Okay, you guys ready?
Yeah.
Yep.
Okay. We're going to get started with our next session. Thank you for joining me today. I'm Andrew Tsai, Senior Biotech Analyst at Jefferies, and it's my pleasure to have Dyne Therapeutics joining me. To my direct left, John Cox, CEO, and to his left, Wildon Farwell, CMO. Welcome, both of you.
Thank you.
Maybe spend a couple of minutes talking to us about Dyne, for those who are less familiar with the story, what you're trying to achieve, and what catalysts and milestones we can expect over the next, let's say, six to 12 months.
Well, I'll be happy to start it. I've been with the company just for a little over two months. Hopefully, some of you know my background, not new to rare diseases or to launching products, but this company is at a really exciting point in time, as I think you know. So we had talked about presenting data. Before I came, the talk was that we would be presenting data in the second half of the year. The data was rolling in, and we decided to present it sooner. And that was kind of one of the inflection points. It just got moved up, which was fantastic, and I'd love to take credit for that. But it was really nice to see, and it was nice to announce. And the data was on two programs, I think, as people know, and one was DMD, and the other one was DM1.
What we were enthused about was the fact that we were seeing really meaningful biomarker data, single platform, two different payloads, two different diseases, but biomarker data in both diseases that people hadn't seen before, arguably. Small patient numbers, but arguably very differentiated. But maybe even more importantly, what we saw was that that biomarker data was suggestive of some functional trends that you could also argue hadn't been seen before in both diseases. So I think we wanted to share that. We wanted to announce it, obviously, and we thought it was important enough. And then we had also had some conversations with the FDA, one in particular on this surrogate endpoint approach, where we had done a lot of work on the splicing index.
The team had really put a lot of weight behind that because they felt that the splicing index was ultimately the best kind of indicator of changing the fundamental biology of DM1. Whether or not you could use it as a surrogate endpoint, whether or not our data was strong enough to do that, and so on, we wanted to get that in front of the FDA. We did, and they let us know that that pathway was open to us, and I thought they were really quite positive through all that. So that takes us to your question about what do you have ahead of us. I think in the second half of the year, we're not announcing the data that we're going to present at this point or actual date, but you can expect some data. I think we'll have opportunities to present data later in the year.
But one of the reasons we're not is because we moved up the presentation of data. And the other is we just have the way these trials are designed is there's multiple cohorts, different dosing durations. We're increasing dose. We're getting to some very interesting doses now, and that data will be coming in kind of in batches as we get biopsies, and that'll inform our models, and then we'll decide what we want to present. It also informs regulatory discussions, but what really is a priority for us is to have the right regulatory discussions to get clarity on the registration path going forward.
Okay. And John, you came as a CEO in an interesting time back in March. Why exactly did it happen then ahead of some of this important data readout, and what would you do differently as a new CEO?
You know, I think people might have been a little surprised by it because in the middle of clinical trials, there was a switch, and so people were thinking, "Oh, there might be some bad data they know about," to be honest with you. We kept saying that's not the case. My own perspective, first of all, I thought Josh and the team had done a phenomenal job in five years to take two programs with a single modality forward the way they did as rapidly as they did. But I also think that you get to a certain point in time where it is time to move towards registrational trials and start thinking about how you're going to commercialize a product or products, and the phenotype of a company really evolves. It's a big transition at that point. We're just starting to move into that.
And I think if we, and that's what I love doing that. So for me, you just don't find too many companies like that. At that point in time, two programs, rare diseases, huge unmet need, and the potential to launch two programs around the globe. So from my standpoint, it was just an ideal time to step into the company, and I'm glad I did.
Okay. And was it your decision as CEO to pull forward the second half readout, or was that the plan all along?
