Dyne Therapeutics, Inc. (DYN) Earnings Call Transcript & Summary

Okay. Hi. Good morning, everybody. This is Kristen Kluska, I'm one of the biotech analysts at Cantor. Very happy to be hosting a fireside chat with Dyne Therapeutics. From the team, we have Dr. Wildon Farwell, who is the CMO; and also Dr. Oxana Beskrovnaya, who is the CSO. Thank you both so much for joining us today. We really appreciate it.

Thank you.

And as part of Cantor's Muscular Dystrophy Symposium, we've essentially tasked each company with a theme, with the goal of really helping to understand these conditions better, and we're also going to spend time, of course, asking about Dyne's programs. But for your team, the big question and theme we have is, given the potential for complicated dosing regimens, what do oligo therapeutics offer for muscular dystrophy patients that gene therapies cannot offer? So, to start off, I think it'd be really helpful to talk about the promise of oligo-based therapies in the muscular dystrophy space. What does the therapeutic modality do so well that it could be turned on the genetic causes of muscular dystrophies, such as DMD and DM1.

Thank you very much, Kristen, and the whole Cantor team for inviting us today. And, I'm happy to take this question, but before I begin, I just wanted to remind everyone that during our session we will be making forward-looking statements and people can refer to SEC filing for more information. I would like just to say that it's really great to be a part of the community that is focused on development of oligo-based therapy, specifically in muscular dystrophy space. These kind of genetic medicines are highly desired. And why that is, is what we know as a community that oligos work with precision, based on design against specific target. As long as you can deliver them to that target, and that target is causing the disease. So what is the hurdle for oligonucleotide therapies? It's really delivery. Delivery to the tissue and to the target. So, we founded Dyne, and the development of our FORCE platform that is really based on solving delivery to muscle tissue. And so, we have now co-lead programs in Duchenne muscular dystrophy and myotonic dystrophy where we know that oligo approach could address the genetic basis of the disease. But naked oligos were unable to do so just because they can -- not enough for them to deliver substantial amount to modify the target.

And then, what advantages do oligos have for subcellular targeting? And depending on whether you're using a nuclear or cytoplasmic target, how could you potentially modulate this with an oligo-based platform?

Again, I want to start with ultimately oligos. Oligos are well-positioned to target the genetic cause of the disease. We understand sufficiently about behavior of single stranded oligonucleotides or siRNA to choose the best methodology that is designed to target the genetic cause of the disease. So when we designed FORCE platform at Dyne to enable uptake of oligos, we can navigate either to the nucleus or payload, if we choose ASO, and if we want to target nuclear target, or we can navigate our oligo to cytoplasm, in this case very potent catalytic oligos are siRNA.

Great. And then, on the flip side, what are some of the limitations of oligos in terms of delivery or sensitivity to the nucleases and how can they be added to platforms with antibodies or other targeting molecules to maybe bypass some of these disadvantages?

The initial approach in the field in general for oligonucleotide delivery is of course designing them such that they become resistant to nucleases. For example, any given oligo would have sugar modifications, also backbone modifications using phosphorothioate, for example for ASOs, as well as we know from the more recent data, stereochemistry helps with delivery as well. And these modifications are really, really helpful. They improve sensitivity to nucleases. But by themselves really not sufficient because we are still facing the limitation of delivery to extra-hepatic tissues, and muscle is one of them. And so, even if you can go ahead and give this highly chemically modified oligos, they're still unable to drive meaningful pharmacodynamic effects, just because now we begin to run into toxicity due to really high doses. So, what is in the way and how we can help it? We are focusing now and developing effective delivery platform, but we are using it in addition to leveraging this well established chemistries to deliver oligo to muscle. So, it's in fact a combination, modified oligonucleotides and attachment to it specific system which we call FORCE to facilitate delivery. So, maybe I can take a few words because I've been saying FORCE a lot just to say what that is. So, the FORCE platform is designed to bind to transferrin receptor 1 that is highly expressed on the muscle, and then we are attaching payload to this Fab fragment via linker. We are using cleavable linker known as Val-Cit linker, this linker is used widely in multiple approved ADCs, for example. So, the key here is to rationally select the payload to target the genetic cause of the disease. And so, we have mentioned briefly, if we want to get to the nucleus where for example toxic DMPK causing DM1 resides, we would select ASO. And for other targets that mRNA is able to be expressed in the cytoplasm siRNA is really a good approach. The key is, we have a plug-and-play technology where we can use the same Fab, the same linker and attach payload depending on what causing the genetic disease.

