Good afternoon, everybody. My name is Ted Tenthoff. I'm a Senior Biotech Analyst at Piper Sandler. And before I begin, I am required to point out certain disclosures regarding the relationship between Piper and our next presenting company, Dyne Therapeutics, which are posted at the back of the room and also at the registration desk. Dyne is developing targeted oligonucleotide therapies to treat muscular dystrophies, having reported positive phase I-II ACHIEVE data on DYNE-101 for type 1 myotonic dystrophy, and also DELIVER data on DYNE-251 in DMD. Here with us from Dyne is President and CEO John Cox, Chief Medical Officer Doug Kerr, and also Oxana
Beskrovnaya.
Beskrovnaya.
Thank you. I am glad you pronounced it and I didn't butcher it too badly. So we also just published a BioInsights report this morning on muscular dystrophies, highlighting Dyne, and hosted a great panel this morning with Doug and a couple of other people from the industry. So really a lot going on in the space. And the one thing I was just mentioning to the team is, you know, I thought I knew how big this opportunity would be, but there is just so much going on in the space. There's so much opportunity here to provide better therapies to not just boys with DMD, but really a host of patients in what I think are even bigger indications. So we'll get into some of that. But I'd like to start off by really talking about the FORCE platform.
What are the specific components, and what are you able to accomplish with the targeted delivery of the oligos?
Well, thanks, Ted. First of all, I will say we'll make some forward-looking statements here, as usual. Maybe I can just start it, and then it'd be great to have the person who actually created the platform, Oxana, talk to it. You know, I joined the company, I don't know, about seven months ago, and I joined it because of the platform, and the platform was starting to show real pharmacology in humans last January. I joined roughly in March, and the concept was that in some of these muscular dystrophies, the challenge has been getting the drug or a payload broadly to the tissue, so if you want to deal with many of these types of diseases, you've got to get into billions of muscle cells and the heart and the diaphragm and so on and GI, and you also need to even cross into the CNS.
The Fab that Oxana had designed really has a unique distribution kind of profile into all of those tissues broadly, deeply. She had shown that in animals. The question was, would you get that in humans? If you used a linker and attached it to a particular payload, the payloads were relatively known in some of these diseases. The question was, could you get it to these tissues? In both DMD and DM1, we were seeing that we were having clearly that we were distributing the payloads. Shortly after I joined, the data started coming in on DMD, for example. It was at 10 mg/kg. We were seeing dystrophin at levels that people had not seen before and at 3% or above.
And the other piece of the (I'll just say, and I'll turn it over to Oxana) is that I think the beauty of this particular modality, FORCE, has been that what it's showing is that distribution matters. That if you do get broadly distributed across the muscle, you just might start seeing functional benefits sooner than you would expect. And although we're in small patient numbers through phase I-II in both DM1 and DMD, we have reason to believe that that's exactly what we're seeing. So it's a really exciting time. And I agree with you, the potential in these particular markets, the unmet need is massive. And it's a real opportunity. But anyway, let me pass it over to Oxana.
Thank you, John. I just want to kind of continue on the story that you started to emphasize important key components of our platform. First is selection of fragment antibody, not full length. One-third of full-length monoclonal antibody allows us really to achieve deep tissue distribution, widespread muscle, skeletal, smooth, and cardiac muscle. We have carefully selected all of our payloads, oligonucleotide payloads, really matching genetic defects of disease. So it is a plug-and-play technology where we can use charged oligonucleotides, for example, single-stranded gapmer ASO for DM1. We have selected neutral oligo PMO for—excuse me, skipping in DMD—siRNA for FSHD, whichever is more appropriate to effectively target disease biology. And what I'm particularly excited about is that we moved now beyond oligonucleotides, where we can also deliver biologics, for example, enzyme for enzyme replacement therapy. And I'm happy to talk more about this.
But in general, we have proven that we deliver to skeletal, cardiac, smooth muscle, and CNS. This is also unique to our ability of our Fab to deliver through the blood-brain barrier. And we are dealing with neuromuscular diseases. They all have CNS components. And so this is an added benefit to our technology.
