And those are interesting continued academic experiments to really think about that translation to function. I think again the most important endpoints for us should be the quantity of dystrophin that we produce and the translation to function endpoints. But again, when you see that that opens up a lot of possibilities to then continue to look and understand better the dystrophin biology and ultimately the translation of that.
Joseph Schwartz: Excellent. Thanks for taking my questions.
Operator: Thank you. One moment for our next question. And our next question comes from the line of Eun Yang from Jefferies. Your question, please.
Eun Yang: Thank you. Another question on DMD. So, when you produce dystrophin protein and obviously it’s close to full length versus a micro-dystrophin. I mean you mentioned there is — there are like academic testing to assess functionality of a protein itself. But when you measure the protein levels do you assume that the protein is all functional?
Paul Bolno: Yes. So, when dystrophin protein is translated to the outside of the cell, at that point that’s the functional protein. That’s after — I mean that’s why this protein takes time to both produce and then locate itself onto the external part of the cell, right? So, I think that’s the piece over time. That is the functional protein. When I was talking about the academic work that’s more on how that distribution takes place over time. Our view and obviously it will be important as we study this and we have longitudinal both the 24- and 48-week opportunities to really look at the progress not just in the quantity, but in distribution, I think those are the points that were interesting to assess over time. Obviously, the key metric as we think about the potential for accelerated approval filing will be the quantitative as that’s been long-term plan of the protein.
But functionality of the protein is definitely something where we will obviously look at the distribution of the protein in the cell.
Anne-Marie Li-Kwai-Cheung: I would just add just from a logical point of view you would expect that a protein which is as close as possible to the native dystrophin in length is most likely to be functional. And I think with these data we can see the EMBARK data really significant questions as to whether micro-dystrophin has the ability to deliver function benefit.
Eun Yang: Thank you. And then you mentioned that obviously there is the need for new treatment for DMD patients. So, given what’s out there what we are seeing what level of the dystrophin levels do you think you would need in order to file for approval to be differentiated commercially?
Paul Bolno: To be differentiated commercially, I think there are several ways to be differentiated. Obviously one for Exon 53, which is the immediate commercial space we’d be entering. We are powering the study to a show that we can deliver greater than 5% that’s the commercial threshold within the Exon 53. We believe based on our levels of transcript and the time and duration we’re treating that we should be able to see that level of protein above that current threshold. As we talk to patients and physicians, there’s other areas of points of differentiation even amongst the current programs. So, we’re already less frequent in terms of dosing administration as we talk to these patients about impact on their life in terms of travel transit costs having weekly IV infusions versus whether it’s biweekly and as we saw in our data from Part A 25-day half-life means the potential for monthly or less frequent treatment.
That in and of itself as we talk to families is a huge advantage. So, we see that in the profile of the stability of our drug. We have a profile in terms of safety too at least in the early pieces that tells us that we shouldn’t look differently than the existing standard of care. So, we can provide these patients an opportunity to switch with less frequent administration and substantially more protein which is what we are powered to see and the ability to get the satellite cells and the fact that we see higher levels and I think you need to go back to remember that data 53% transcript was seen in skeletal muscle. We’ve shared data that shows that we see substantially higher transcript production in both our NHPs and in our double knockout mice in heart and diagram.
So we think about the overall profile, differentiated profile from the existing standard. And what’s going to be important to patients it’s high levels of cardiac distribution and muscle dystrophin protein, high levels of diaphragmatic protein expression that treats the underlying respiratory and cardiopulmonary complications that these patients suffer from in addition to the high levels of skeletal muscle concentration. So, the totality of the profile and I know people tend to think about all exon skipping as being the same. The profile and the reason we started this program after our prior experience this year is not just because of the quantity of dystrophin but the localization, the exposure, the profile, it’s differentiated from the existing exon skipping therapies without the need for conjugates and other modalities that potentially impact liabilities on those molecules compared to standard-of-care.
Eun Yang: Thank you. And then last question is on AATD RNA. So when you deliver a proof of mechanism data sometime in 2024. Can you kind of talk about the level of data, we see in terms of number of patients? What kind of data we would see in order to determine proof of mechanism? Thank you.
Paul Bolno: I’ll let Anne-Marie, define kind of — I think it’s important that we benchmark proof of mechanism. Obviously, a lot more updates to your other questions in terms of numbers and designed as the study progresses. But, do you want to talk about that?
Anne-Marie Li-Kwai-Cheung: Sure. So proof of mechanism is detection of additive protein in serum. And that will be a very significant milestone, because it will be first evidence that ADAR editingcan translate into humans. And in our study we have multiple assessments of M AAT throughout the cohorts low medium and low and so we can achieve proof of mechanism as soon as we detect it. And that’s before the completion of the trial and potentially before completion of the first cohort.
Q – Eun Yang: Thank you.
Operator: Thank you. One moment for our next question. [Operator Instructions] Our next question comes from the line of Luca Issi from RBC. Your question, please.
Q – Unidentified Analyst: Great. Thanks for taking the question. This is Lisa [ph] on for Luca. Just a couple on A1AT. You mentioned that multiple CTAs have been accepted. Just wondering, if you can share which geographies you have cleared the CTAs. And on the SAD data I know you’re expecting to dose healthy volunteers soon. Given there’s no mutation to correct in healthy volunteers what clinical information are you hoping to gain from these subjects? And what will help inform further treatment in A1AT patients? Thanks.
