Let's go ahead and get started. Thanks for joining in, everyone. Next up, really happy to be joined by Pratik Shah, who is the CEO of Design Therapeutics. Thanks so much for joining. Let me turn it over to you just for an overview of the company, where things stand today. Then we'll get into it.
Great. Thank you for the invitation, and since this is a webcast, I will remind everyone that in this discussion, we'll be making forward-looking statements and discussing the state of our business, R&D, financial position, and, of course, actual results made affirmatively. Please refer to our most recent risk factor section in the 10-Q filed with the SEC, so with that out of the way, Design Therapeutics is a very unique and exciting company to us because what we're able to do is dial up or down the expression of an individual gene in the genome with small molecules, and small molecules have an inherent advantage. They can distribute widely, and they get into all the cells. They have pan-cellularity, and what we're doing is pursuing some very significant monogenic diseases where we know exactly what the root cause is.
We are in clinical development in three major categories: Friedreich's ataxia, myotonic dystrophy, or the DM1, and then also Fuchs' corneal dystrophy. We also have a program in Huntington's that's preclinical. It's a really exciting time. We have a strong cash position with runway going into 2029. That enables us to get important clinical information on these three programs. Our FA program is we have a trial ongoing. It's a multiple-dose trial in patients with FA. It's called RESTORE-FA . We expect to have data from that with frataxin, where we're trying to increase endogenous frataxin, which is the root cause of Friedreich ataxia. We should have that data from multiple doses in the second half of 2026. Our Fuchs corneal dystrophy program, our eye drops for dialing down the mutant TCF4 gene that drives the pathology.
We also expect to have a phase two biomarker study ongoing that we should have data on the second half of 2026. And then we have the green light to begin our trials in DM1, where we expect to begin multiple dose studies in patients with DM1 in the first half of 2026 with data in 2027. So lots of exciting things happening.
Yeah, really set up for a big 2026 and beyond. Maybe we can just start on the Friedreich ataxia side of things, not to spend too much time here. Maybe you can just kind of recap the first-gen program that went into the clinic and what you've changed since then.
Yeah, so we have a molecule called DT-216 that dials up endogenous normal frataxin expression. Patients have about half the level of frataxin as carriers who are clinically normal, and carriers have about half the level of frataxin as unaffected genotypes, and so the goal of the therapy is to increase endogenous frataxin. We had run a trial in 2023 in patients with FA, where we had sort of a bad news, good news story, and the bad news was that we saw very limited duration of exposure, and the plasma PK was short, and the muscle exposure was only for two days, so what was supposed to be a multiple dose study turned out in hindsight to be a series of single-dose studies one week apart.
Despite only seeing about 8 nm to 10 nm of drug in muscle at day two, we saw an unmistakable increase in frataxin RNA expression from the locus. That validated all of our preclinical expectations on what exposure we needed. It wasn't clear at the time if we could create a version that could have sustained exposure. Everybody abandoned the stock at the time. Since then, we have developed what turned out to be a solution based on just having to do a new formulation of the same active that we had validated as being pharmacologically active in humans. We have this new version, version two, or drug product two. We call it DT-216P2. We wanted to understand dose-to-exposure relationships. We did that in healthy volunteers. We announced that PK data.
We see an over 10x increase in exposure, nice sustained duration of exposure. The other issue with P1 was that we had seen some vein thrombophlebitis that was sporadic and infrequent. But we saw it right away in the single-dose studies, even in the past, had reported it at the time. And the new formulation, we have resolved that issue. So the vein thrombophlebitis is no longer rate limiting or observed in any of the studies that we've done. And that allows us to now move forward to do what we were originally setting out to do, which is to get this increase in endogenous frataxin. So that's the FA story.
Awesome. And for the prior study, when you were seeing the thrombophlebitis, was that right on the first dose, or was that a subsequent dose?
Yeah, it was seen right away with single dose.
Yeah. All right. That makes sense. And I guess on that point, you've been dosing in healthy volunteers, now dosing in patients. Did you see any cases of thrombophlebitis, like even mild? And what about on the injection site reactions?
Yeah, the vein thrombophlebitis is a fully resolved issue at this point, we believe.