And then to better understand the cell biology at play and oligo-based therapies, what's the pathway that oligo therapies go through when they're entering the cell, and how are these approaches able to take advantages of the cell's own membrane to get at intracellular targets?

That's a great question, because the answer would depend on which technology is being used for oligonucleotide delivery. Apart from technology we are using, there are alternative technologies, for example, using cell penetrating peptides or endosome escape vehicles. In either case, those are delivering, but they are designed to achieve the delivery inside the cell via destabilizing the membrane. So, while you can see effective delivery, it is often associated with a narrow therapeutic window and toxicity. So there is a limitation to which you can drive the pharmacodynamic because you will at some point very quickly meet potential toxicities. So, this is where we want to break the membrane. What we are using in the FORCE platform, we are using approach that is working with biology. We are trying not to work against the biology of cell. And we do not use any agent that would destabilize the membrane. So, we have really capitalized on natural cell biology of receptor recycling, and so when our conjugate, FORCE conjugate binds the transferrin receptor 1, it is internalized with the receptor and then finally travels via endosomal trafficking into the late endosome, at which point the payload is cleaved, and can be released from the late endosomal compartments. This release again is happening naturally. So, what we observe is it's a slow process. It's basically you have this load of your payloads within the cell now that is released slowly. And that's why we say that in the case of our platform, which clearly has advantages because of low and infrequent dosing, allows us to get to the PD. If we want to drive the dose, we also can drive the dose, because our technology allows for a large therapeutic window relative to, for example, cell penetrating type peptides.

Okay. You introduced your FORCE platform to us, but I wanted to also ask about how this specifically targets the genetic basis of the disease and muscle that an oligotherapy wouldn't be able to just do on its own.

All right. Again, we keep coming back, with oligonucleotides, the key is delivery. And so, once you deliver, and again, multiple delivery technology can be used. And we are focusing on receptor mediated technology, and really linking fragment antibody to the payload allows us to inject our FORCE platform, FORCE conjugate into the bloodstream. And then, we very quickly see distribution of our FORCE into the target tissue in the muscle, for example. We selected Fab for this low timing of circulation and quick target obtained by the tissue, by the muscle tissue. And this is -- again allows us wide therapeutic index, why we are able to deliver sufficient amount payload to drive pharmacodynamic. We have demonstrated this preclinically across multiple models, and we are now [ seeing the ] translation of our findings preclinically into the clinic. Maybe Wildon would like to add anything here.

Yes. Thanks, Oxana. Kristen, I think DM1 is a really good example of this. So, we've known the foundational biology of DM1 for a very long time. It's this genetic disease with these triplet repeats in the DMPK gene. When I was at Biogen, we actually had a program in partnership with Ionis, where we targeted this disease with a naked approach. And we achieved high concentrations, but we never saw the PD and the clinical benefit in that program, which we've now begun to see with our data release in January. It was the power of delivering to muscle this targeted approach that really excited me about Dyne, and it's what I believe we're really seeing this in the clinic now. It's this opportunity to really allow the therapeutic to reach the target of interest. That's the difference. That's the key.

Can we spend a little bit more time talking about the role of the ERF-1 receptor?