I'm going to start with DMD. In September, you guys disclosed three SAEs and two boys at 40 mg per kg monthly, DYNE-251. I just want to touch on this briefly. Doug, what have you learned about these boys? Then we'll kind of move into the data at the 20 mg per kg dose.
Yeah, what we learned is that one of the two boys had a hemolytic uremic syndrome, what's called a thrombotic microangiopathy, probably due to an infection, or that was a major contributor. There were other people at that hospital in that region at that time who were not in the study who developed the thrombotic microangiopathy, and these are almost always due to E. coli or Shigella. This particular patient had heme-positive stools and diarrhea, so it looked very much like a standard kind of infection-related, but the patient came into the hospital. The patient was quite sick, so we had to be very cautious here. The patient had to be on hemodialysis for a short period of time, received an empiric treatment with eculizumab, even though complement levels were normal, recovered, was discharged as fine, is still in the study, but the patient was also put on antibiotics.
So cultures were all negative. We could not find the definitive infectious cause. So therefore, we had to say that there is potentially a relationship to study drug. The second event was much milder, really only an SAE because it was in the same country two weeks after this first event. And it was a transient one blood draw drop in white blood cells, red blood cells, and platelets to a very modest degree, which spontaneously recovered. Could have been just variability of the measure. No clinical sequelae. Patient discharged, still in the study, still receiving drugs.
Now, all that said, you guys showed fantastic efficacy at 20 mg per kg. And that's where you're going forward. Tell us what you showed there. And maybe we can even start to move into what the registration cohort looks like.
That's right. So that was at 40 mg/kg. Everybody got down-dosed to 20 mg/kg. Everybody got up-dosed to 20 mg/kg. So we're generating a huge amount of data at 20 mg/kg. That is our go-forward dose. A registration cohort is now enrolling 32 patients at 20 mg/kg Q4. The reason for that is this very compelling functional data that we saw in the original 20 mg/kg Q4 cohort, in which we saw patients actually recovering from their baseline on multiple functional measures. So not just slowing of a decline or a delta relative to placebo, but actual improvement on 10-meter walk, run, North Star Ambulatory Assessment, and most notably SV95C, stride velocity 95th centile, which is qualified to be the primary endpoint for DMD in Europe under current consideration in the FDA.
But the EMA has also qualified not only this as a relevant primary endpoint; it's an accelerometer-based endpoint. So it's not effort-dependent in a clinical setting. It's actually what the kid can do. So it's a very good measure that is correlated with those gold standard endpoints in Duchenne, but better. The MCID there is 0.1 m per second. We were well above that, both at 10 mg/kg and 20 mg/kg. So that really gives, you know, very robust dystrophin data, but profound improvements, albeit with small numbers at 10 mg/kg and 20 mg/kg on multiple endpoints at multiple time points. That's a very robust data set. That's why we decided to lock in the 20 mg/kg.
How soon could we get data from that? How quickly could you also now take this platform into other exons?
Yeah, really good question. So the 32-patient cohort is enrolling right now. We'll know kind of when you could probably start to do the math with a six or 12-month endpoint once we finish the enrollment of that. So we're not done with that. We're bringing people into that cohort right now. So we're really excited about that. And we'll have more information next year, certainly when we have our last patient into that cohort. I will say that the FDA is very interested in these basket cohorts where you can accelerate the development of other very similar molecules for very similar diseases. This is the kind of poster child for what a basket trial would look like.
The idea being, do not do a completely independent clinical development program for other exons in the sense that this is the same Fab, the same linker, the same chemistry PMO, the same disease, the same endpoints. So this is the quintessential basket trial. And what we hope to do is to take our exon 51 experience and now broaden that to multiple other exons in a very expeditious way.
Maybe Oxana, you could just go with what we have available.
Yeah, we have put together, you know, all appropriate modeling in vitro in vivo to rapidly move other exon skippers. We, in fact, already progressed with 53, 45, 44 exons and just really expecting to apply this some sort of platform approach to quickly move them forward.
Very exciting. And again, really remarkable results. Now, a lot of investors I speak with are even more interested in DYNE-101 and myotonic dystrophy type 1. Maybe we can start out talking about that disease for a minute and again, how DYNE-101 works in DM1.
