All right. Thank you very much, everybody, and it's good to see a bunch of folks here in the room. I'm happy to be hosting this panel with John and Oxana from Dyne Therapeutics. I'm sure most people know the background of the company well, but maybe I'll kick it over to John quickly just to give a quick snapshot of where Dyne is at with your DM1 program, your DMD program, other efforts, and then we'll do Q&A, so thank you both very much for attending. Appreciate it.
All right. Paul, thanks for hosting us. We appreciate it. First of all, I think the title says Doug Kerr would be here, but I'm going to fill in as the CEO, so I hope that's okay, and then we've got Oxana here as the CSO. We'll be making a few forward-looking statements, obviously. Yeah, I think the DM1 program, we recently in our kind of quarterly announcement or update, we provided some updates on DM1, and hopefully people saw that in a very positive way, the way we have as well. One of the updates was that we had IND clearance for DM1 in the United States. I know there have been some questions about when we'd have that done. We had talked about an update by the end of the year. We accelerated that and wanted to let people know.
The second piece that's probably, to me, is really significant, maybe even more significant, is that we have been talking about providing some updates on higher dose data by year-end. We hadn't been specific about how much data or what doses and so on, but we were. And that is that at 6.8 mg per kg, we're going to provide six-month data. And we're going to provide 12 months of data for 5.4 mg per kg. That's meaningful to us. I mean, I'm sure from an external standpoint, people are interested, but even from an internal standpoint, the six months of data gives us splicing data, which we think is fundamental to the disease. At three months, at six months, it also gives us functional data and gives us PROs. We had seen interesting data before at three months with 5.4. Now we're going to be out to 12 months.
So it allows us to start thinking through and frankly, to determine our registrational cohort in terms of dose and number of patients. And we want to be able to do that. So we've stated that early in January, we will come forth with that kind of data, and we'll be talking about a registrational cohort.
Okay. That's great. So maybe to kick it off, as it relates to this next higher dose cohort, what's your base case? Do you think we're going to see deeper splicing? Do you think that that might plateau? And what clinical endpoints are you most focused on as you sort of compare doses and try to figure out the best one to move forward?
Maybe I'll start it. First of all, base case from a regulatory standpoint for us is an accelerated approval pathway. So just like we've done with DMD, where we picked a dose, we selected the number of patients, which we're happy to talk about. The ACHIEVE trial for DM1 has been designed to be registrational. We've kept it blinded, and we'll pick a registrational dose, and we'll be going forward with an accelerated approval pathway as the base case. Now, as far as endpoints, we had talked, I think Paul, we had talked before about our conversation with the FDA some time ago about pursuing a surrogate endpoint using splicing. And that conversation had been, I think, favorably received and was quite clear. And what they told us was splicing can be a surrogate endpoint for accelerated approval, but you need to correlate that with function or PROs.
When you say correlate, because I think people sometimes interpret correlate as patient-level correlation with an X-axis and a Y-axis and an actual R-squared, do you mean that or do you mean corroborate that in showing that it transits in the clinical trial?
Trends.
That's what I'm talking about.
I probably shouldn't use the word correlate.
No, it's okay. I just want to, I feel like there's so much confusion in this space, and that's why I wanted to clarify.
And we're not, at some point, we'll have patient-by-patient data that we can be clear about. But to your point about endpoints that matter, the FDA, in terms of trends and surrogate endpoint, we're pointing to going beyond vHOT and myotonia. You've seen our vHOT data. We feel good about it. In fact, we feel great about it. And we can talk more about that data and what we'd expect to see. But when we talk to whether it's physicians or patient advocacy organizations or clinicians, the hope is that we see improvement in functional endpoints beyond that, such as strength measures, QMT, ankle dorsiflexion, hand grip strength. And the other piece that people are interested in are patient-reported outcomes, particularly those that might relate to CNS. What we know about our platform, and Oxana can get into it, is that the Fab gets to the CNS.