Let me take this question. So, as I mentioned before, we were looking for developing delivery technology that is working with the biology. So transferrin receptor is highly expressed on the muscle cell, that's number one. Its recycling time is relatively fast, within 15 minutes or so. And so, what we are able to do is identify the binding site and transferring receptor itself that is not interfering with normal function, which is uptake of the iron. So, we carefully designed our Fab fragment, that is binding to the receptor, does not interfere with this function, and is being internalized, just by the way a typical transferrin receptor is internalizing. That allows us to bring across the cell membrane our payload. Again, we tried multiple ingredients before we selected final configuration of our FORCE platform, and we have proven that the best thing is not to add anything to this relatively simple design. And so, we internalize payload is now captured in the endosomal compartments, and we can see how without adding any additional ingredients, we get this high potency with wide therapeutic index. We've seen this in our preclinical studies, and we continue to see it now in translating into the clinic. And so, our initial programs in DM1 and DMD now actually validated the promise of FORCE platform in developing this targeted therapeutics to the muscle tissue. And also the unique property of armed FORCE platform, we are delivering not only to the muscle, but also very effectively to CNS. And as we are looking into neuromuscular diseases, both DM1 and DMD, CNS component is very, very important. So, we are very pleased that we have designed our FORCE platform to really go after multiple pathologies of DM1 and DMD.

Okay. So, it's hard to ignore the potential advantages that gene therapies can bring with one time dosing. So, what is it that the FORCE platform does to be able to offer in terms of durability, as well as individualized patient titration? And what does the treatment burden currently look like for patients? And how might this be an advantage?

Yes. Maybe I can take this one, Oxana. So, look, first of all, it's great that there are so many different modalities that are being investigated in this space. There is a very significant unmet medical need. Patients are waiting and have been waiting far too long for effective therapies. There are challenges, as you note with gene therapy there is the challenge of being unable to redose, the limited transduction across cells, the limited durability within cells, pre-existing immunity, and there's challenges with a safety profile as well. And then, there are the unknowns, like look in DMD, the microdystrophin, this is not a naturally occurring protein. And so, we still have a lot to learn with that. There is the opportunity with oligonucleotide-based therapies to dose. Unfortunately, with the currently approved therapies, this does require a weekly dosing administration, and so, unfortunately, in many patients, that requires a port to be able to receive this on an ongoing basis. With the data that Oxana and the team have generated, we really believe we have an opportunity to truly transform these diseases. We have developed an exon skipping franchise that really has focused on delivery that we've talked about as a means of achieving efficacy while maintaining the overall a positive safety profile. In the DELIVER trial, this is again among boys with a mutation amenable to exon 51 skipping, we're evaluating once monthly and now actually evaluating even less frequent every 2 months. So, we believe the therapeutic window with this targeted approach to oligonucleotide-based therapy allows us the opportunity to dose less frequently while maintaining the efficacy that we know the community will be looking for.

So turning attention now to DYNE-101 and DM1, you had 3 month Phase I/II data earlier this year. How did the muscle concentration results line up with what you would expect to need for knocking down DMPK? And how did you utilize the 22 gene panel to get a sense of the effects of splicing?

