All right, good afternoon, and thank you for hanging out, hanging around for the last talk of the day, saving the best for the last year. Good afternoon, and thank you for participating in Guggenheim's Inaugural Healthcare Innovations Conference. My privilege to welcome John Cox, President and CEO of Dyne Therapeutics, and also Doug Kerr, Chief Medical Officer. John, maybe take a minute to introduce the company before we get into the Q&A side.
Yeah, happy to, I think I'm obligated to say we have some forward-looking statements today. I think everybody knows about the company. We're very focused on neuromuscular. We have two areas that we have put a lot of attention into. One is DM1, and the other is DMD. We have trials moving forward quite aggressively, both pursuing accelerated approval pathways. Recently, our Chief Medical Officer, Doug Kerr, who's here, really called it with the 20 mg/kg data as a registration cohort for DMD, and we're moving forward with that aggressively.
We just had a press release, as you know, Debjit, talking in part about DM1, and part of that was that we had our IND approved, which we were expecting, but maybe more importantly, the ACHIEVE trial, which is intended to be registrational, has been moving forward per plan, and so much so that we had also made a statement that we would be providing data at our higher doses, 6.8 mg/kg in six months, which is a meaningful data point for us, and also 5.4 mg/kg, which we had had some very nice data at three months. Now we'll be presenting 12-month data in early January for that program.
Got it. So let's start on the IND side. Any limitations on the scope of the IND in terms of the doses you can explore in the expanded ACHIEVE study for registration?
Not at all. And I don't think we stated that in the press release, but that is the case. We're not limited on dose. And I'll just remind people, the company's strategy, and this was even before I joined, was to pursue the ACHIEVE trial outside the United States, and we're doing that across Europe and some other countries, so that we could, in a very speedy way, move up to pharmacologically active doses and test, and then come back to the FDA. And that's what we did. And we were hoping to do that so that we would be able to have human data at higher doses, and that the FDA would be fine with us pursuing the higher doses, and that was the case. So I think that strategy worked out well.
So given where the program stands today, the prior expectation was the go-forward dose would be somewhere between 3.4 and 6.8, right? So you do not think you need to go beyond 6.8 at this point?
Well, we don't. And Doug can talk in more detail, but you followed us for a long time, and I think you even made some predictions about when we might be pharmacologically active. Our view was that somewhere between 3.4 and 6.8 would be the dose that would get us to splicing as a splicing improvement, and this is a spliceopathy, that would get us above a 20% type of threshold. We saw at 5.4 that we were at 27% in this cohort as a mean, and that was a very meaningful number. So we're very happy with 5.4, and we'll see if the 6.8 takes us even further, but 5.4 was terrific. Anything you want to add to that?
I mean, just the safety has been great at both 5.4 and 6.8. We're really pleased with that. What we'll get and report in the beginning of 2025 is three-month and six-month data at 6.8. That's really valuable to us because we do believe that you've got to be above a threshold on splicing to have an impact on the clinical manifestations of myotonic dystrophy. 5.4 was, and we'll see what 6.8 does. It may decrease the variability.
It may increase the change from baseline as a mean, but that plus the PROs plus the functional data plus the strength allows us to have a very robust data set to lock it in and decide, "We're done. These are the data. We're going to go forward with a single dose toward registration," and we'll tell you about that in the beginning of January.
So let's step back a little bit. When you say you'll tell us that in the beginning of January, that's just the data, do you think you'll also have the regulatory clarity from the FDA regarding what that expedited pathway could look like?
I can start it. We already have the clarity. We had the clarity with the FDA back in May that splicing was a surrogate endpoint. They were very clear about it. They also were clear that we needed to show some correlation or trends with function or with a PRO, and that's exactly what we've been seeing so far. There's nothing that is gating for us in terms of regulatory to move forward with the registration cohorts should Doug decide that we've got a dose and that we're in a position to do it. It's not unlike what we just went through with DMD, and we said, "We've got data, and let's pick 32 patients for a registration cohort and move at 20 mg/kg.
Got it. So if you choose whichever dose, doesn't matter 5.4, 6.8, do you have a sense of how long you need to follow the patients for before you can file the NDA?
We're not completely sure. That's why we've got to get these data in the end of this year, the beginning of 2025. That's a lot of data. And what we then will do is we're very confident you will have splicing change that is above that threshold. We're very confident you'll have an impact on myotonia. What really matters to us is the things beyond that: functional, timed test, strength, even CNS manifestations, other things that are being gathered in ACHIEVE.
What we'll do is rank order them and say, "Okay, this is what we think we can get in a registration cohort within ACHIEVE," and we'll lock that dose in and we'll go. But those things that we can't necessarily get in that registration cohort, we'll do in a phase three, and that will be a confirmatory phase three.
We will get some clarity from regulators about that phase three, a standard kind of clinical development end of phase two design, but that will help shape what exactly that phase three looks like.
So let's step back again. For the registration cohort, it's going to be splicing coupled with something else, whether it's myotonia or a FORCE measurement remains to be decided. How do you decide on suitable powering of that segment?
