We got the clock going. We're good. Great. Good morning, everyone. Now, welcome back to the Cantor, day three of our health care conference. I'm Eric Schmidt. I'm one of the biotechnology analysts at the firm. My pleasure to welcome our next presenting company, Dyne Therapeutics. We're delighted to have with us today John Cox, the company's President and CEO. Also, Eric Lucera, the company's Chief Financial Officer. I think we also have Doug Kerr, the company's Chief Medical Officer, in the room as well with us, as well as some members from the IR team. I'm joined by my colleague, Michael Bell, who's going to conduct this fireside chat with us. John, just kind of high-level stuff. You've had an eventful year. Give us the state of affairs at Dyne Therapeutics.
Yeah, we have had an eventful year. It's just the beginning, actually, of events. We're in a really nice place. This company has been built for delivering medicines that offer functional improvement in areas that it's really needed. We're building a pure-play neuromuscular company. Building that company is the foundation of it, really, of building it is the next two products or programs that we have, DM1 and DMD. The heart of the company is the platform. I think you know about this platform, but it is, I think, next generation, best in class in terms of delivering and overcoming the big challenge in neuromuscular diseases, which is delivering genetic medicines to muscle and to the CNS. I hope we can talk a little bit more about the platform as well.
At a high level, I think both Eric and I, Eric more recently, but me about a year and a half ago, we joined the company to get to this point because over the next year and a half, we have some major milestones. We see ourselves in a position to commercialize two products, the first DMD, beginning in 2027. That opportunity to start generating revenue for a company like that, it just transforms a company that has been in an early stage, and not just in one program, but in two. To do that right and do it well requires that you build a great management team. Over the last year, I feel like we've put those, I'm kind of proud of that. I feel like we've put the right team in place. Eric's a key component of that. You mentioned Doug is a really important component of that.
That ultimately will give us a chance to create some long-term sustainable value for shareholders.
Great overview. Just remind us of kind of those key milestones that you're looking for over the next 12 months that drive that value inflection. Eric, you can also remind us of the cash and cash runway.
Yeah, let me start with the milestones. For the company, we've been just calling it 2-2-1. We have two programs where we're going to have top-line data in the near term, DMD top-line data from a registrational cohort towards the end of the year. Then we'll have, following that, top-line data from a registrational cohort for DM1. Beyond that, with both of those programs, you're talking two BLAs to be filed. Those are near-term. Two BLAs, two top-line data points, two BLAs, and then followed by a commercial launch in 2027, early 2027 for DMD. All of that are, I mean, those are really key milestones and all within a certain cash runway, which Eric can highlight for you.
Yeah, thanks, John. As you folks know, we did do an equity raise in early July in conjunction with a venture debt facility with Hercules, with whom I've worked with several times before. All told, the pro forma cash at the end of June was $900 million effective for the July 2nd raise. That gets us into the third quarter of 2027, which does encapsulate the 2-2-1 that John just mentioned.
OK.
Maybe before we get into each of the key programs, John, we will spend a minute or two on the platform. What is special about it? Why do you think it's best in class?
People have been trying to figure out how to deliver these genetic medicines, as I mentioned before. Our company, others in the first-generation companies, started looking at transferrin receptor, which, as you know, is found highly expressed on muscle and also in the CNS. It transfers iron and transferrin into the cells, and it does it in a very efficient way. People have started with using a monoclonal antibody targeting that receptor. You can transfer, you can dupe the receptor and transfer in molecules that way. The challenge with that has always been that you occupy the receptor for a long period of time, and you essentially are blocking what the receptor is meant to do in terms of iron transport. The side effect of that tends to be anemia, and it limits dosing.
Dyne Therapeutics was developed on the basis of using an antibody fragment to hit a particular epitope on the transferrin receptor to occupy it for a very short period of time and just unload, transfer load, and move on. In theory, the idea was you would be able to dose higher. With a fab, and that fab, you'd be able to not only get to muscle, but you'd get to the CNS. We had always thought, and the company had always thought, if you were able to do that, you could broadly and deeply distribute a payload. If you do that, you might see functional improvement faster than you otherwise would expect. When I joined the company, the reason I joined the company is just at three months and six months, we started seeing functional improvement in DM1 and DMD.
