All right.
We're going to go ahead and get started. Thanks for joining, everyone. Next up, we have the team from Dyne Therapeutics. Really happy to have John Cox and Erick Lucera here with us. Before we get into it, why don't I turn it over to you guys for an overview of the company, where things stand today?
Yeah, thanks, Gavin. Thanks for having us. We'll make some forward-looking statements. Dyne is a company that is on a mission to deliver functional improvement in neuromuscular diseases. We're building a pure-play neuromuscular company. The first areas where we'll have a chance to show functional improvement, we believe, will be in DMD and DM1. It is an extraordinary time for the company. We're transitioning from kind of an early-stage company to a company that's getting ready to launch two products. The DMD product, we will be providing data this month. That will be our top-line registrational data. We're incredibly excited about that and looking forward to seeing the data. We would be anticipating filing a BLA in Q2 of next year for DMD. In DM1, we're enrolling a registrational cohort.
We're anticipating that product being a product that we could launch in early 2028. DMD, we could launch in early 2027. DM1, in early 2028. We're a company that has, thanks to Erick, we've got the cash at this point to execute on these ambitions of ours. We've also built out, I think, a management team to execute on two launches.
Awesome. All right. Given how close we are to the DMD data, I wanted to dive into some of the more detailed questions we've been getting from investors. We will kind of zoom out after that.
Sure.
One place to start, the baselines for the trial. I know you haven't disclosed them, but have you said directionally how similar they are to your prior study or any other studies in the space?
We haven't, but the inclusion-exclusion criteria are essentially the same. We had, for DMD and DM1, done multi-ascending dose cohorts up to 56 patients. In DM1, the registration expansion cohort will have about 60 patients. In DMD, 32 patients, all with the same inclusion-exclusion criteria. We would expect similar kind of baseline ranges.
Yeah, that makes sense. On the safety side, you previously have spoken about the background rates of aHUS in some countries, kind of in Europe. Do you think, what do you think currently about the risk of this not being drug-related, but just the background therapy or background country, I should say?
I think it is fairly low risk. The safety incidents that you referred to happened back in the summer of 2024, so quite a while ago. We have not seen that type of incident since. That was an atypical hemolytic uremic syndrome with one patient. With that particular patient in that region, that type of issue had been seen, typically due to infection. We were not able to rule out the drug, and we were not able to definitively determine it was due to infection. There had been a second case that was an SAE that had manifested itself with fever, tonsillitis. It was in that region. The doctors had sent the patient to the hospital. There was no therapeutic intervention, and they were sent home. That patient remained on drug. Those were some time ago and were pretty unique instances. We have dosed since then.
We have been at the 20 mg per kid cohort. That was done at the 40 mg. We have not seen that type of case again. We provided a safety update. I think the last one was at MDA in March. Seventy-seven patient years of data, almost 1,000 doses. We'll have another safety update by the end of the year with our next DMD update. If there had been some material change, we would have talked about it.
Yeah. I would suspect this is something that DSMB monitors pretty closely. If there were a serious event, maybe we would have heard something. Given where we are, we should probably feel pretty good about safety at this point.
Fair.
All right. Dystrophin side of things, what's a good outcome?
Let's talk regulatory-wise, because we are pursuing, as you know, accelerated approval for DMD. The historical bar had been set by Eteplirsen with Exondys . That has shown a change from baseline of 0.3%. Our mean dystrophin numbers not adjusted for muscle content, so the more conservative number had been 3.7% in our study, so roughly 10x of what the baseline had been. We're at similar, like I said, similar type of inclusion-exclusion criteria. We'd love to see kind of dystrophin that's robust like that. We are so far above where a product has been approved before. From a regulatory standpoint and from a statistical standpoint, we feel very, very good about that. I'll also remind you that when we adjusted for fat content with the muscle-adjusted number, the mean number was 8.7%. That's at six months. We would expect dystrophin to improve.
Even at six months, those are really meaningful numbers. In fact, I don't think anybody's ever shown numbers like that for Exon 51. At the same time, we had seen really clear, strong functional trends at that point as well.
Yeah. All right. I think for investors, probably the number one focus, those points we just discussed aside, is going to be on the functional trends, especially in light of the ESSENCE data that we saw recently. I guess one of the questions here, if you're looking at the host of different measures, you have NSAA, SV95C, time to rise, 10-meter walk-run. What measure is easier to show a functional signal on at a six-month time point? You showed interesting SV95C data earlier, which maybe we've been wondering might be an easier marker. I'm curious how you think about the host of measures.
