So it's my pleasure to announce our next guest from Dyne Therapeutics, President and CEO, John Cox, and CMO, Dr. Doug Kerr.
Hi.
So, gentlemen, welcome. Thank you for joining us today. John, maybe to start, can you provide a couple of minutes of the state of the business for Dyne and some of your key accomplishments year-to-date in 2024?
Yeah, I'd be happy to. I think the company's in great shape. You know, I joined six months ago, and I joined because I thought this company had a chance of being best-in-class. I feel that we're in a very fortunate place. I mean, our investors have been with us. We've raised well over $800 million this year, so we're funded to really pursue our clinical dreams and ultimately try to register a couple of products.
You know both the programs, but they're both in areas where there is a tremendous unmet need, and we've seen so far data on both programs that shows not only movement of surrogate endpoints and biomarkers in the direction we had hoped, and in some cases, beyond what anybody has seen before. We've actually started to see some early functional benefit, and I mean early meaning normally, you might take a year or longer to see the kind of functional benefit that we're seeing in months, which was more than I think any of us had expected.
And then, you know, the company's not only in a position to move forward with launching some products in the next few years, maybe two major programs, but at the same time, the same platform now has four different payloads that we've used, two in humans, and two in preclinical. And so we have a chance not only of having programs that are moving to registration and also to approval, but right behind it, we have a chance to build a pipeline all off the same platform. I just, I don't know if I've ever seen that before, so we're in a really special place.
Great. John, as you mentioned, you've been with the company now about six months, and there's been some other execs coming and going, but let me ask you this question. You know, we all know that the CEO has to wear a number of different hats. You know, within that six months, tell me some of the things that you know now about the company, wearing your hat as the head coach, let's say, of, you know, what it takes to drive this team down the field as they move their development efforts forward.
I like the sports analogy stuff. We can really go with that. Look, I think the company had moved the ball down the field very, very well, really well, and I don't know if we should say we got to the 50-yd line or further, but it's a team that's executed and we continue to execute. So, you know, coming onto this team, I feel great about the execution. What has also been something that we're gonna be communicating, and that I'm excited about, is when I talked about the kind of functional benefit earlier than we expected, I really think it relates a lot to the fact that the distribution profile of this product is differentiated as well.
If you look at the preclinical data, and you know, guys like Doug, who came in a number of months ago, people who are real deep neuroscientists, and they start looking at our preclinical data, and they see the distribution to the brain and deeply and broadly across the brain, when they see the distribution across muscle, within muscle, when they see it get to the heart, to the diaphragm, and not just to kind of dispersed in pockets, but broadly dispersed. As a consequence of that, we're getting payload to the places that you need to get it, to the diseased tissue, and I think that's resulting in us having distribution that's differentiated and results in functional benefit sooner than we would've expected. So I'm having fun coaching the team.
Well, great. And so let me ask you what you've learned in your role as, say, chief spokesperson for the company in communicating the story to the streets. You know, some people know you, some people know Doug, others are trying to get to know you. And, you know, obviously, it's always a situation where you gotta earn their confidence. So in terms of that communication role, what would you say you've learned over the last six months?
Uh
A nd for this story of Dyne?
So I, I touched on part of the communication and the messaging, but I, I'll say, you know, communication is something you always work on, and I, I think some of the communication that we have been highlighting for investors recently has been about building of the team. So, you know, if you're coaching a team, stick with the sports, you wanna keep bringing in the best players that you can. When I see how the company has evolved, we've had terrific people at this company. Where it's taken the company to this date, in five years and two programs, both at this registrational position, is phenomenal. Now it's a question of, how do we prepare ourselves for getting the products registered in, in pretty complex areas like DM1?
