Microdystrophin Proposed as a Surrogate End Point in DMD


Jeffrey S. Chamberlain, PhD, Professor and McCaw Chair, Muscular Dystrophy, and director, Sen. Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Washington School of Medicine, discussed the potential use of microdystrophin as an end point for clinical evaluations of gene therapies for DMD.

Jeffrey S. Chamberlain, PhD, Professor and McCaw Chair, Muscular Dystrophy, and director, Sen. Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Washington School of Medicine

Jeffrey S. Chamberlain, PhD

For slowly progressing diseases, like Duchenne muscular dystrophy (DMD), evaluations of clinical efficacy for investigational treatments can be complicated, especially using traditional outcome measures. Although, the FDA has accepted the use of microdystrophin as a surrogate end point for some exon skipping therapies, marking a step toward combating this challenge.

In a paper recently published in Human Gene Therapy,1 Jeffrey S. Chamberlain, PhD, professor and McCaw Chair in Muscular Dystrophy, and director of the Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center at the University of Washington School of Medicine, and colleagues argued for the use of microdystrophin as an end point for clinical evaluations of gene therapies for DMD. Pointing to the available literature supporitng its use, they noted that "the use of microdystrophin is based on the biological relationship and the primary defect of DMD"—the lack of dystrophin. Importantly, based on both preclinical and clinical data, their research suggests that microdystrophin can be assessed as a surrogate end point as soon as 2 months post dose to aid accelerated approval.

CGTLive spoke with Chamberlain to learn more about the rationale for the paper and use of microdystrophin as such an end point.

CGTLive: Can you give us some background information about your recently published paper?

Jeffrey S. Chamberlain, PhD: The gene therapies for muscular dystrophy in general, and particularly for Duchenne muscular dystrophy, are really an important component of the ways to combat this disease. And, ultimately, we think gene therapy is really the way to go. It's a genetic disease—it's generally a no-allele disorder, so there's no dystrophin made, it's a recessively inherited disease. The long standing goal is to get approval for these therapies and make them more widely available.

Based on many things, going back 20 to 30 years, there's a lot of evidence, initially and in a variety of animal models, that gene replacement therapies for Duchenne can be very effective and potent. But at the same time, for somewhat slowly progressive diseases like this, it takes a long time to really evaluate efficacy and all that, particularly using the traditional methods that the FDA applies. [The FDA wants to] follow patients for a long time and see a clear clinical benefit. Yet, at the same time, they're a little cautious in setting up these trials and most of the early kids that have been enrolled in these trials are still fairly young. They're not as weak or severely affected as some of the older boys unfortunately are—that complicates waiting for a clear clinical benefit.

What was the recommendation put forth by your group?

There's so much data from the animal models showing that production of the missing protein has a clear benefit. We're seeing early indications of that; I think everything in the clinic is supportive of that. So then, one of the questions becomes: How much can you rely on production of the missing protein as a predictor of clinical benefit? Some of the main things that the PDC group was interested in was just to evaluate the data at hand and make the argument, which we believe is is extremely valid, that production of the microdystrophin protein is going to be a surrogate end point.

The FDA has been traditionally a little reluctant to just use protein expression as a surrogate end point. They've done it a number of times, they're doing it increasingly often, and even in the case of Duchenne muscular dystrophy, they've clearly latched onto that, to approve some of the exon skipping therapies that are out there. Yet, we feel that the microdystrophin [gene] therapies are making more of the protein, they're going to have a greater clinical benefit, and so those same considerations should be applied. So the goal really was just to do a critical evaluation of the existing data from from animal models and from the extensive clinical trials that are going on to make the argument that we have enough data on predicting clinical benefit and that we'd like the FDA to hopefully evaluate all that data; and we think they will come to the same conclusion.

What is the main challenge that you identified with traditional end points?

You know, it's not like with an infectious disease: if you have a new antibiotic you may know in a week or so whether it worked or not. Unfortunately, with a with a lot of these genetic developmental disorders, where you have slow progression, it's a slower process to follow that. Yet, I think a lot of that work that came out of the preclinical studies and the development of these technologies over the last 20 to 25 years have shown an absolute clear relationship between production of this missing protein and benefit down the road, but it can take a while to measure that.

Transcript edited for clarity.

1. Chamberlain J, Robb M, Braun S, et al. Micro-dystrophin expression as a surrogate endpoint for Duchenne muscular dystrophy clinical trials. Human Gene Therapy. Published online January 24, 2023. doi:10.1089/hum.2022.190
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