Yeah, so myotonic dystrophy, very common disease, and it's the classic multi-organ, multi-systemic disease caused by a repeat expansion in DMPK with retained nuclear pre-mRNA. This is intrinsically a splicopathy, which means that that nuclear pathology has sequestered splicing factors, resulting in the mis-splicing and all of the organ dysfunction. Myotonia is kind of easy to recognize. It is the failure to relax after forceful contraction. But there are many, many other things which are probably more important to myotonic dystrophy patients. That is weakness, clumsiness, CNS manifestations, smooth muscle manifestations, and then the cause of death in many of these patients is cardiac arrhythmia or respiratory failure. It's an interesting disease because it can take five, 10, 12 years in some cases to actually get the diagnosis, but underlying all of myotonic dystrophy in all of the organs in all of the patients is this sequestration of transcription factors.
So what you must be able to do is to modulate that nuclear pathology to release these splicing factors so that they can accurately splice other genes. So we felt, as we were developing this program, that we had to cross a threshold that we have known to be clinically relevant from modeling and natural history experience, that you've got to correct the splicing at least 20%-25%. And we do. And we've shown that at, for example, 5.4 mg/kg, there's a mean change in that splicing index called CASI of 27%. So, you know, what then happens is once you've gotten the splicing corrected, myotonia resolves. And then over different kind of temporal patterns, you will, we think, restore function, strength, CNS, and cardiovascular. And that's what we're doing in the context of the ACHIEVE study so far.
I might just add to your first point about the market and the opportunities. This is one where there's roughly 40,000 patients estimated in the United States, 70,000 ex-U.S. It's a phenomenal disease, sadly, in the heterogeneity of how it's expressed, and Doug touched on it. I mean, when I first joined the company, I went to one of the patient events, and you know, you sit there with patients, and a significant portion have CNS issues. I mean, that's their fundamental issue. So helping them with myotonia is not what they're concerned about. They're concerned about the fact that they cannot keep their eyes open sitting here in this room. They can't function. Others are having GI problems. They get misdiagnosed for 10, 15 years.
So, you know, I love the way that Oxana has done in that she's designed a drug to get to the nucleus, address the fundamental biology that Doug has just described. And our view is that by addressing that fundamental biology, now you address a broad range of effects. vHOT, myotonia, sure, we see nice results with that. But that's not the primary thing the patients are concerned about. And we're looking at everything from patient-reported outcomes to even CNS effects and so on. So I think it really comes down to the fundamental design of this drug that we have.
Now, Doug, you touched on some of the efficacy endpoints. Just because, again, the questions around the SAEs for 251, even though I think we've largely put them into appropriate perspective. But just to ask the question on 101, how has the safety data been?
Here, you're at a dose significantly lower, I think, maybe going as high as 6.8 mg per kg. So have you seen anything from the safety side? And what should we expect from the update in early next year?
Yeah, so we've seen nothing from a safety perspective that is concerning to us in ACHIEVE at all. That is 7, 18 or 20 doses, 60 years plus of patient experience. We've seen no related severe TEAEs, nothing like that. So we're very, very comfortable with the safety profile. What happens next is, you know, we've got the 6.8 mg/kg data. We've always said that we would go forward with a registration cohort at a dose that we will pick based on these data that we'll see over the next four weeks. We anticipate that being between 3.4 and 6.8 mg/kg. And so we will look at those data as they come in, make a decision on what exactly the go-forward dose will be. We will then initiate a registration cohort within ACHIEVE. And the goal of that is for accelerated approval.
We'll have a series of endpoints, the ordering of which I don't know yet, but we'll be dependent upon that data. It will certainly start with CASI because we know the FDA will accept that as the proxy accelerated endpoint for approval. It will certainly also then include myotonia and then various strength and functional measures in some hierarchical order.
How large do you think that registration cohort will have to be?
I don't know yet. I'm going to have to look at, you know, the data that we get, which means the effect size and the variability of the measure, and then what I'm going to do is, you know, come to John and Oxana and say, look, if we did 15 patients, I can get this series of endpoints, but if I do 30, I could get this, this, and this, so we'll have to make a decision where we cut it. I mean, I think the way we think about it is CNS and cardiovascular are tougher to get in the context of a registration trial. Those will probably wait for the confirmatory phase III trial.