I think you've just hit on kind of the four key functional measures. All of those are meaningful to patients, and they're clinically meaningful. We showed very clear trends on all four of those, and not just a slowing of decline, but improvement from baseline at six months. We also showed in the 10-mg and 20-mg cohorts at 12 months and 18 months sustained or continued improvement on function. I really do think, Gavin, the world of DMD has been so focused on the dystrophin biomarker because that's all you could really see. Functional improvement was really not seen in the past. If anything, you saw a slowing in decline. The conversation is going to move more to what you just described, discussions about efficacy. Now, which one you would see first? There are publications that tell you that SV95C tends to move earlier.
We saw improvement on SV95C from baseline in the 20 mg cohort. That was a very, I would say, a group of patients that were at a point in the disease that you would expect rapid decline. Yet we saw improvement, SV95C, but also on others. I am very interested in what we see on things like time to rise, because clinically, that's what doctors tend to follow from the time the child is very young. Any one of those measures, I think, would be really positive for us.
Have you said anything about the dropout or discontinuation rate in the trial also?
You know, we haven't. I would say the dropout rate has been quite low, but it is something that we can provide more information on.
Yeah. Are all these patients crossing over into an OLE also?
Yes.
Is that going to be along with this update or a next-year type of update?
We haven't committed any data on the OLE yet, but stay tuned.
Okay. Makes sense. I guess just on the pricing side of things, I think Exon 51 goes around $1 million a year, depending, yeah, if you're non-ambulatory, how heavy you are, etc . Is that kind of the pricing range you're looking at? Is there any reason you would not price at parity, I guess, is the question?
You know, I think it's a bit early for us to decide on pricing. I won't get into too much detail with it. As you said, Eteplirsen, which we can argue is modest at best if it's having an effect, is also a once-a-week dose, which is really inconvenient for patients. It's roughly $1 million a year per patient. I see that as kind of a floor or base. We could certainly argue based upon data, and I hope our data will continue to show that we actually are showing functional improvement. You could see an argument for a premium. I think it's just let's see the data, and we'll discuss that more in the future.
What strength of functional data would you need to take this package right now to European or ex-U.S. regulators before kind of doing a whole phase 3, which is actually powered for the functional measures?
We do want to share the data with regulators around the world and get their feedback. I will say that we feel like we have a really clear path in the United States for accelerated approval. The conditional marketing authorization for Europe tends to be a higher bar and a higher expectation. In terms of kind of setting expectations for the market for investors, we think we will need a phase three. Now, let's see how strong the functional data is. If that changes, that would be great. Our base case is that we will need a phase three for Europe. Our intention and our plan, and we're on track to start our phase three by Q2 of next year. We will have phase three data, and we will execute it in a fairly timely way. We would submit our appropriate packages.
Thinking about the U.S. specifically, I don't have this in my notes, but I think Exondys is doing around $400 million a year run rate in the U.S., give or take. How much of an opportunity is there to expand that number via patient volume growth? I'm wondering if you guys have done a claims analysis looking at patients who were on therapy but no longer are, Exon 51, untreated, or even on other therapies. How much is this growth versus just a switch story?
We think it is a very significant growth story. I think the switch story is clear and fairly obvious. The kind of data that we've shown so far relative to what patients are dealing with Exondys . As I mentioned earlier, with Exondys , they're dosing every week, which is really onerous. You're right. We estimate, and we have a commercial organization that the leadership has been in place. We've been building out the commercial organization. We're studying that market deeply in the United States. Our estimates right now are that there's roughly 400-500 that would be on Eteplirsen. We think there would be rapid switching with that group. Beyond that, we're estimating that 300-400 patients quit using Eteplirsen and dropped off.
Hopefully, they would come back when they see the kind of functional data, and the doctors can share that information with them. There is probably another 800-900 beyond that. It takes you out to 1,500-1,600 patients in total that we estimate that at best have been on things like steroids. They just have not believed that there is a drug that is going to help them. A handful have been on gene therapy, and that has been waning in terms of effect and so on. In terms of opportunity to grow, clearly the switch is early. Those that have been quitters to bring them back into the fold. We have to get to that other group that really have not been exposed to a treatment.
Thinking about the speed of switch, how frequently are these patients managed? I guess from all your interactions with providers, patient advocacy groups, etc. , how quick do you think the switch will be?