And also, how do we start positioning ourselves to be able to launch products globally? Those are two things that are not easy to do, and we've brought in some great people to help us do that. One of those is Doug Kerr, and I feel like we've just brought in a superstar to kind of get us across the finish line in terms of getting products registered globally. We also brought in a person named Johanna Friedl-Nader that I've been wanting to communicate about because I think in some of these diseases where the endpoints can be quite complex, like in DM1, you need somebody who has really launched products globally in rare diseases, and can be thinking about the label and how you're going to position and educate the market, and Johanna is just perfect for that.
So getting additional great people on the team to augment the people we've had, that's been another part of my role.
Great. So, Doug, let me switch over to the data. You, the company has presented positive data for both of your lead programs this year, DM1 and DMD. The most recent data for DMD, exon 51 amenable, skipping, was continued to be positive. I think the one thing that caught people a little by surprise was some of the SAEs in a couple of patients. Help us understand while, okay, sure, it's a non-zero probability that the drug's involved, it's not something that we should be worried about.
Yeah, that's right. So, you know, let me just start by saying I'm a neuromuscular neurologist. I've had an academic career treating DMD boys, DM1 patients, FSHD, so I've been following the Dyne story for an awful long time, really since its inception out of Atlas in 2017. And I, over the last year have been just amazed at how transformative this platform can be, in truly delivering payload cargos to the muscle to really modulate genetic muscle diseases. So got really excited, got really involved, now have the opportunity as the chief medical officer, really excited. The DMD data is profoundly important, right? So, we're tremendously excited about the efficacy. We should talk about that because, it differentiates this approach from, I think, anything else that has come around in, in DMD.
In terms of the safety events, there were two SAEs at 40 mg per kg that were probably due to infection, but we don't know with 100% certainty. One of them presented with nausea, vomiting, fever, and bloody diarrhea, which likely is a Shigella-induced hemolytic uremic syndrome. We could not find definitive evidence for that. So we did the conservative thing, which was to ultimately down dose patients at 40 mg per kg down to 20 mg per kg. All of the rest of the patients in DELIVER, which is the DMD study, have been up dosed to 20 mg per kg. So we have an immense amount of data at 20 mg per kg. That will be our registration dose. We are initiating those registration cohorts right now, and the reason is because of the profound functional improvement.
So whereas the dystrophin number, I think in this field, as I have seen it over the last 25 years, has been kind of the barometer as to whether you're doing something, I think that's kind of a false narrative because you haven't had function to go by. And so the notion was that you needed some number, 5% or 10% dystrophin. That's not true, and I think that relates to the FORCE platform, where this diffuse delivery to skeletal muscle, smooth muscle, diaphragm, cardiac, and CNS mediates functional improvement earlier and more robustly than with other platforms. And we really like that it's not only one cohort at 20 mg per kg, it's also at 10 mg per kg. And it's not just one endpoint, like North Star, it's also SV95C and other strength measurements, and it's at multiple time points. So that's what tells us that that's real.
That's what's gotten us very excited about going forward with that.
Yeah, so as John said earlier, you know, we are seeing that improvement in the functional benefit, which is differentiated from what we've seen from other programs, so give us a biological rationale for the trends we're seeing at six months, why they should continue to improve for the functional benefit measures at longer follow-up?
I think one reason is, you know, we talked about it a little bit, if you deliver to small pockets of muscle dystrophin replacement, but those areas of dystrophin replacement are surrounded by deserts where there is no dystrophin replacement, that's very hard for that muscle to move. It can't move a limb, it can't move a boy, and if you deliver it diffusely, it does, and I think that's what we're seeing, but dystrophin isn't at its plateau at six months. It will probably plateau at twelve, eighteen months, so the reason that we're optimistic, we've seen it early, that's because of diffuse delivery, but the dystrophin is going to increase. It's got a very long half-life. It's a very complicated protein, but we'll see it going out to eighteen months, which is why we think we'll continue to see functional improvement over time.
You know, going back to your call a couple of weeks ago, you did mention that, you know, you still possibly wanted to explore dosing at levels higher than 20, but given how good 20 is, especially compared to the approved product. Sure, it's great to have a more fully characterized product, but do you really need to do that?