That makes so much sense. Just in the time that we have left, we could probably spend an hour up here. But at World Muscle, you guys reported preclinical data on DYNE-302 for facioscapulohumeral muscular dystrophy or FSHD. Walk us through the DUX4 biology and what's the medical need in these patients.
Yeah, maybe I can answer, so FSHD is a relatively large muscle rare disease with manifestations that are surprising patients sometimes. It's a very asymmetrical disease that sporadically affects muscle over lifetime, but it's a debilitating disease in the end, and the molecular culprit of disease is aberrant activation of a gene called DUX4 that should be silenced in, you know, normal muscle. And as it activates, it's a transcription factor. It, in turn, turns on genes in the muscle that should not be, again, activated, and this sends a cascade of events that leads in the muscle cell to cell death effectively, causing then fibrosis, tissue replacement, muscle wasting, and the best way to think about how to stop this disease is really to go after the genetic defect, stop this gene from activating, and shut down, ideally, its activity so it does not send these downstream effects.
And so we have selected DYNE-302. This is a conjugate, FORCE conjugate with payload, which is siRNA. Because DUX4 normally gets expressed, delivers to the cytoplasm, it's best way to stop it is to meet it in the cytoplasm with siRNA, where it's more potent, catalytic. And this disease requires this quick action, long-term action of shutting down mRNA and protein production from DUX4.
When do you think that could advance into the clinic?
So we have recently shared preclinical data in the model. This model is fairly well recapitulates this sporadic nature of DUX4 activation. And we have shown we can profoundly knock down DUX4 and its transcriptome. We also have an effect on improving function as well as tissue architecture for this specific disease. So these studies are done. And now we have entered IND CTA enabling studies and progressing actively through this phase towards the next stage.
With the time that we have left, you mentioned this a little bit earlier, but I was really intrigued by the poster you guys showed on FORCE-GAA, which is for Pompe disease. So here you're using FORCE platform to deliver alpha-glucosidase rather than an oligonucleotide. Tell us how that works. Really, what's the potential here for the platform beyond just these orphan muscle diseases we've been talking about?
Yeah, as I started today, I'm particularly excited about this program because it really opens up a new field for us and new fields for the FORCE platform. You can think about additional LSD-type indications. So Pompe disease, the current standard of therapy is enzyme replacement therapy. Obviously, enzymes do not cross BBB, so there is no effect on CNS. A good effect for the heart, but very moderate marginal for skeletal muscle. So patients continue to progress on treatment. So what we bring in, different way of delivering, superior delivery in preclinical models over naked enzyme to heart, to muscle, but specifically to CNS, where not only clearing substrate, you're normalizing the size of lysosomes such that section on the brain, throughout the brain, widespread, their lysosomes look normal. And we barely detect any GAA after treatment.
So I think this approach brings substantial benefit, potentially, additional unmet need for these patients. And again, very exciting that you can attach enzymes to the same platform as you develop for oligos.
And we could see this go even beyond Pompe disease. So in the minute or so we have left, you guys have successfully raised over $700 million this year, healthy balance sheet. How long does this fund Dyne? And even more important than that question, what's it enable you to accomplish?
It takes us out to the second half of 2026. We've been fortunate. The amount of money we raised, obviously, is significant this year. I want to thank the investors. We've got a number of them here today. It's enabled us to move forward rapidly with these trials. You know, as Doug was describing, we announced that we'd be providing data on the 5.4 mg and the 6.8 mg. That 6.8 is out to six months and 12 months out to 5.4. That means we've been moving and investing in these trials rapidly. It also puts us in a position to move forward with these early stage programs. We haven't given the exact timelines on that. I would tell people that the urgency this company had had to move DM1 and DMD into the clinic is the same urgency that we can continue.
So we don't need to back off on our research and development. And we shouldn't because, as you've just pointed out, we have an ASO, siRNA, PMO, and now an enzyme. Just the opportunities are significant. So the money is being put to good use.
Good. Thank you all for being with us. Just really excited about where things are going into 2025. Looking forward to more data soon.
Thank you, Ted.
Thank you.
Thank you, Ted.
Thank you.