Eric P. Hoffman, PhD, outlines the variables in measurement of dystrophin levels in patients with Duchenne muscular dystrophy and how they translate into clinical benefit.
Vamshi K. Rao, MD: How much dystrophin is good dystrophin? How much dystrophin is enough? There’s been a lot of evolving literature about the percentage of dystrophin in children in natural history studies. My understanding is that anything above 0% is good, but how does it translate into a clinical phenotype where you’re seeing meaningful strength measures? There has been literature where even 1% was good. We have looked at literature that has broken it down to 0.5% to 5% and 5% and higher. In the study that we participated in together, we introduced the concept of 3%, and our study showed dystrophin of being higher than 3% or even 5%. Based on all that, why is this so important for us to think about?
Eric P. Hoffman, PhD: It’s very important. Remember that under accelerated approval paradigms, you’re saying that so much dystrophin induced by drug is reasonably expected to confer clinical benefit later. Of course, zero is not enough to be reasonably expected to confer later clinical benefit. The question is: What is that number that’s reasonably expected? As you said, there’s extensive literature going back for years because nature has done many of those experiments for us in the context of thousands of patients with Duchenne muscular dystrophy and Becker muscular dystrophy.
You also mentioned female carriers who sometimes show symptoms. Those have all been studied by international collaborative teams, me and you included. There are some generalizations. One of the generalizations, which is very important to remember in this context, is that patients are variable. Duchenne muscular dystrophy is a variable disease. Becker muscular dystrophy is an extremely variable disease. Female manifesting carriers are even more variable.
The first thing in any discussion like this and trying to find a number, is patients are going to respond to that number differently. You have to realize in that anticipation of clinical benefit, when you pick any number of how much dystrophin is enough, there’s going to be a significant amount of error. With the same number, some patients will do well and some patients won’t. Everybody really needs to acknowledge that. Then you say, “OK, I get that, but still give me a number.”
We’ve studied lots of patients with Becker muscular dystrophy who have very different levels of dystrophin. What has generally been seen is unique. Remember that Becker dystrophin is abnormal dystrophin. It’s not normal dystrophin. With an abnormal dystrophin that is missing amino acids, you’d probably want over 5% or 10% to really slow loss of ambulation beyond 20 years, whereas Duchenne typically loses ambulation after 10 or 11 years. If you want to slow ambulation beyond 20 years for abnormal dystrophin, you’d better be above 5% or 10%. All those biopsy studies supported that.
You cited a really nice recent paper out of France. I don’t remember the author’s name. They found that much lower levels could also be associated with milder disease; even down to 1%. It’s important to point out that this paper studied normal dystrophin, not abnormal dystrophin. They were looking at specific types of splicing mutations that still led to normal full-length dystrophin that you expect to retain more function—more bang for the buck—for normal full-length dystrophin than a semifunctional Becker dystrophin or a gene therapy dystrophin, which is micro-dystrophin. There are so many variables: what you’re looking at, what your denominator is. When you put any number on that, you have to realize that some patients will do well and some will not do well.
Vamshi K. Rao, MD: I thank all of you for watching this Neurology Live® Peers & Perspectives®. If you have enjoyed the content, please subscribe to our newsletters to receive upcoming programs and other great content in your inbox. Thank you.
Transcript Edited for Clarity