Now, what kind of effect can we have? We'll see. But the patient-reported outcomes will be important for that. And that's a big factor for a significant number of these patients. So the point is splicing, fundamental to the disease. We've seen dose response with splicing, as you know. We'll see what we get with 6.8. And then let's see some trends with endpoints that really matter to clinicians.
Okay. Anything you wanted to add, Oxana?
Just, we will be positioned to see a really differentiating story with our platform where we can connect all the dots from affected molecular defect, which is splicing; it's spliceopathy, dose-dependent increase in splicing correction as we go up the dose. And that is going directionally in the same way as we see improvement in function. So looking forward to see the data.
Can you talk about your confidence in the safety profile as you go dose higher in DM1? And I think specifically, it'd be helpful to kind of better understand from a transferrin target engagement perspective the margin you're at in DM1 at 6.8 versus where you saw that SAE in DMD. And look, I'm not necessarily implying it's transferrin related. We don't know, but I think it's good context for investors.
Yeah.
Go ahead, Oxana.
Sure. Maybe I can start with speaking of approach for each indication. In DMD, the idea is to facilitate splicing, splicing where you need to titrate basically the site in each PMO for exon 51, which is steric inhibition. Typically, a higher level of PMO is required. For DM1, we are using enzymatic RNase H activity, which degrades DMPK. Typically, one oligo can degrade multiple RNAs.
Catalytic.
Catalytic. So you need typically lower amounts. So just to put us all on the same page, suffice to say, in DMD, where we saw the SUSAR, which was at 40 mg per kg PMO, we are not dosing that high at all in our DM1 patients. Just different mechanism, different payload.
Have you said whether the DAR is the same between these two?
We have looked very carefully about DAR for each payload type and for each approach, and I can tell you this is where the uniqueness of each platform comes to play. This is what we consider our secret sauce, and so it allows everyone else to compare across trials by using payload concentrations.
But I guess to maybe put it into a context that we can all understand just in terms of fold margin. So you got 40 mg per kg and 6.8. I mean, assuming you can't divide them, right? I mean, they're apples and oranges in terms of different cargo. But what are we talking about here? Like a threefold margin, a fourfold margin in terms of the transferrin component of it?
Yeah. It's typically lower at all doses that we are testing relative to 40 mg per kg in DYNE-251.
Makes sense. So John, going back to you, I mean, I think you've talked about wanting to leverage splicing as an accelerated path, but also needing to, one, sort of corroborate splicing with some clinical data, and two, generate the most robust data set to sell the drug, right, and show that your drug is differentiated. What are the different permutations of, I guess, a study design within a registrational cohort that could satisfy multiple stakeholders like that?
Let me just back up for a second. The data that we're trying to put together towards the end of the year, I think it's going to answer the question because we've seen with the splicing this kind of dose response up to 5.4. We've seen an effect on things like 10-meter walk-run test, important functional measures. We've seen the vHOT, myotonia measures. We see that at 5.4. Now, we want to round that out, obviously, and look at it at 6.8. We'll have all of that data over a period of time. We'll also see whether we have deepening of effect on whatever features. Now, each cohort is a small number of patients, but you put it all together, and it's quite a few patients. We have our statistical team will be working on all of that data.
I see Doug Kerr and the team coming back and saying, "Let's rank order each one of these important endpoints that matter to patients." It's tough for me to say, "Well, will it be QMT or will it be ankle dorsiflexion?
Yeah.
Oh, which one it'll be. But if we're seeing an effect on those and we think statistically we can get a trend, or if we could get some statistical meaningful result with it, we will then say, "This is how many patients it will take, and this is what our registrational cohort should look like." As you kind of alluded to, my view has been that we've got to think longer term about when we're on the market and we're talking to payers or we're talking to clinicians, what are they going to care about? Now, it varies significantly from patient. If you look at what patient groups have had conversations with the FDA and they kind of go through what matters, myotonia is not anywhere near the top of the list.
What is the top?
It tends to be CNS. That's maybe.
Is that like fatigue, like things like that?