I think the switch will be rapid. We've talked to KOLs. I know you've talked to KOLs. When you present this data and you talk to them about what it would take to switch, and then you add to that, on top of that, the convenience factor with a monthly dose, the kind of response they say is, "Look at this. This is a no-brainer in terms of switching." I think it will be fairly rapid. Now, switching in this kind of market is about getting reimbursement and the timing to get people on drug and so on. Those are kind of the gating factors. I would think it would be relatively rapid.
That makes sense. I was looking ahead to BLA submission. PRV was reauthorized recently. Will you guys get a PRV for this program?
You've been looking into that a little bit.
Yeah. I think we have a really good shot of getting a priority review voucher. And the most recent ones have been going for about $150 million. I do not know whether that level will be maintained, but it is something that I certainly have my eye on to think about whether we could monetize that. I have had conversations with the folks that do that. I am on top of that.
Yeah. That makes sense. I think before the price went up to kind of the $150 million range, it was still at the $100 million range. Maybe it is somewhere in there.
Yeah.
All right.
I guess while we're actually on the topic of kind of expenditures, before we switch gears, go back to DM1, how much do you need to invest over the next year or two, not just to grow the organization commercially, also from a CMC supply perspective too?
You want to tackle that?
Yeah, absolutely. Yeah. In terms of growing the company, let's just start at 30,000 feet. Remember, we're preparing to launch two products, preparing to do two phase three trials as we're launching the two products. It is an organization that is growing very rapidly. We haven't disclosed much with respect to the financial projections beyond the cash runway. That is something that I have historically, as a CFO, given much finer details on. As you may remember, from AVEO or Editas, I gave a lot more detail on expenditures. Being a former buy-side person, I understand the value of this in terms of building models to come up with price targets. As we get closer to commercialization, the plan is to be much more specific about guidance on an individual P&L basis. You're starting to see that in the queues.
On a historical basis, we're disclosing a little more information. The plan would be to continue to expand that from a guidance standpoint.
Awesome. Makes sense. What about partnering considerations?
The nice thing about rare diseases is that you are able to launch these diseases and launch the products in these areas in a fairly efficient, especially commercially efficient kind of model. You do not need thousands of sales reps. You do not have to spend tens of millions on Super Bowl ads. It is really about the relationships. I do think in the United States, we are in a very good position to launch these products ourselves and go forward. There is certainly, in terms of interest of partnering, plenty of interest from others to do that with us. Partnering in Europe, partnering in other places, ex-U.S., are certainly things that we are considering and are open to. At the same time, I think there are markets ex-U.S. that we could also go it alone.
That'll be a matter of kind of discussions between our business development team, Erick, and myself of what is in the best interest of shareholders and for the company.
All right. That makes sense. Last two minutes. I'm just going to ask one or two DM1 questions. It's been such a discussion over the last couple of years. I figured we didn't need to spend that much time on it today.
Sure.
I guess increasingly, as functional measures come up in DM1, we started running some of the analyses. We're kind of seeing, even in your relatively small study, which you're using for accelerated approval, if you use a 6% QMT benefit, 6 point MDI benefit, you're getting like 50% power on each of these measures separately. You have some other to consider. I think there's actually a decent chance you could hit on one of these functional measures in that relatively small short trial you're running. Is that how you guys think about it also, or you have different kind of odds, assumptions than we do?
Let me start with what we know we are powered for. One is vHOT, and that is our primary, so hand myotonia. The other piece that we are powered for that I think is really important is splicing correction. You know this well, Gavin, but this disease is so heterogeneous. The one thing that is core to the pathobiology is splicing. If you want to have a broad effect, you need to show splicing correction. We are powered for that. Nobody else has ever done that. Beyond that, it is about these other functional measures. With QMT, we are not fully powered. I like the fact that you have taken a look at it because with the quantitative muscle testing, we had shown at World Muscle that we had improved in six months on the strength test. That is upper and lower limbs by 10%.
At 12 months, we had increased by 20%. What we need for AA are some trends. I think we feel pretty confident about getting trends across multiple measures. The other measure that is of interest to us, but we're not claiming statistical significance to it. The other measures that we are very interested in is around the patient-reported outcomes, MDI. The CNS subscales are particularly enlightening because that is such a significant aspect of the disease. Our particular modality using an antibody fragment, we know through animal studies that we get to the CNS. We think you have to do that in order to address the totality of this disease.
Yeah. Perfect. We're actually just at time here, but I think this was a really good discussion. We'll be talking again pretty soon as DMD data comes out.
Looking forward to it.
Thanks for joining.
Thanks, Gavin.