No, it wasn't the plan all along. I mean, the data shortly after I joined, we started seeing some of this data, like the 10-mg data for DMD. And you've seen it, Andrew. But we saw that data at 3.2% dystrophin level, and we already had enrolled the 20-mg, and we're going on the 40-mg, and here we are at 10 with numbers like that. So this team, Rob and Wildon and some others, we sat around and said, "Man, we should get this data out there." So I'd like to say it was all my call, but I probably could have vetoed it, but I was pumped for it. But it was a team effort. We were energized.
It's important to note that you share the data with the FDA who gave you the updated—not just blast—I don't want to say blasting, but just they reaffirmed or suggested again the pathway remains open for an accelerated file.
That's right. Specifically DM1, which I think people have been very focused on. That was sort of the sequence.
I see. And maybe taking one step back, how did you guys know to choose the right payloads for each of your programs? Because arguably you've chosen the right payloads.
Well, I wish I could. I'd love to go back in time and take credit for that in a big way, but I haven't figured out how to do it. So go ahead, Wildon.
Yeah. Look, at Dyne, we have always been about following the science and really making sure that we're choosing the science that matches the foundational biology of the disease. So in both indications, both DMD and DM1, these are indications where we know ASOs make sense. We know a lot of experience with PMOs and DMD. We know that exon skipping works. The challenge has always been getting enough of the payload where it's needed, getting enough of it into the muscle. So with FORCE, we've been able to begin to see just that. With DM1, again, we know that this is a nuclear toxic RNA disease. We know ASOs, gapmers, get to the nucleus, and so we chose to do just that. We're not limited to ASOs. We're not limited to PMOs. We have the ability.
We are very open to conjugating other payloads when it's appropriate. And so I think folks will see that as time moves on with the rest of our pipeline. But for both DMD, DM1, it made sense to use a PMO and use an ASO. And right now, the data are very consistent with that.
Then maybe one higher-level question again before we dig into the DM1 program and DMD afterwards: you did raise cash on the heels of these data sets. So why do that if you've already had a good amount of cash already? What are you going to do with the cash?
Well, we're trying to advance two programs, both registrational. We did have cash. You know, we raised some earlier in the year. Obviously, I thought the company earlier in the year in January had done a terrific job of raising around a time that there was a good inflection and appreciation for value and so on with the company. And essentially running that play again made some sense with that time. The question is, what are you going to do with the cash? Running these two programs takes us out until second half 2026 with the additional cash. So I think it was an appropriate time to raise. We didn't get carried away and raise too much, but we raised money that'll get us to a good point, so.
Right. Okay. And so speaking of the DM1 program, at this juncture, do you think you guys have a superior DM1 program, and why?
Well, look, we like the payload. We like just what was just explained by Wildon before. When I joined the company, I don't like to—we're all here to help patients, and we'll get out there, and it's a big market, and we'll all compete. And I'm not negative on anybody else getting some good results. I hope they do. It's terrific. It is a big market and a big unmet need. But when we look at—when I joined the company, the arguments that I went through in my own head was with DM1, this is a nuclear-based disease. We need to get to the nucleus. We have a payload that gets there, and the data so far has supported it. The other big issue is, Ben, could you ever dose high enough to get enough payload across all these tissues? That data in January suggesting maybe we could.
The science around the Fab, which is pretty unique to us, seems to be bearing out. It's not accidental. The company intentionally, scientifically said, "Let's design a Fab that would hit a particular epitope without disrupting the TfR1 receptor." And that should allow us to dose to higher doses and get more payload in and avoid the kind of anemia that people have seen with this. So far, that seems to be bearing out. So there's just a real sound rationale to it all. And then when we're looking at the clinical data, I know people are really caught up on vHOT. Listen, I'm kind of new to this, but when I asked our team and our scientists why we see Avidity sees results, we see results as early.
