Unidentified Analyst: This is Beth on for Joe. We are wondering how much precedent you believe that EXONDYS’ Accelerated Approval on the basis of dystrophin expression provides for 9001? Specifically, we’re also wondering if you’ve been able to quantify the benefit of higher expression of a less complete micro-dystrophin compared to the lower expression of a more complete shortened dystrophin produced by exon skippers and if this is something that FDA has been considering throughout the review.
Doug Ingram: Okay. Let me — yes. Let me answer this question. Let me start with the second part of it then work to the first part of it because there’s a fundamental misunderstanding and it’s understandable that you have the misunderstanding but there’s a misunderstanding of the underlying science when one assumes that the 9001 dystrophin which is shortened, is sort of vastly shortened. And then the dystrophin that’s made by EXONDYS or VYONDYS or AMONDYS or in the case of one of our competitors, Bill, is very lightly edited. I think there are those who might imagine that the resulting dystrophin is one exon smaller. That isn’t the case. The exon skipping occurs to place to restore the reading frame and allow the messenger RNA to make dystrophin.
That reading frame is restored by the removal of that exon and then it will naturally include also the removal of the parts of the gene that are associated with a mutation. And so for instance, the resulting dystrophin that you can make can be 40% shorter, smaller and get very functional versus wild-type dystrophin. And that’s the same case in natural history with Becker-like dystrophin. Becker dystrophin can be 50% or more shortened from full-length dystrophin. But so long as the reading frame is impacted, it can make dystrophin and it retains the right hinges and repeats and the right anchoring places, then it’s functional. And that’s the same thing with the 9001 dystrophin. This is a reasonable approximation of another — any other Becker-like dystrophin, just like EXONDYS and AMONDYS and VYONDYS and they’ll tests to make .
And so that — so from at least our perspective, the precedent for EXONDYS and VYONDYS and AMONDYS and Bitexco is very relevant here. Those therapies, while there’s — it’s a different mechanism to get there because it’s the use of exon skipping and anthronic therapy, it is the same underlying concept, where what you’re doing is providing to the patient a shortened but functional dystrophin which will protect them. The biggest difference in addition to the mechanism of action being different, here, we’re using a gene cassette to make the dystrophin. The biggest difference between these 2 is the amount of dystrophin we’re making. We are making well over and multiples of an order of magnitude more dystrophin with our gene cassette than we can make with the PMOs today given the delivery limitations there.
And so a couple of things. And then kind of going on here but so we say, number one, do I think there’s a significant amount of precedent? I absolutely do. And I think there’s an enormous amount of precedent for the idea that shortened functional dystrophin is the right kind of biomarker recently likely to predict clinical benefit. It’s the right kind of upstream biomarker that we should all be looking for. And then second of all, there is not a significant difference in what’s happening with 9001 and what happens with the PMOs other than the amount of dystrophin we’re making. And then, one final thing I’ll say as long as I’m on my soap box on this topic, one must remember that in nature, better dystrophin is the result of mutations. So the fact that these kids can make dystrophin — kids or adults in the case of Becker, I think the average age — average mortality rate of Beckers as well into the 60s on average, the fact they can make dystrophin is a happy accident.