We'll do that based on the data that we'll get here coming up in the 5.4 and 6.8 mg cohorts.
What gives you confidence that you'll see good level of splicing with longer follow-up? Do you already have the 5.4 mgs longer-term data or the 6.8 three-month data in-house?
No, we're going to talk about the 5.4 at a year, 6.8 at six months in the first of the year. So we're not commenting on what we've seen, but we do think that the splicing corruption will deepen over time. Time on drug really matters. Now we're getting a three-month biopsy. We're getting a six-month biopsy. I think you will show directionality of that, and when you combine that with PROs and function and strength, it gives you a pretty good set of data to go forward on and lock it in.
Got it, and you did mention safety looks great, 5.4, 6.8. The update that was on the website before, I haven't checked today, but that's from August. Any material changes to the safety at the higher dose, longer follow-up on the safety side?
No.
Awesome. With DMD, the choice of 32 patients, 20 milligrams, why limit yourself to 20 milligrams if the two SAEs that you saw may or may not be an infection-related issue?
Yeah, I mean, we do think that the two SAEs that we talked about back in September were confounded by and likely due to an infection. We couldn't say that for sure. And we also saw really profound functional benefit at 20 mg/kg Q4. And so seeing SV95C move, 10-meter walk run test, all of those going in the positive direction at an early time, relatively few number of patients, but was really compelling to us.
And we thought, like, "Look, we could dose find this forever, but given that functional benefit, we have to get this to DMD boys." And so it's time to lock in. Now we could go to higher doses, 30 mg/kg, 40 mg/kg. We'll do that at some point, but right now it's time to get this registered.
Excellent, so sorry, I had to jump back into the ACHIEVE study. I believe your competitor plans to get the phase three enrolled by middle of 2025 and maybe have the data out sometime in middle of 2026 or back end of the year. Is there a way that Dyne can leapfrog that?
We're not making predictions right now on the time. Obviously, we're working in an accelerated pathway, and we're working as fast as we can. And the trial's been moving appropriately, which is why we were able to make some statements about data that would become available. I will just say that in, I think, our view with DM1, what is really important is that a company is able to demonstrate that they can go beyond myotonia, beyond vHOT. We're collecting splicing data for all the reasons that you know. It is ultimately, we think, will be indicative of a broad effect, myotonia included, and you've seen our vHOT data.
And what I really would love to see coming out of Doug's analysis later this year and when we start talking at the beginning of the year is that we are able to come up with a cohort that gives us not only strong splicing data, not only strong vHOT data, but hopefully more than that. And that's what patients and that's what clinicians are looking for. Now, it'd be great to be first, but in this market, it is a big market. It is a market that is nobody's going to own this market in the first six months.
This is a market where patients and doctors are looking for a drug that affects the CNS, that affects muscle strength, that affects GI, that affects a broad range of factors that are really important to patients. Hopefully, we have a chance to do that and we can prove it. If it means we get there first, great. If it means we're a little bit later than that, but we're differentiated, fine.
Just talking about the CNS, one of the things that the docs had communicated to us was these patients are not particularly welcoming to treatment because of excessive daytime sleepiness, fatigue, et cetera. Are you measuring or collecting any of that information, especially in the PRO, which point to these things changing?
We are. We're measuring that. We're very interested in the CNS. We do think one of the things that the FORCE platform does very clearly is it gets into the CNS, and that is a huge aspect of myotonic dystrophy. We are gathering it. We'll look at excessive daytime sleepiness, fatigue, apathy, the various measures. We've got PROs that allow us to do that. We will think about other ways in which we can gather CNS data.
We don't know how quickly that will change. We know that some of the muscle strength manifestations change very rapidly. We just don't know that with myotonic dystrophy. We may need to continue following them further and further. We have an open label extension, a long-term extension. We have the phase three, but it's very important for us to gather those data.
Got it. So moving on to that DMD program, 32 patients, the agreement is primarily using dystrophin expression, right?
Say it again.
It's just dystrophin expression-based accelerated approval with the current cohort or the expanded cohort in DMD?
The plan is dystrophin, and you've seen data that we've had now with Exon 51 skipping that the dystrophin data is beyond what I think anybody's seen before, whether it's adjusted or unadjusted. But beyond that, I mean, what really has gotten our attention is that we have seen functional benefit in small cohorts, and particularly, I think what Doug and our team have been anchored on is the SV95C because there's a minimal clinical endpoint that you can hit with that of 0.1, and we've seen even in 20 mg that we're above that endpoint in six months.
So yeah, dystrophin is obviously important. It's been important in the field. We've had it at a six-month data point. We'll see over time, particularly since a half-life is 90 days on that, so hopefully it continues to increase.
But what is really in our minds differentiated about our approach and our platform is the distribution, and that distribution seems to be resulting in functional benefit sooner than one would expect. That's what's got us excited. I mean, people, you're talking about going up even higher. At 10 mg/kg, when we first presented that data and showed dystrophin above 3%, people were like, "Why don't you just file that immediately?" We're already now at 20. I think for the reasons Doug stated, it's time to call it, but it's more than just saying we got a certain dystrophin number.