There's just been this, there was always an expectation that it was calcium channel-based, and you could get a quicker result with that potentially. So great. But when you meet the patients and you see the patients, they're typically not just talking about, well, they're not talking about vHOT. They're talking about all kinds of other issues, GI issues, and often cognitive issues. And we've made the argument across this platform that we get across the blood-brain barrier. That's what we've shown preclinically. Some of the data that really got my attention from this last set was that in the patient-reported outcomes, we saw a trend of improvement in fatigue. I hope that holds up. I mean, small data numbers, but really want to explore the CNS benefit as well as all of the muscular-related benefits.
Hopefully that results in a product and a label and so on that really differentiates us for patients.
Makes sense. Because all of these endpoints could be potential endpoints for an accelerated approval, technically speaking.
Correct.
Right. And so in the data, let's start with splicing, actually. You've already, I believe, exceeded the 20%-25% threshold with the third dose. You're dosing higher. Is there such a thing as too much splicing? And secondly, in the next data cut with the higher fourth dose, which I believe is 6.8 mg/kg, would you expect even higher splicing benefit at month three?
Yeah. We're not seeing anything in the data that suggests that we've reached a cap or that we wouldn't have the opportunity to continue to see improvement in splicing with the 6.8 mg/kg dose level. We've not seen any of that data yet, so we'll obviously be very interested to review it once it's available. But everything that we have seen and done preclinically, it's playing through to what we are seeing in the clinic. We projected in the clinic that we would see the 20%-25% improvement somewhere between the 3.4 and 6.8 mg/kg. As you say, Andrew, with the 5.4 mg/kg data at three months, we saw a 27% improvement in splicing. And so I don't think that there's any challenge with getting too much splicing.
Again, in normal non-disease people, their CASI is zero, right? And so the people who came into this trial, their CASI was between like a 0.6-0.8. And so there's still unmet need from improvement in splicing, even with the 27% improvement. So we still have room to run. But we do believe that with time on treatment, that CASI has the opportunity to continue to improve, and we'll have to see just what the 6.8 mg/kg data look like.
Makes sense. For the lower two-dose cohorts, there has been longer follow-up. Can you confirm that you're seeing durability on splicing out to, say, months six to 12 for the first two doses?
So we do have an 11-month biopsy within the trial. And so we have begun to have some of that data in the 1.8. It is consistent with what we've reported. So I do believe that with time on drug, we will see a continued and deepening improvement in splicing. We reported that with the vHOT, where with more time on drug, we continue to see improvement in the vHOT. And I would expect that to be true for other functional assessments as well.
Okay. Interesting. And each dose cohort is relatively small in sample size. So the actual question is, are there patient outliers driving the benefit in splicing? Not only splicing, but vHOT or any of these other functional measures. Are you seeing a consistent patient response, more or less?
Yeah. So you're right. This is rare disease, and so all of these cohorts are going to be relatively small. What we have seen, though, is first in the splicing, as we increase in dose level, we see more participants that have improvement in splicing, and that improvement is consistent. And so we feel good about that. The functional assessments, look, it's true for all neuromuscular disease that the magnitude of benefit is very much going to depend upon the level of abnormality when you start a treatment. We've seen that in our data. And so, but what we see consistently is the cohorts where you see the most improvement are those cohorts that have the greatest improvement in splicing. So we see that the greatest benefit is occurring in the participants who receive the 5.4 mg/kg dose level.
So we believe that that will continue, and it will continue to deepen just as the 1.8 mg/kg data continued to improve with more time on drug.
Okay. So continued dose response. Okay. And then Avidity is using vHOT for their phase III primary endpoint. I know you have a lot of flexibility with other endpoints. We'll wait for that. But they have also set that precedent. So how does your vHOT data compare to theirs at the higher doses so far?
Well, we're very pleased with our vHOT data. If you look at the 1.8 mg/kg at the 12-month time point, we saw that it was an over four-second improvement. If you look at the 5.4 mg/kg at three months, you saw that it was over a four-second improvement. So we believe that we're as good or better than what else has been reported out there. And so, as John alluded to, when the data came in, we were very excited by the splicing. We were also very excited by the totality and the breadth of benefit that we're seeing across all these functional assessments, whether it's myotonia, whether it's strength, whether it's time function tests, whether it's activities of daily living, whether it's quality of life. We just continue to see benefit for those people that were in the cohorts with the drug.