Right. So in January, we did share initial data from our ACHIEVE clinical trial. This is the trial among people living with the DM1. We shared 6 months data from our lowest dose cohort and then 3 months data from our 3.4 mg per kg cohort. And what we showed was that we were able to demonstrate dose dependent delivery of DYNE-101 to the muscle, as well as dose dependent knockdown in DMPK and improvement in splicing. You'll recall again, DM1, this is a disease of a toxic RNA accumulation in the nucleus, which then leads to this abnormal splicing. And so, what we were able to show is that with our 3.4 mg per kg dose level, we saw 19% improvement in splicing, and the consistency in that improvement across participants at 3 months. So, our goal for the ACHIEVE trial has been to be able to see 20% to 25% improvement in splicing, because we believe that's what really unlocks the opportunity for clinical benefit. And actually, at our lowest dose, at our 1.8 mg per kg dose level, we've already begun to see some improvement in function. We were able to see improvement in myotonia. So myotonia, it's the inability to fully release after contraction. And so, what we saw was that 6 months, the video hand opening time, which is the measure of myotonia, we saw a 3.8 seconds improvement in that assessment. And people coming into the trial required about 11 seconds in order to fully open their hands. So at our lowest dose, we're already seeing a very significant amount of improvement in myotonia. We also began to see early data suggesting potential benefit in the CNS. Again, we know that this is a very significant aspect of the disease. Many patients complain of fatigue or complain of daytime sleepiness. And so, in a validated patient reported outcome measure, the MD high, we were able to see trends towards improvement overall as well as on the fatigue subscale. So, we believe that all of this data is quite positive. Going back to your question specifically on splicing, and how we're measuring that, we have been very focused on understanding spliceopathy. We've been partnering with the leaders in the field, Dr. Charles Thornton from the University of Rochester is on our Scientific Advisory board. We've been partnering with the [ anti-DM-1 ] natural history study as well as others to really understand what is the foundational biology of this disease and how does it impact the clinical phenotype. And so, we know that to be this spliceopathy, that can be measured in muscle biopsies in the natural history, that's done focusing on the tibialis anterior muscle, which is on your shin. And when you evaluate that muscle, you see that there are genes that are inappropriately spliced. And so, we focus on a 22 gene panel, which gives us overview of this abnormal splicing. And so, when one looks across this panel, one is able to calculate what's called the CASI, or the Composite Alternative Splice Index. And that has a score of 0 for a non-disease population and then 1 for the most severe DM1 population. So the goal is really to move people down in that CASI score. And so again, when in the ACHIEVE trial, we're seeing a 19% improvement in that CASI score at 3 months, at our 3.4 mg per kg dose, that is a very important finding, and we believe that will then translate to clinical benefit over time. We have designed ACHIEVE to be potentially registrational. We do believe if one can show improvement in splicing, then be able to correlate that change in splicing to function. That's one path to accelerated approval. Another path could be showing improvement in myotonia and then linking that to other aspects of clinical function. So, we believe there are multiple paths, and we believe the early data that we began to present in January, demonstrate that opportunity.

Okay. Great. Before I switch gears to DYNE-251, are there any other comments you want to make about DYNE-101?

I would just say that the safety profile has been very favorable. We believe we have a reasonable safety profile which has allowed us to continue escalating our dose and continue evaluating different dose regimens. And we believe this gives us the opportunity to further evaluate the dose regimen at either 4 week or in every 8 week, and then continue to escalate in dose. We're now evaluating a 6.8 mg per kg dose level. So I think that's an important aspect of the program as well.

Okay. Switching gears to 251 then in DMD, can you talk about how the Phase I/II exon skipping results compared to eteplirsen historical data, and then as well as with the focus on the treatment burden?

Absolutely. So, in DM1, there is a product that is available for patients, the eteplirsen, as you described. We believe that the data from the liver, again, this is our ongoing clinical trial in boys between the ages of 4 and 16, amenable to exon 51 skipping therapy. We believe this data is already beginning to show improvement in dystrophin beyond what has been able to be seen with the eteplirsen. So, at 6 months, at our 5 mg per kg dose level, DYNE-251 demonstrated 0.88% dystrophin greater than 2.5-fold higher expression of dystrophin at 6 months compared to what's been published for eteplirsen. So, this is with 24-fold lower dose administered 4x less frequent. So we believe that this also begins to demonstrate the power and the promise of delivery to the muscle by FORCE. Again, our goal is really to transform the lives of patients living with DMD. So, we believe that, we're certainly on track for doing that. We also believe we have the opportunity as we move into the higher dose levels in the trial. So, right now, we are dosing participants at 10, 20, we even have started our 40 mg per kg dose level. And so, in these higher dose levels, we believe we have the opportunity to see between 5% and 10% dystrophin at 6 months. And that, as we know, because of the half life of dystrophin, will continue to increase. And I want to point out that the preclinical data that Oxana and the team generated really shows that we don't just deliver to the peripheral, skeletal and increased dystrophin, we also increase dystrophin in the diaphragm and in the heart, and now, with this new data showing FORCE is able to deliver to the CNS. We have a very significant opportunity, I believe, to truly transform this disease for people living with DMD.

Okay. And going back to the theme, I think you made a very important point about localization. So here, can you also talk about where there might be more benefits with this approach relative to a gene therapy?