Yeah, that's a very good point, and where we got to on that point is we want and we can explore higher doses, but we have to get this to DMD kids now, and so this is a transformative dose and dose regimen. We are going with that. That doesn't mean that we won't explore higher doses. We can. There's a lot to do in life cycle management, and we will do that, but it's time to get this. We could dose explore forever. We're beyond that.
Great, so lay out the timeline for DMD 51 going forward.
Yeah, we're initiating those registration cohorts now. We'll see how they play out. We don't know exactly when we're going to file or anything like that. We're building in functional measures. We think SV95C, which is accepted as a primary endpoint for full approval in Europe, and of course, the FDA is considering this. The reason we like that is, one, it is not effort dependent. It's not what a kid does in front of a clinician once every six months. It's in that child's home over a three-week period. It's very objective. It correlates with relevant clinical gold standard endpoints, such as North Star and six-minute walk test, so the EMA has already signed on. We already know exactly what the minimum clinically important difference is, and if you have something which induces a change of 0.1 m per second, that's it.
That's all you need to do. The reason for that is because it correlates with falls and loss of ambulation and 30 m on a six-minute walk test. We've already exceeded that in our early studies. So we think that that will potentially be a registration, full approval, certainly in Europe and other regulatory bodies, including the FDA, are thinking about it. So we'll move as quickly as we can with those data.
Okay, great. Well, let's switch to the other program, 101 for DM1. You have presented data on this program as well. The dose dependency looks really good. I think one of the things I've always thought was interesting about the different approaches that the companies are utilizing to you know eventually free up the MBNL protein. You're using an ASO designed to facilitate RNase H degradation. Others are using an siRNA to engage a RISC complex in the nucleus. Others are using different approaches you know steric blocking. So talk about what you see as the advantage of your approach.
Yeah, that's a very interesting point, and we'll see how this plays out. But our view is, fundamentally, myotonic dystrophy is a spliceopathy mediated by intranuclear pathology, expanded triplet nucleotide repeat of DMPK and sequestration of splicing factors. That's a nuclear event. The way to get a therapeutic benefit in myotonic dystrophy is to release those splicing factors, full stop. So we chose a cargo that gets into the nucleus that can knock down intranuclear DMPK, freeing those splicing factors. So the way we see it is you must have an impact on splicing. And what we've shown so far in our May data release is that there is a dose-dependent and relevant alteration in splicing, a correction as defined by the CASI.
And we and others have said that you probably need to have a correction of roughly 20%-25% to unlock the clinical consequences thereof, and we're there. We're there at 5.4. We'll see data, a longer-term data at 5.4, as well as our first look at 6.8 mgs per kg. And so we think that we've already shown that you have modulated the core pathobiology of myotonic dystrophy, and early on, multiple functional measures, strength measures, quality of life measures, we're showing movement. So we're very excited about that program. We will get data as we go through the fall, lock in a dose, and move into registration cohorts there as well.
Great. So I guess the question is for investors. You know, you've talked about filing for an IND to move into a US study. You've always talked about the study design being registrational. So square for investors, perhaps a desire to have an endpoint based on spliceopathy compared to what Avidity's doing, who's got a phase 3 ongoing, where the primary is vHOT, which you also have positive data for.
Yeah, I mean, we've had a meeting with regulators in the U.S., the FDA, about the suitability of CASI as an approvable endpoint for accelerated approval, and the answer was unequivocally yes. It must be contextualized with something else, but yes, it is suitable every bit as much as dystrophin is for DMD. So we're very encouraged by that as a registration path. So we're doing that, and that path is open to us. We will likely get that. Myotonia actually moves quite quickly and quite robustly, but it's not the totality of what we want to show. We think that actually, as you look at patients with myotonic dystrophy, it's much more than that. It's GI dysfunction, it's cardiac dysfunction, it's strength, it's mobility, it's CNS dysfunction, all of which we think can be modulated by FORCE and DYNE-101.