It's brain fog, fatigue, and it is a daytime sleepiness issue. If you go to a patient, if you go to an event where the patients are there, I'll just guess at a percentage, but say 30% or so, you will see will barely be able to focus, to keep their eyes open. It's incredibly debilitating to their life. Now, that's not true for all of them. Others not having a CNS effect, but you will see that they shuffle along the floor because they're worried about balance. They don't have the strength. Others you'll see have a significant GI problem, some of which gets all the way into the throat where they can't swallow and chew, and eating is a big problem. So it varies by the patients. But myotonia falls down on the list. But myotonia is something that we see a response in very, very quickly.
So it's from a clinical sort of indicator, fine. But I do think when we get to the point that it's time to be making the drug available commercially, whether it's Europe or the United States, we need to show some differentiation in a label that matters to these patients. And whether that is a muscle strength piece or it's GI improvement, we're measuring all of these different factors right now in our studies. And we've seen trends that give us promise and hope. And this final set of data will give us a chance to say, "This is what we're going to go after for accelerated approval versus those that might take longer in a phase III.
Yeah. Okay. That makes sense. Do you want to talk about your regulatory strategy here? So you're going to have the data, I guess, late this year, disclose it publicly early January. What type of meeting or meetings do you want to set up with the FDA? How much engagement can you have between now and then, if any? What are your thoughts?
I don't think from a regulatory standpoint, we don't need really any more clarity for accelerated pathway.
Okay, so you're rock solid on splicing. This has been validated.
Absolutely.
You have a good sense of the clinical measure or clinical data you'd want to generate to corroborate splicing.
That's right.
Okay.
And that's similar with DMD. Now, at some point, I think the fact that we have the IND open now puts us in a position to be following as you typically would with clinical development and a phase II, preparation for phase III, and have conversations about what that would look like. We haven't guided to timing around that, but you can imagine that that's something we would want to do for the U.S. and for Europe.
Yep. Yep. Okay. Makes sense. I'm trying to think about anything else related to DM1. I guess, again, it sounds like you're pretty firm, but historically, you had kind of, I think when we talked over the summer, you said you've been weighing different possibilities of expanding the current study versus starting a de novo phase III. It sounds like the latter at this point is pretty much off the table. Is that fair?
No, listen, we have a base case.
Or doing more?
Okay. So the nice thing about our approach, the fact that we've seen this kind of dose response with splicing means accelerated approval is a pathway we can pursue. Let's see how all that data comes together. The data so far looks like, man, that's what we should do it.
Yep. And is it important to you to see better splicing with 6.8, or if it looked the same as 5.4, you'd still feel good?
I thought the splicing data at 5.4 was a mean or median of 27%.
Yeah.
Everything that we've believed and studied and kind of hoped for was that you would get that you needed to get above 20+% to start unlocking a wide range of outcomes.
That's kind of.
Small data is what's telling us, that's what's happening. Now, if we get deeper splicing effect improves it more, great. If it doesn't, but you see a tightening of the number of patients, the range around that, and you see a deepening of effect over time, anyway. So 5.4 would be fine. 6.8 would be great too.
Yeah. Have you thought about just taking forward multiple doses?
I think if the data suggested that, it'd be one thing. But if the data is as showing us right now, tells us we have a dose, pick it, run with it, and get this to patients as fast as we can. It doesn't preclude us from considering some phase III work and so on that the data can guide us.
Yep. Okay. So it's obviously a really, I mean, it's a big market, right? You're talking 40,000 patients. And in the context of that, right, you've got an antibody drug conjugate, like manufacturing is not trivial. What kind of investments are you planning on making, assuming you're moving forward as fast as your guidance you're right now?
CMC side?
CMC, everything. Yeah, for process control.
Listen, one of the announcements we made, I guess, a couple of months ago, was that we just brought in a commercial leader, Johanna Friedl-Naderer, who had launched Spinraza globally. And I encouraged people to kind of look at her background and CV and resume of doing this. So part of it is, with rare diseases, first of all, we fully own our assets. With rare diseases, you don't need to build out a thousand-person commercial infrastructure. I think you can be very logical about how you build out market access and so on. But you got to start doing it, particularly if you have accelerated approval, two, three years in advance. So Johanna's going to lay out some plans to, in a very efficient economical way, think about how we build out some infrastructure there.
