and it’s a very exciting time.

Also, there has never been a time before in muscular dystrophies in general, not just in Duchenne, where there were so many new and different ideas, as well as old ideas that finally started to work in the man. The second part of my talk briefly covered other treatments, ideas, and strategies that are not aimed at restoring dystrophin. These are not genetic treatments, but they act more on the pathology downstream of Duchenne muscle degeneration, such as fibrosis, inflammation and regeneration. There are some interesting drugs out there, probably a few that will soon be approved. We are probably looking at some type of multifactorial treatment, it may be a combination treatment. There has never been a richer period in terms of treatments for Duchenne. Also, it’s exciting because some of the lessons learned, for example, with genetic treatments, are extremely useful for the larger field of neuromuscular diseases and even neurology. The learning was fantastic.

With SMA in mind, we’re headed for more muscle disease [with gene therapy], but the lessons learned are still very valuable. Plus, we’ve seen this collaboration between different sponsors, pharma and academia to share learning because it’s just going to help get things done faster and better and safer. It is an unprecedented positive phenomenon, which contributes to accelerating science in a safe and effective way.

Are there advantages to investing in one approach over another?

There are still many questions left. All of these gene editing approaches have been exon skipping or gene therapy replacement. They do not replace full length dystrophin as it is a very large gene. It is a biologically modified type of dystrophin, so there is no doubt that it will have considerable benefit, but I think there is a lot of room for improvement. Obviously, gene therapy is not yet approved, so it remains to be seen in terms of clinical improvement. But even in exon skipping, I think we’re going to see the much more exciting next generation, the exon skipping that people are working very hard on right now. The field of science and medicine is always evolving. What we have now will only get better in a few years. I have no doubts, and the Duchenne community is working very hard to improve even the medications we have now.

What are some of the challenges of Duchenne’s clinical trials right now? How did the estate attempt to overcome them?

Sometimes, for the more generalist neurologist or certainly for the general public, it is 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 FDA definition for a rare disease is less than 200,000 total patients in the United States. For Duchenne, for example, we are talking about around 12,000 patients. It’s not [multiple sclerosis], or Parkinson’s disease or Alzheimer’s disease. There are challenges in clinical trial designs that are unique, and they need to be understood. Part of the accelerated approval of some of these drugs is part of that challenge and that difference. For example, particularly with the genetic approach, some of these genetic approaches like exon skipping, only target a specific mutation in maybe 10-13% of patients. Now you’re taking a subset of an ultra-rare disease that’s only 10% of that population. Then you have to conduct clinical trials that will have a chance of proving a difference, and so you limit the inclusion criteria to a specific age. Then you’re really challenged to find enough patients to be successful in a placebo-controlled trial. It’s important to keep this in mind that there is a lot of room for improvement to make our rare disease clinical trial design more efficient, less time-consuming for patients, and improve the approval process.

I also want to say that to Duchenne, the amount of data that has been produced over the last few years in terms of motor parameters, natural history, the six-minute walk test, the North Star [Ambulatory Assessment], etc. These prospective outcome measurement cohorts have been incredibly valuable. This is just to recognize the incredible amount of work that researchers, families and patients have done over the past few years which is helping the field immensely. We are in another era, it is an exhilarating, exciting era. I think the rare disease community like Duchenne has worked incredibly hard and consistently to move the field forward, which is very refreshing.

Transcript edited for clarity. Click here for more NeuroVoices.

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