We're seeing the functional kind of improvement, and we hope that continues. Now we're going to have about 80 patients at 20 mg/kg moving forward because we up-dosed everybody, all moving forward with this registration cohort. So that should give us a chance hopefully to see Dystrophin, but I'd love to see a bit more than that.
So let's talk about that 80 patients up-dose. Does that include the two patients who you had to stop dosing, obviously because of the SAE? Are they on therapy? They're back on therapy right now?
They have not withdrawn from the study, but we don't know whether they've continued to receive dosing.
Okay. Has there been any talk with the FDA in terms of the threshold of dystrophin they would like to see, or precedent is already set and it doesn't really matter?
No threshold that we're aware of. We think that this is a big number. This is obviously a number that can get it done, but that functional data, just to emphasize what John said, it's multiple endpoints at multiple time points in multiple cohorts, and they're not just slowing their decline. They're actually improving from their own baseline, so that makes you feel very good about those data, and so dystrophin will be the basis for the approval, but we're going to go in and bring them all this functional data as well.
There has been no Exon skippers approved in Europe. I believe there was a 5% threshold CHMP wanted to see. Have you had any discussion or are you thinking about what to do with Europe?
Well, we're interested in a conditional marketing authorization in Europe as well. We're going to go in with the data that we get. The functional data, you know, SV95C has been qualified as the primary endpoint in Duchenne muscular dystrophy. And frankly, the EMA has been farther ahead of the FDA to date. They've done really beautiful work on why SV95C as an objective measure of functionality is really the way to go in DMD. We'll see if the FDA gets there. We think they will. But since we've got such functional data, we believe that not only dystrophin, but functional data can be the basis of the conditional marketing authorization in Europe.
Big picture, Doug, we do think there's a global opportunity here, and Europe, for obvious reasons, has a massive unmet need. The fact that the regulators are looking for functional benefit and they're really clear about SV95C, let's see if our data holds up, but that certainly plays to this type of drug.
So as you move exon 51 into a registrational study, are there other exons which will be fast followers?
We have several additional exons kind of in preclinical work. We'd love to move those forward, and I think we will. But some of that, I really do think that when we start seeing positive reactions, if we see really positive reactions from regulators, which I hope we will with this first drug, it's time to start talking to them about platform approaches that others have brought up before and to see if we can accelerate multiple Exons. That's what we'd love to do. I think it's gated by us having some good results with Exon 51.
Got it. So Doug, you mentioned almost 80 patients in DMD. Any other SAE's that have cropped up outside of those two?
Nope.
Okay. Awesome. From the rest of the platform then, thoughts on Pompe, FSHD, very different approaches. I surprisingly get questions on when is the Pompe program moving to the clinic?
I mean, we're excited about both. FSHD would be the next to get into the clinic. We haven't said exactly when, but we're in the midst of IND enabling studies right now on that. One of the things we really like about FSHD is it's not only a really large disease and with a huge unmet need, but there are some really good biomarkers that enable you to make rapid decisions about dosing pharmacodynamics.
You don't necessarily have to use just muscle biopsies, which obviously is cumbersome and invasive. So having a blood-based biomarker where we can ask whether we're modulating a key feature of the disease is really important. Now, we will use DUX4, DUX4 transcriptome, as well as a serum-based marker, but all of that's available to us that we think is really important.
Pompe is a little bit behind that, but one of the fascinating things about Pompe is obviously the Force platform gets into the CNS and is incredibly good at removing glycogen from the CNS. Now, this is the kind of fourth cargo on the Force platform. This is a recombinant enzyme, but it gets into the brain, breaks down glycogen. It does so also in the heart. It does so also in the skeletal muscle. And so for all of those things that are kind of unmet need, we think that there's an opportunity for this to address that.
I'll just state the obvious, Doug. I think people are starting to ask about the pipeline, which is great, and it points to the versatility of the platform. We've now had an ASO, a PMO in humans, both on the same FORCE. Doug just described an enzyme or a recombinant protein attached and an siRNA, all preclinical. So one platform, four different payloads, and we're seeing pharmacology, whether it's in animals or in humans, is pretty impressive.
So between DMD and DM1, how many doses have been administered to date? I'm just thinking because there are still questions we get on the safety, the long-term safety of engaging the transferrin receptor.
I forget the exact number, but it's over 700 for each doses.
At what point do you think this gets de-risked or this question stays in the back of everybody's head because, hey, you had one episodic PE case in DM1, you get these two kids in DMD?
We're very pleased with the safety profile. We got the right dose. There has been a lot of experience on this, 60 years' worth of experience across all those doses. So we're pleased in both programs. We got the right dose. We're showing functional benefits, and as fast as we can, we're going forward.
Awesome. I don't want to push you anymore on the DM1 data because it's coming pretty soon, and let's see how it all plays out. Thank you so much for your time and really.