Manufacturing-wise, we already have been working on kind of scale up and so on to be able to deal with these types of launches. And I feel pretty good about that too.
Okay. Okay. Great. Anything else to add on DM1, or should we switch to DMD?
Just wanted to iterate about the dose a little bit. We've seen with 1.8, 3.4, dose-dependent effects on splicing and clinical measures. But what I also wanted to say that it was cleverly designed to also address, for example, frequency of dosing, where we introduce with early doses, recovery cohort allows us to dose and then follow up with placebo after six months and see how long our effects last. That also contributed to our understanding of the platform and performance in humans, which gives us this additional confidence that we will be able to pick the right dose with the right schedule.
Paul, I may just say, this is my first time, I think, sitting on one of these with you. So when I joined the company, it just seemed to me the science added up, okay? And you know the biology with DM1. Oxana had designed a Fab for a certain purpose, had a particular epitope, and that you'd be able to dose a certain way, and that you would also have an ASO that would get to the nucleus where the splicing issue is. And there were various predictions based upon all the preclinical work that you would somewhere between 3.4 and 6.8, you'd start seeing effect that you could dose every two months. Everything that she has laid out from a translational standpoint has been adding up. So it's fun for me to listen to her talk science.
That's pretty good.
Yeah.
Yeah.
Amazing.
So, DMD. You've generated some promising clinical and functional data. The recent update you gave where you're forging ahead with the registrational cohort, I think there was. It's funny, right? I think there was almost, I mean, that was actually better than expected or faster than expected. But I think there was some expectation on the street side that you might have needed another layer of FDA engagement before doing that. So maybe just talk to us why you guys had this level of confidence to just forge ahead and go for it.
I'll start it, and Oxana can add a little more kind of rigor to it and scientific backing to it. But again, to the kind of the fundamental principles around the platform. The belief has been that with the Fab, you would get distribution into tissue, heart, diaphragm, into skeletal muscles, into the CNS too, but set that aside for a second, that you wouldn't just get it to those tissues, but you would get it diffusely distributed throughout.
And we can talk about that all day because the data adds up in humans and animals, and that's what it shows, unlike a naked PMO or whatever. And the hypothesis was that if you got that kind of distribution broadly, you just might see at certain dose levels and in a short period of time, functional benefit. And so when we saw the 10 mg per kg data, we were ecstatic.
I mean, just from the dystrophin numbers, above 3%, unadjusted, straightforward. When we saw the 20 mg per kg data, and we saw in six months that SV95C, functional, six patients, not statistical, but you saw the SV95C, which is a validated endpoint for the EMA, you saw functional improvement that was above a minimal clinical endpoint and well above it and above what anybody had seen before. So that kind of functional improvement, everybody's caught up on the dystrophin and dystrophin. Why? Because nobody's been able to say, "Here's functional benefit." Now, we could not wait to take the 20 mg per kg, do the analysis, say, "Let's use 32 more patients, and let's move." And that's what we're doing. So I think we have now, it's tough to predict. We'll see how it shakes out.
But if we start seeing, if we see that kind of functional trend holding, and that's at six months, we would expect the signal to grow over time because of the half-life. There's an urgency to just get this to patients. They need it, and they need it in the U.S., and they need it in Europe. Anything you want to add to that?
Yeah. I just want to point a few key things that you mentioned. Imagine you deliver naked PMO, and you get focal localization of dystrophin at the right place at the cell membrane, but not throughout the muscle, but in patchy type of appearance. You cannot expect to see a profound functional outcome. Even with low dose of 5 mg per kg in DMD patients, we looked at distribution of dystrophin, and we saw in every section we looked at uniform throughout the muscle section, we saw localization of dystrophin to the cell membrane where it needs to be to perform its function. So not surprisingly that as we up the dose 10 and 20, we see now effect on function. For exon skipping approach, this is quite a unique package.