Because the data does seem very compelling, does it make sense to file for breakthrough designation for both programs, actually?
For DM1, first thing is to get the IND open. So that is definitely on our plan for this year. Then for DMD, we agree that this data is very compelling. So we look forward to having conversations with the FDA around it.
Okay. And going back to the accelerated approval pathway, what advantage would that give you if Avidity is already evaluating vHOT at month six for the primary endpoint? Because my understanding is your pathway entails splicing, correlating that to a functional outcome, or myotonia, correlating functional outcome. So that's like two variables. Avidity technically has one variable. Why do that to yourself? So what is the advantage with an accelerated approval?
Look, I think at this point, we believe that we have every option available to us. That's a great position to be in. As we review the data that's still emerging in the program, typically at this point, you're having to take options off the table because the data just doesn't support it. Everything we're seeing in the data continues to support that if we choose to, we could use splicing as a path to accelerated approval. We could use vHOT as a path to accelerated approval. We'll see how the data continues to emerge at these dose levels to see if we want to use full approval. Those are all options that we're considering.
On the safety profile, can you confirm you're absolutely seeing no signs of anemia?
We are not seeing any anemia. We've talked about this for a while. We've talked about the fact that with FORCE, as John said, we specifically designed a fragment of an antibody with a very specific epitope to make sure that we do not interrupt the iron homeostasis. And so we're not seeing any related persistent anemia in ACHIEVE or in DELIVER.
There were technically two cases of pulmonary embolism. Why should that be a non-issue? Why is it not linked to, say, stroke, which has prevented Avidity from dosing higher, for instance?
So again, I don't know all of the specifics of the event in MARINA, so I'll let Avidity speak to that. I'll just say, in our case, both events, again, these were in the open label period. They occurred after multiple doses. Participants have remained in the study. They've actually been escalated on dose level. Unfortunately, people living with DM1 are sick. They have risk for thrombosis. In fact, one of the participants had previously had DVT. And so we did not see anything in the data that suggested that these were related. The investigators didn't see anything in the data. The participants remain in the study. They're still receiving drug. So obviously, we continue to monitor the safety profile. We've not seen anything in DELIVER consistent with this. We've not seen anything in the preclinical studies consistent with this. So we're quite comfortable with the safety profile so far.
That's great. And then maybe one more on the safety is some investors just wonder longer-term dosing, neutralizing ADAs. Are you seeing any of that?
So again, we've not seen anything consistent with neutralizing antibodies. We're not seeing anything in our PK profile and our efficacy profile that is consistent with that.
Okay. The data was pretty compelling that you met with the FDA. You wanted to accelerate it. If the next dose cohort for DM1, for instance, is striking too, is it fair to assume you would aggressively topline that?
Look, we're always, as John said, we're always going to do everything we can to bring the therapy to the patients as quickly as possible. We understand the fierce urgency of now to bring a therapy to patients who have been waiting far too long for a therapy. So we'll do everything we can. We will look at the data for the 6/8. We'll see where we are with the overall program. And then I'm sure we'll have conversations with regulators about that.
Great. Then maybe last 30 seconds, why is DMD also looking like it's best in class? Sorry, ran out of time.
Look, we love our data for DELIVER. We've talked a lot about the data in ACHIEVE, but if you look at the data in DELIVER, we're, again, a favorable safety profile. We're seeing a dystrophin at six months at 3.2%. That's unadjusted. When you adjust for muscle content, that becomes 7.6%. When you look at the functional assessments, again, small data set, but they're stable or improving compared to placebo, where you see worsening of function.
Okay. I think that's all the time we had. So thank you, both of you, for this team. Thanks, everyone, for listening.