Consideration of the measurement and standardization of dystrophin improvement to infer clinical benefit and the FDA distinction between exon skipping dystrophin and micro-dystrophin in Duchenne muscular dystrophy.
Vamshi K. Rao, MD: As we start to think about all these clinical trials, we are trying to look at biomarkers or what makes a successful clinical trial. One of the key questions that comes up is: How do you measure dystrophin to say that you have actually made an improvement?
Eric P. Hoffman, PhD: That’s an excellent point. The FDA has said that if you can show you’re bringing dystrophin back in patient muscle through a therapy, then that is a surrogate biomarker worthy of accelerated approval. In those settings, which are fairly rare in FDA drugs, you don’t have to show clinical improvement. You can show that later. Instead, you just show that dystrophin is being produced in patient muscle. That is reasonably expected to confer later clinical benefit because dystrophin is the clear cause of Duchenne muscular dystrophy. There’s no question about that, so it seems to make sense that if you can bring dystrophin back, it should help—particularly in muscle.
There are some drugs that are approved for exon skipping that are bringing dystrophin back to some extent in muscle. That has been the basis of accelerated approval. It’s interesting that it seems that the FDA has made a distinction between exon skipping dystrophin and gene therapy dystrophin, or what you call micro-dystrophin. Maybe we should briefly explain exon skipping. There are 4 approved drugs that are small oligonucleotide drugs—little snippets about 20 letters long that, when given intravenously, bind to the RNA of the dysfunctional gene and convert a Duchenne gene into a Becker gene. An inactive, nonfunctional Duchenne gene repairs it at the RNA level into a Becker gene, which is residual semifunctional dystrophin. The FDA has said that when you do that, the semifunctional Becker dystrophin is good for the basis of drug approval. They have not said that for the gene therapy dystrophin. The FDA may believe that’s too far away from normal dystrophin, it’s too small, and we’re not sure how well it will function in the context of a patient. To my knowledge, the FDA is asking for clinical benefit in gene therapy trials.
Vamshi K. Rao, MD: That’s a really important point. Many of our viewers and many of us in the field sometimes gloss over that really important distinction, so I’m glad you brought up that point. That also brings up something else. Because there are so many sponsors, players, researchers, and patients involved in clinical trials, because we need lots of people concentrating on and treating this disease and finding a cure, how do you standardize what people are looking at? For example, let’s go back to your point about measuring dystrophin. Clinical trials have measured dystrophin as a marker for what the FDA needs. How do you look across dystrophin in clinical trials and compare 1 against another, if it’s possible?
Eric P. Hoffman, PhD: Dystrophin is a protein and where it should show up to be most clinically beneficial is in skeletal muscle. It would be great if it were in the brain, heart, peripheral nerve, etc, as we discussed earlier, but the first step is to see if we can get it in the skeletal muscle and preserve strength. To see dystrophin coming back, you take a muscle biopsy. These trials that are using dystrophin as a surrogate marker for approval generally have pretreatment and then post-treatment muscle biopsies, often after 6 months or a year of drug treatment. The goal is to see that you’re bringing dystrophin back.
There are a couple of standard ways of measuring dystrophin. One that pathologists are very familiar with is immunohistochemistry, or immunostaining cells or tissue sections and then looking under a microscope to see if it is there or not. Those are extremely powerful pathologic tests. They’re not so great in this instance because they can be very challenging to make quantitative, or to put a number on how much dystrophin you’re actually inducing. There can also be issues with background. How do you really know it’s missing before the treatment and compare that difference? The FDA has not been enthusiastic about considering immunostaining or histochemistry as a valid end point when considering accelerated approval. They want something more quantitative.
The most quantitative test, often used by pathology labs, is immunoblotting, or western blot. That’s where you dissolve the tissue, resolve it electrophoretically, and then use antibodies to see how much of the protein—the target protein in this case is dystrophin—is in that biopsy. That’s what the FDA has accepted. All 4 drugs that have been approved based on dystrophin levels for exon skipping in Duchenne muscular dystrophy have all used western blotting as their primary outcome. That’s what the FDA looks at. They really want to see those blots. They want to see the pen in the gel and they want to see it go up after treatment. That’s what all companies have used. Western blotting is a fairly standard approach that has been around for almost 50 years. Of course, the specific method you use for western blotting can vary a little—which gels, which transfers, which antibodies you use—but they should be comparable across studies. There’s no reason to suspect that they’re not.
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Transcript Edited for Clarity