And that tells you the quality of the delivery, how deep your delivery is bringing the oligonucleotide, the skipping, how widely distributed throughout the muscle tissue is to be able to elicit how much is required for function. So I think it's a combination of the platform that allows this widespread deep tissue penetration, allows us to see a relatively low doses and early time point, six-month trends in all of our functional measures.
Any questions for the Dyne team from the audience? As it relates to the DMD landscape, I understand your level of enthusiasm comes not from just the dystrophin data, but also a number of clinical endpoints, right? I mean, I think that looks super interesting in the context of dystrophin historically at these low levels, not really translating to benefit. That being said, did you raise your eyebrows at all when you saw the recent update from Sarepta with their PPMO and receiving communication from the FDA that the dystrophin filing path wasn't open to them? I mean, how comfortable are you that that is program-specific and more driven by some of the safety baggage that they've been public about?
Maybe I'll just, I'll start it. I mean, our interpretation, first of all, we had, I think with the cell penetrating type of approach, the question was around safety. And there had been some, I think, hypomagnesemia type of issues. So I don't think it was a big surprise for anybody. They said the risk-benefit profile. And I think that was probably what was driving it. From the standpoint of accelerated approval, it just doesn't make sense to us. It is not a path that's open. And.
You've had that conversation, right?
We've had that in the past. I haven't commented on anything recent regulatory-wise, but it just, we didn't see anything in the press release that suggests in any clear way that accelerated pathway is not available.
That changes the landscape, is your point?
Not at all.
Okay. Is this registrational cohort that you're running powered for clinical endpoints?
It's certainly set up to ensure that we have trends around each of those. I don't think we've really told people about the specifics on the stats yet.
Okay. But you think it's at least set up to demonstrate stuff there?
Just the number of patients that we have.
Yeah.
32 patients.
We're setting up 32 patients plus another 50 that are already there, and everybody's moving forward, so 80-plus patients. So that should give us a meaningful set of data.
Yep. Yep.
Patients from lower dose cohorts all dosing up to 20 mg per kg as well.
Makes sense. Beyond DM1 and DMD, you guys had an FSHD program that was, I'm not saying you don't have anymore, but it was part of the story, and then it was kind of for cost reasons in a tougher capital raising environment. It was slowed down a bit. Where are you with that now that we've got some validating data in that space?
Yeah. I should let, since it's in IND enabling studies, maybe I'll let Oxana.
Yeah. For DMD exon skipping, very early on, we have set up screens for exons 53, 45, 44. So we have identified skippers, and our path is straightforward. We will wrap up DYNE-251 and engage into possibilities of creating some sort of umbrella, some sort of developing these other exon skippers together. That would be a very straightforward path forward.
He was sitting on FSHD, though, as well.
Yeah.
FSHD.
FSHD is now, it's a third type of oligonucleotide payload for FSHD. We're using siRNA, so it just shows versatility of our platform. We have generated and shared our preclinical data where we can get a very effective knockdown of DUX4 to desired level, and we are currently in IND enabling studies, so we will be going forward providing more updates.
We're full steam ahead on FSHD. We haven't given any timeline around the IND, but it's IND enabling, and we think the platform is perfect for that. We think it's a very, very large market.
Yep. Yep.
It's a great opportunity.
Okay. Great. In the last minute or two here, anything else you'd like to add, John?
We touched a bit on the pipeline. I'll say it seems to me that what we've demonstrated in terms of the platform, people talk platform, the capability here of the platform. We've now got an siRNA, we've got an ASO, we've got a PMO, and we haven't even talked about Pompe where we've got an exon. So in all of those, whether it's animal studies or human studies, we've been seeing what we had expected to see. The end of this year, from my standpoint internally at the company, as you can imagine, we are to have the kind of data coming together for DM1 at these doses, six months and 12 months means that the clinical execution has been very, very good, and it's exactly where we want to be.
I mean, that is where we wanted to be in a position where we could talk splicing and see what we could correlate it to and relate it to. So we're excited where we are at the end of the year.
Great. All right. No other questions. Thank you both very much. Appreciate it.
Thank you.