These are slowly progressing diseases; you wouldn't have expected that, which portends to we're getting this kind of broad, deep distribution. The final thing I'll say with it is that we've now shown that we can put on that same platform an ASO PMO in humans. We've done it in a way that we do not see this type of anemia response you typically see with antibodies. We've also, in preclinical, now used an siRNA, and we use an enzyme. The versatility of it is something that we can really build a pipeline behind.
It is a great platform for sure. We're aware of the functional benefits. We'll talk more about them in a moment. Are there also biomarker or empirical results you could point us to in terms of the amount of muscle delivery or even CNS delivery that you can highlight that provide a further proof of concept? Is that just going to be a functional readout?
No, listen, I think I would refer to some of our preclinical work first, and then we can talk about even some of the human work. I'll try to be quick on it because we want to get into more data, I know. At one point, we had presented, I think it was in 2022, a nucleic acid research. We had presented an MDX model that's an MDX model for DMD exon 23. It's a common model that people use. Others have used it as well with a monoclonal antibody approach. When we did that approach, you could, in that model, you would see distribution to the CNS, to the heart, to the diaphragm, to muscle. You could break down the distribution based upon not just the amount of medicine getting there, but on the PD, on the dystrophin expression in those tissues.
When we compare that to a monoclonal antibody approach, others had done the exact same thing and presented that, for example, at AAN. Competitors have done that. We had 15x the expression of dystrophin in the cardiac, 2.5x the expression in quadricep. Virtually every tissue was multifold beyond what people have seen. The fab, I think, is really unique in terms of its distribution. That was also, you see it distributed in the CNS. We have plenty of imaging models around that. You take that into humans. The question is, does it translate? Listen, we're in clinical trials now. You see the kind of functional benefit. We've also shown PK data in the muscle. We've shown, for example, in DM1, that we are affecting the splicing correction, which is in the nucleus, splicing correction at levels that people haven't seen before.
That really gets to delivery right to the nucleus in the tissue. The final point I'd make is that, with the CNS, we're not taking biopsies of the brain, obviously, in humans. There are patient-reported outcome studies called MD-High. There's a subset scale of six measures that may not be completely CNS, but are certainly related to CNS, and at least in part, pain, stress, sleep, all kinds of other features. When we got to the higher doses for our DM1 product, you saw virtually every one of those measures move in a positive way. Small patient number, we'll evaluate that further.
Let's dive a little bit deeper into some of the programs. Let's actually start with DMD 51. Just give us a little bit of background on what the standard of care is for these patients, how many are treated with the exon 51 skipper, and how your approach is different.
Yeah, I'm glad you're asking about it. Let's start with the market in general. For DMD, the most prevalent mutation that you have within DMD is exon 51. That affects about 13% of these boys. It may be the most aggressive in terms of the disease because it's the toughest to skip. Naturally, in these boys, the level of dystrophin is close to zero. They progress rapidly. You know the progression of the disease in terms of wheelchairs and death and so on. We've taken that particular challenge on. That represents, in the United States, about 1,600 patients. Within that, the standard of care, if you want to call it that today, is Eteplirsen. That's a non-targeted naked PMO. It's probably the right PMO, but delivery has been the challenge to get a real effect. It's dosed on a weekly basis. That's kind of the standard of care.
That means the boys have a port and so on, and efficacy has never been proven. That's 400- 500 kids we estimate. You go beyond that, there's probably equivalent to that many that have tried it and dropped off the drug because it's for the reasons I just said. It's very onerous to be going through this IV every week. Then you've probably got another 500 or so, maybe 600, that are treatment naive. They probably get treated on steroids and so on. A handful have been treated with gene therapy. I think I won't get into the gene therapy story right now, but you know the story, and it's kind of waned in terms of enthusiasm. The market opportunity and the need for efficacy, it is a huge demand within that group. The only other piece I would add to it is, well, two other pieces.
