Unidentified Analyst: Good morning. This is [indiscernible] on for Joon. Thanks for taking my question. I’m just wondering, do you plan to analyze the guide molecules for Cas12a or Cas9 using your platform now that you’ve demonstrated progress in ASOs, RNAi and RNA editing. And then just on INHBE the timeline is [indiscernible]. I’m just wondering, do you think you could have progressed faster with an ASO? Thank you.
Paul Bolno: So can you repeat the second question? I just want to make sure.
Unidentified Analyst: Oh, yeah. I’m just wondering if you could just elaborate a little bit on if you think you could progress faster within Antisense Oligonucleotide as opposed to an RNAi approach for the INHBE program? Thank you.
Paul Bolno: Oh, Okay. Sorry, I’ll take the last one. So I just want to make sure for INHBE, because it was not clear with AATD or INHBE. So you’re saying could we have gone faster for an ASO. No I think actually our experience in siRNA and as we shared earlier in our collaboration with [indiscernible] we’ve been working in double-strand siRNA for a while now with our format. So I don’t think that there is any speed disadvantage by pursuing siRNA for the INHBE program. In fact I think, we’re quite on track and I think competitive in the field right now in siRNA and I think as we’ve always said having multiple modalities lets us really evaluate what is the best modality for treating this given disease. And I think what we’ve seen in not just potency but durability the GalNAc in hepatocytes on silencing, I think we actually have the best modality and format frankly to treat this where we can think about potential for biannual or annual dosing.
So I think we’ve got a competitive program here. I think our goal is to stay ahead in the space and we’ll continue to watch it. As to your first question it’s an interesting one because as we think about the power of guide trends and we have discussed with numerous companies around our GMP manufacturing capability and process development, I do think we have the ability to work in these spaces. What I don’t want that to be translated to on this call is that, Wave is going to work on RNA-controlled guide strands for CRISPR right now. But I think the capability we have in collaboration to apply our chemistry and apply our manufacturing know-how and our process development across multiple formats in Oligonucleotides is definitely translatable. I think our focus right now is RNA editing in the case as we shared earlier has a lot of advantages.
But the approach, we’re taking our chemical modifications again, proprietary debate are definitely transferable across other oligonucleotides in the space.
Unidentified Analyst: Thank you. And then just one more. So I noticed that the single dose data was that originally you were going to get it this quarter. And now, it’s going to come out with the multi-dose data in the second quarter of 2024. If you could just elaborate a little bit on that? Thank you.
Paul Bolno: I’m happy too. Anne- Marie…
Anne-Marie Li-Kwai-Cheung: Yeah. Sure. So the single dose data are not informative for our next step. And as we’ve rolled over the single dose data into the multi-dose cohort and fully enrolled multi-dose cohort, we’re reading them out together because these are the important data enabling decision-making.
Paul Bolno: Yeah. I mean, just to follow up on that. I mean, the single dose is complete. When we cut data, and I think this has been discussed before it is critical when you do assessments of data particularly on studies as they go to evaluate all patients simultaneously to avoid any discrepancies across the assay in comparison. And so with that complete to Anne-Marie’s point with those patients having rolled over in a fully enrolled 30-milligram repeat dose cohort, those repeat dose data as we shared earlier on prior calls are going to be critical in informing the next step of the program.
Unidentified Analyst: Thank you very much, Paul.
Operator: Thank you. One moment for our next question. And our next question comes from the line of Joseph Schwartz from Leerink Partners. Your question, please.
Joseph Schwartz: Thanks very much. So given what we recently saw from EMBARK, I was wondering, if we could get your opinion on the merit of NSAA as a functional assessment. And what other endpoints do you think could be more informative if any? And what functional assessments will you be focusing on now in the FORWARD-53 study? And what is the bar for success on each? And then I have a follow-up. Thank you.
Paul Bolno: I think the first — and it’s a great question, Joe. I mean, I think when we look at these data at the beginning for us the translation between and we think about Becker-like functional dystrophin, making functional dystrophin should translate to a functional benefit. It was always a question we remember the AdCom that was one of the FDA’s questions, but would micro-dystrophin actually translate to a functional benefit. And I think consensus across the reviewers is no. So I don’t think, this is necessarily the application of saying well how do you make the North Star the endpoint better, our focus is on how do you make the protein better and that’s been creating functional protein. So our view is we’re not changing our functional endpoints.
We’re going to look at North Star. We’re going to look at other digital endpoints. We’re going look at a whole host of endpoints on function, but it gets back to the primary driver of the biology of the disease. The reason we’re developing exon skipping oligonucleotide for DMD is because the premise of the biology foundationally was how can you create Becker-like functional protein that has all of the properties that are required there. So I think our goal is to deliver on that protein and then look at the translation of that into function.
Joseph Schwartz: And when you do your muscle histology biopsy analysis, do you think there’s any potential to see evidence of a differentiated profile from having more activity in the satellite cells on the muscle cell architecture given what you said about the actual protein that could be produced as a result?
Paul Bolno: It’s a really interesting question. So, obviously one we have longer duration right a follow-up in terms of the FORWARD-53 than the three doses at six weeks which is a more static time point. And so there are opportunities to see the evolution of satellite cells the evolution of where dystrophin is located. The important thing obviously is the quantitative functional protein and then looking at endpoints beyond that. But there are interesting discussions happening. I know in muscle biology thinking about population and translation of satellite cells into how that dystrophin translates onto the myoblasts and how do you actually expand dystrophin coverage of myoblast, again a lot of that work being academic I think the fact is — the fact that we get there actually should let us be able to look at dystrophin architecture over time.