Right. So, just to build a little bit upon what we talked about before. With gene therapy, because of the size of the dystrophin RNA, they're not able to create a full length dystrophin protein, they create a micro dystrophin, or an altered form of that dystrophin, which is much shorter than the dystrophin that's produced by an exon skipping approach. The dystrophin that's produced by an exon skipping approach, this has actually been seen in the natural history, many people living with [ Becker's ] dystrophin in a similar manner to how it's produced with the exon skipping therapies. And so we know from the natural history that people living with Becker's are able to have much greater function for a longer period of time than are people living with Duchenne. So, we believe again the DMD landscape, it's evolving multiple different approaches, multiple different companies in the space, we'll see how this unfolds. I go back to my experience at Biogen again, where I led the development of SPINRAZA, obviously Zolgensma is also available. You still see lots and lots of patients choosing SPINRAZA, and some patients actually who receive Zolgensma also choosing to receive SPINRAZA. We think that the DMD landscape will likely evolve very similar to how it has evolved in SMA.

Okay. So, both programs have proof-of-concept, and you do have an important second half of the year ahead. So, I wanted to ask how we should be framing expectations for these readouts?

Right, so as you said, we are planning for data to be able to share in the second half of the year. Our goal for both programs this year is really to optimize a dose and dose regimen with the goal of initiating the registrational cohorts. The second half what we are anticipating is meaningful updates from both DELIVER and ACHIEVE. This will include data from higher dose cohorts, different regimens, longer time points. We also have the opportunity to speak to regulatory feedback that we've received on how to think about the registrational cohorts going forward.

Okay. And since this is a total muscular dystrophy symposium, wanted to make sure we had time to talk about the earlier stage pipeline. So you have a program for FSHD DYNE-301. So, given the aberrant DUX4 expression in the FSHD muscle, can you give an overview of how your platform could reduce the incorrect expression, and maybe just a general explanation about your expansion opportunities ahead.

Sure. I can provide some thoughts and Oxana may be able to add to these as well. The FSHD community, again, here is another community that has been desperate for therapeutic options. There is a very significant unmet medical need. The size of the population is actually quite similar to the myotonic dystrophy, the DM1 population. We really have been focused on advancing our co-lead programs in DM1 and DMD to this clinical stage. As you correctly state, FSHD is caused by activation of the DUX4 transcription factor and this unfortunately then does lead to skeletal muscle loss and progressive muscle weakness and wasting. Our approach has really been again to focus on delivery and then address the genetic basis by reducing the DUX4 messenger RNA expression. There is activity in this space, there are other companies and we have the opportunity to learn and apply those learnings to our own program. So, we're excited by the opportunities we see, and we believe there's opportunity to leverage learnings from our ongoing programs as we continue to evolve the pipeline. Oxana, do you want to add anything to that?

Thank you, Wildon. I just wanted to say that beyond FSHD that we've been continuously working, we are looking into other opportunities in our pipeline. The platform offers rich applications, has demonstrated clinical proof-of-concept. So, one of which includes building our global DMD franchise and again DELIVER trial reinforced that we have a potential for best in class for DMD. And we have focused on preclinically on other exon, including 53, 45 and 44 to really been able to offer this type of therapeutic approach to a majority of DMD patients. I'd like to also mention that we just touched briefly on ability of FORCE platform to deliver to CNS. We are open to the opportunities in CNS space as well as heart for our pipeline expansion. And we have shared specifics of how our platform delivers to CNS. We have shown our data last year at ASGCT and what is interesting that we see delivery throughout the brain and this is very unique for this kind of a platform. And what as Wildon mentioned earlier in our ACHIEVE trial, we see initial improvement in one of the PRO from [ MDA, ] particularly on fatigue. And so, even with the lowest dose, we begin to see potential benefit to CNS. So, what I'd like just to finally say that we just scratched the surface of our platform, and this, our FORCE platform, really has opportunity for targeted therapies for rare skeletal, cardiac, and CNS diseases.

Okay. Great. Well, thank you both so much. Really appreciate your insights and for answering my questions.

Great. Thank you.

Thank you.

Thank you.