One is they need functional improvement, and the profile of our drug we can get into, but I think it fits that bill. The second piece is the reimbursement path for this group has been established. Rare diseases, you need pricing that is appropriate for a rare disease. These patients are paying roughly, or the payer is roughly, $1 million a year for a drug with, at best, a modest effect. I think, and that's 400, 500 patients. The opportunity in that marketplace for us, we think, is we are, it is like perfectly positioned for a next-generation exon skipper. That's what people, clinicians, patients are looking for.
Let's chat a bit about the target product profile for DYNE-251.
Sure. I'll be pretty straightforward about it. It's a 20 mg per kg dose. It's dosed monthly, not weekly, once a month. It is a drug that we think will be best in class based upon the data, and I think we can say that with some strength if you've seen the data so far. It is first in class in terms of a targeted delivery for this patient group. In simple terms, that's it. In terms of a description of function and so on, we're talking about a drug that we think will have functional improvement as well as a very, very significant jump in distance.
Can you share a bit about the clinical data so far?
Yeah. We presented, for those listening, the latest data set we presented was at MDA in Dallas. That was back in March. That was really impressive. It was fun to present that. Doug had a chance to present some of the data as well. I went and listened to a number of different presentations on different medicines for different exons and so on. The only presentation that showed functional improvement from baseline was ours. The other piece we showed is that with exon 51, which I mentioned is very tough to skip, it's six months. We had shown dystrophin levels of 8.7%. That's muscle-adjusted, but 8.7%. That's just at six months. Dystrophin has a half-life of about four months. Our models would suggest that it would go up from there at 12 and 18.
The functional data, which I think really impressed people, was we saw improvement from baseline on stride velocity, 95th centile. I don't think anybody's ever shown that, and certainly not in six months, and certainly not at levels of 0.2 m per second improvement. Improvement, not slowing up decline. We've shown 1 m walk run improvement in the patients. We've shown time to rise improvement in the patients, NSAA improvement in the patients. These are fairly small patient numbers. We understand that. That's why we're doing the registrational cohort. Very powerful data in terms of kind of functional improvement. Not just at six months, we also showed it out to 12 months and 18, which means we're showing sustainability, which is really one of the major shortcomings of gene therapy.
In regards to the registrational cohort, what is needed to establish efficacy for the FDA? What are you looking to have on the label, potentially?
The precedent, first of all, the precedent for getting it approved for accelerated approval is dystrophin, full stop. Really, a modest effect on dystrophin has gotten these drugs, this type of drug approved. 8.7% is so far beyond the modest improvement. We have a registration cohort, 32 patients moving forward. We had 50-plus patients in the multisending dose study. All of that data, 80-plus patients coming together, becomes a robust package. That's the bar, the accelerated approval bar for this in this field, well established. Beyond that, we're talking about clinical effect and functional improvement. We ought to show, we intend to show, and we have shown the kinds of trends that relate to improved dystrophin. Now you see 10-m walk run. I won't repeat all that functional improvement data. That's not required for approval. The stat sig is on the dystrophin. We'll have those strong trends, we believe.
We'll follow it up with a confirmatory trial.
What data are needed to convince the DMD community of DYNE-251's superiority to the existing therapies on the market? Do you expect to see reductions in creatine kinase as well?
I think convincing the community, when we've presented the data, the community is excited about it. I don't think there's a, we don't have to go out and just convince like you would do on a product where you're competing against 10 other things. The functional improvement is when people see it, it means something. We had a group, it caught our attention, and I think patient advocates as well and clinicians, is that one of the cohorts, the 20-mg cohort, the mean age of that cohort was eight years old. In exon 51, at eight years old, that is when you are rapidly getting to the point that you can't get up off the floor. You're declining. In a few years, you're in a wheelchair. It's almost uniform. They were improving. Small patient number. That data is convincing in and of itself.
I think you asked about CK, creatine kinase. The definitive biomarker for the field is dystrophin. CK, we'll monitor, we'll track, we'll look at it. CK is one of these things that the field knows bounces around depending upon activity. Dystrophin, very clear biomarker. Frankly, even with dystrophin or CK, we're a company that's now talking about something beyond that. We're talking about efficacy. That's where the dialogue has to go.