So we're building in a path where we will lock in a dose, we'll look at data, we will look at splicing, we will look at myotonia... We will then order beyond that, how quickly can we determine a statistically significant difference in other measures of strength, function, CNS, cardiac? And we'll go from there.
Okay, great, well, let's talk about maybe a third program, actually, before I get to that one, let's go back to DMD, so you do talk about having other programs targeting other exon mutations amenable to skipping. When's the correct time to put the pedal to metal and advance those more quickly?
I mean, this is the perfect example of a potentially basket approach for other exons. There's already proof of concept with other modalities, but the FDA is very interested in this, global regulators are interested in this, that you don't have to do a complete standalone clinical development for other related disorders, and this is perfect for it because the fab is the same, the linker is the same, the chemistry of the payload is the same, the endpoints are the same, the population's the same. We are very interested in very quickly getting regulatory alignment, that we can do a basket approach, ultimately, we hope, leading to a franchise of exon skip amenable DMD patients that goes far beyond exon 51.
I'll tell you, we have... After seeing the functional data that we saw at 51, and seeing the kind of feedback from patient advocacy groups, the next question is, when are you gonna be introducing the next exons? And I think we feel a certain, just an obligation to try and make it happen. As Doug said, we need to understand from regulators, will they accept more of a basket approach so we don't have to go step by step by step, exon by exon? But nobody has seen the kind of functional benefit that we're showing. People talk about dystrophin numbers, but you gotta really look for some kind of functional benefit.
If we can really demonstrate that definitively with 51, then you ask when. I think when we show 51 that we've got absolute clear functional benefit and regulators believe it, we're in a position to start moving forward on the others.
Okay, and so, I did want to ask about FSHD. I think what I like about this program is that your cargo's an siRNA. So again, demonstrating the versatility of your design platform. What's next there? How far away from the clinic are we with that?
We're initiating IND enabling studies right now. So although we haven't given a time, you can kind of work forward from IND enabling studies to the IND. We really like that program for several reasons. One, it's an siRNA. It's the right cargo for that disease. What you need to do is repress DUX4. That's a cytosolic event. That's what siRNA does, very potently, and you don't need frequent administration. And what we also like about it is that there are DUX4 transcriptome events, some of which can be detected in the plasma. And so you can use blood to assess whether you've got the right dose and the right dosing interval quickly, rather than just relying upon muscle. That enables you to lock in that dose much more quickly. This is a big population, huge unmet need, pretty clear path forward for us to get there.
Okay, well, let me ask you a final question. Another question I get from investors is, the stock's more than doubled this year, I think I've missed it. Why haven't I missed it?
I think we've touched on a number of those reasons. Listen, I think the opportunity in front of us. I mean, we're happy with how the stock has moved, and investors have been behind us, but the opportunity in front of us, it's just an amazing opportunity. I mean, you look at when you look at DMD. I know there's drugs out there, but the unmet need in DMD is still incredibly significant. Whether it's gene therapy or naked exon skippers, there's still a significant unmet need, and it's right there. The second one with DM1, the opportunity in DM1 is. I think people realize it is massive. And even if there's two players in that field, it is a massive opportunity, so, and it's global.
So this is just the beginning, I think, for both of those, really, those opportunities. And they really are an opportunity to build a special kind of company for the long term. And as I mentioned earlier, and you touched on it, the versatility, I think, was the phrase you used about the platform. I mean, we have an siRNA, as we just described, for FSHD. We've got an ASO, now for DM1. We've got a PMO for, DMD. And we haven't talked about Pompe yet, of which we've got an enzyme, all on the same platform. So, hopefully, hopefully this is just the beginning for us.
Great. We've reached the end of our time, but thank you so much for the stimulating discussion.
Thank you.
Thank you.
Appreciate it.
Thank you. Good question.
That was awesome. Thank you.