When are we going to see the next efficacy update, functional efficacy?
will see that by year end.
What are we, go ahead.
That'll be the registrational data. We're excited for that, Eric. I mean, we can't wait to present it. That data, the registrational cohort we've announced was fully enrolled in Q1. We intend by year end, and it'll be closer to year end, we'll have all of that kind of dystrophin data. We'll have functional data like we described before. Dr. Kerr is going to, I hope, enjoy presenting whatever we come out with there. Hope for good data.
We are now getting close to the FDA submission in early 2026. What is rate limiting for submission? Is there any work needed outside of the U.S.?
The only true rate-limiting feature here is that data, right? Towards the end of the year, we just got to continue, we got to complete running that portion. That's really the rate limiting for putting it together. Obviously, you know, there's a lot of work. We'll be working on the BLA and all the pieces to be ready for that. The only rate limiting is that. For ex-U.S., I'll just say for ex-U.S., I think there's a tremendous opportunity at ex-U.S. There is nothing for patients in Europe. People have felt that Europe is going to be tough to get a DMD drug approved. I think the Europeans have been pretty clear that you need to show some efficacy, and you need to show it with stride velocity. Our data so far is showing that we are above what they have said is meaningful for that endpoint.
I will say our base, so we're having conversations with Europe, Japan as well. We haven't guided around that yet, but we have aspirations there. I will tell you, just to manage expectations around it, our base case is that we will conduct our phase three, and we'll take that efficacy data, including stride velocity, to Europe and also to Japan.
Is CMC completed? Do you have a commercial supply? How are you preparing for the commercial launch?
CMC is one of these things where, as you're getting ready for launch, you're scaling, you're conducting your process validations, all of that. We've had our suppliers in place for some time. We got a team of people that we brought in, people that are experts in that space. I know a few. That's what we're preparing for, and we are preparing for launch right now. Was there a second half to it?
Commercially, have you done anything?
There is a commercial preparation, absolutely. I think I announced a year ago, we brought in a Chief Commercial Officer, Johanna Friedel-Neider. Johanna had been launching Spinraza around the world, as well as many other products. She had built a multibillion-dollar business in her past, rare disease experience. She's been building out her team. I would say on the commercial piece, the beautiful part of that is that in rare diseases, you can build a team in a very cost-efficient way. We can do that across two programs because it's the same basic customer base. We're prioritizing right now the build in the United States because we expect to be launching that first.
Maybe time for us to switch over to DM1 and your DYNE-101 program. This program, John, as you know, had a couple of twists and turns over the last six months. Just update us on where you stand right now and maybe the gist of your optimism.
Yeah, so let's start with where we are. I think we're in a good place right now. I'll go back a little bit in time of how we got here. As I mentioned, we are right now in an accelerated approval mode for that, and we'll follow up with a confirmatory trial. Our view on this market, DM1, is new. It's uncharted territory. There's no products that have been registered in this space. There's multiple ways to register a product here. Frankly, there's room for multiple players in this marketplace. Our approach to registering a product has been accelerated approval because it's a slow-progressing disease, and we think there's early indicators of the disease that you could use for that, followed by a confirmatory trial. Others are using other paths. Our accelerated approval path is based upon a primary endpoint of VHOT as an intermediate clinical endpoint.
I'll touch on how we got there in just a second. We have 60 patients that we will be enrolling. We're enrolling now in the registrational cohort. We had completed a multi-sending dose study with 56 patients. It was guided by splicing correction that allowed us to determine the dose, and then we'll be following up in Q1 with our phase III confirmatory trial. All that's in progress. Kind of the turns that you described, I think you know, Eric, and others know that we have been firmly believers in splicing as the core pathology of this disease in the nucleus. That's why we designed it with an ASO to get to the nucleus. In the field, physicians know, clinicians understand, and the FDA understands, splicing correction and natural history correlates with the disease progression. We anchored ourselves on splicing and did a lot of work on it.
We were making that as our primary. We had been clear with people that was the surrogate endpoint. When we went to the FDA to finalize this and show them what we were doing for the registrational protocol, they had said it's going to need, this is new and novel, and we're going to need more time. That was a shift, and we recognized that. It was a shift for us. When we talked to investors, I think it was a bit of a shock to the system. We recognized that as well. Fortunately, when we talked to them, we said, look, we got to take a pragmatic approach here. We could keep pushing on the splicing, and we continue to collect the data because we need it. We switched rapidly to VHOT as an intermediate clinical endpoint because it is a reasonable predictor of clinical effect.
Both of those endpoints were in our registrational trial, so we didn't have to go back in time. We made the switch, pragmatically did it, kept moving. The one thing we did was we added more patients to make the study more robust around VHOT, as well as get the splicing and give ourselves a chance to see good correlations and trends in some of the other function. That pushed the trial out maybe a quarter or two.
John, you're not the first company to maybe, you know, be led astray. I don't want to put pejorative words on the FDA, but to be maybe unable to interpret what the FDA regulators want. In retrospect, as you go through your conversations with them over the last year or so, how do you think you could have done better in this regard?
As you can imagine, I've thought through this one a lot. First of all, I think when we go back in time, we had terrific conversations on splicing with the FDA at one point. They get it. They understand the CASI 22 and what we do. I think what we underestimated was how long it can take for an FDA to accept a novel, new endpoint in a new space as a surrogate endpoint. We were surprised by that. You're right. We're not the first people that have been surprised. That's not the first time I've been surprised. At the same time, I am actually quite pleased that we had the broad set of data and were able to react and do the things we've done since. It didn't throw us off. We're still going to have that data.
I think people, we're going to have that data from the registrational cohort. It's going to be a powerful set of data to support.
OK, let's say you're fortunate enough to get good VHOT data. If the FDA is willing to accept VHOT as an accelerated approval endpoint, your trial design is a little bit different from your competitor out there. It's smaller. It's shorter term. What can you show on other important functional endpoints that maybe allow you to compete?
Yeah, I guess I would highlight maybe three features that relate back in part to the platform. I'll even mention we're going to have the splicing data. Nobody else has it. People know that getting to 20% splicing represents a functional benefit broadly, and that leads to functional data that I think will stand out. Five times sit to stand, our muscle test, quantitative muscle testing and strength, we had a 20% improvement over 12 months. That's phenomenal. I think that getting to the nucleus and addressing the core pathobiology ultimately will lead to functional measures that will stand out. The safety profile, just the fact that we're using a fab, gets back to the anemia point. Other than the kind of transient anemia you see with just taking blood draws, we're just not seeing that type of anemia effect that you would typically see.
These patients are fatigued as part of the disease. I think doctors will be concerned about that. The other piece is the CNS, and that is massive for this disease. I know you've, I'm sure you've met patients. A significant portion of those patients, what is devastating to their life is, yeah, the physical is a part of it. They just can't function because of the CNS effect. Us getting the CNS, I think, is going to really differentiate and give us a chance to have a very strong label.
Just a few seconds remaining, guys. Anything else that we need to be paying attention to? We only touched on the two lead programs. What else are you excited about, earlier stages of the company, or anything we haven't talked about?
I think you and I may have talked about this at one point some time ago. There's a few things. One is, if we get the kind of functional improvement with DMD, we've got a whole series of exons on the same platform. It's the same fab, same linker, and so on. I very much hope that we can work with the FDA and other agencies on a platform approach. This is perfect for that. You're talking about building a whole franchise. The commercial opportunity and efficiencies from that are so significant. We are clearly, as you know, in a pipeline using the same platform for FSHD. We've been optimizing that molecule for a few features that we think will differentiate. We've also been working on Pompe. I don't know if you saw the preclinical data around that.
Not only were we clearing glycogen in the animal models completely across muscle and across the heart, you saw complete glycogen clearance in the CNS. We've got a few things to be excited about. The big picture is we're building this really special company in the next year and a half. We're excited about that.
John, Eric, thank you so much for the time today. Appreciate it.