Perfect. That's clear.
Yep.
What was the reason to not put out a full detailed safety table from the healthy volunteer study? Was it more on the competitive front and wanting to kind of keep that internally?
The study was really designed with two primary objectives. One was, of course, in general, safety, tolerability. Importantly, the questions we were most interested in is, what is the dose-to-exposure relationship? We announced PK data and corresponding safety at the time. The second was, is the vein thrombophlebitis issue resolved? Having addressed those two questions, we shifted our focus to the patient study because you can't really derive useful frataxin information from healthy volunteers because the drug has no effect on normal genotypes. Given that shift in focus, we've now focused on the MAD. There's some data that we'll be wrapping up on in the single-center dose study, but we don't think that's particularly material for what we're setting out to do now.
That makes sense. Maybe you could just run through preclinically what you guys were looking at on the PK/PD side and the reason to believe that with this new formulation, you will be deriving efficacy.
It was really a duration of exposure issue. And so we saw very good exposure with the P2 formulation in our preclinical studies. We had wide distribution across all affected key tissues, including CNS. And that's something we determined in preclinical studies. So given the non-human primate PK profile being so exciting in terms of showing sustained duration of exposure, that was the insight that gave us confidence to try it out in humans. We've now confirmed that the PK profile of the product in humans is comparable to that of non-human primates. And so exposure bodes well. Of course, ultimately, we won't know whether all of this will result in an increase in endogenous frataxin, but that study is underway. And if that works, I think it would be a very, very exciting advance in the treatment of this condition.
Yeah. Awesome. All right. So let's, guys, double-click on the FA patient study. So could you just run through the trial design, amount of data you will be showing when you show data?
Yeah. So the concept here is to be able to make a definitive determination of what to do with DT-216P2 going forward, and so with that in mind, rather than doing sort of incremental updates, we have focused on generating the totality of evidence, and we are doing dose escalation studies in these multiple-dose regimen in patients. The plan for the second half of 2026 is to have data from 12 weeks of dosing. We will be looking at frataxin in both whole blood as well as muscle, and we're looking at RNA and protein, and by having that, we should have a totality of understanding of the properties of DT-216P2. Whole blood is widely used. It's sort of the matrix that all of the published studies are based on. All of the correlations between natural history and the level of frataxin are all based on whole blood.
We're using the gold standard LC-MS assay that's been developed by academic leaders in the field. And in muscle, we can do essentially more limited sampling because you can do a before and after treatment and maybe one more. But it is an affected tissue type, so that'll give us some sense of what's going on in the muscle. Although there are many other affected tissues as well, like heart is an important organ here for it's the primary cause of mortality is hypertrophic cardiomyopathy. And this totality of evidence will give us a sense of what's going on. We're excited to do that. There's an unknown number of cohorts going forward because we're just essentially dose escalating until we either see frataxin or we run into some sort of a safety ceiling in humans.
But we've developed our guidance with the expectation that by the second half of 2026, we should have sufficient totality of information. Of course, if there's something materially different along the way, we'll report that either good or bad.
That makes sense. Are you doing any cardiac biopsies in this study?
There are none planned at the moment, but that is an option we have.
Yeah. And for starting dosing in this study, have you said kind of a bigger picture where you're starting versus where you think the efficacious range will be?
The starting doses are done in a very standard small molecule development fashion where it's a fraction of what might be therapeutic. So we began the patient studies in June. And so we'll pass the starting dose at this point.
Yeah. That makes sense. What are you thinking about as a bar for what you want to see in terms of frataxin expression? I guess moving beyond the mRNA side too, like talking about protein expression.
You know, it's an answer that's now informed by commentary from other sponsors in the field. We have not spoken to the agency directly about that topic. But if I read into, for example, one of the sponsors has talked about frataxin as a potential co-primary in a registration study for a gene therapy. And based on their commentary, it appears that they've been told that any significant increase in frataxin over a patient's own baseline might be considered sufficient to meet that particular co-primary. And so if that is true for an exogenously administered frataxin, it certainly ought to be true for an endogenous frataxin increase. So that's one end of the spectrum. On the other hand, carriers are clinically healthy. They have about half the normal level of frataxin.
And if one can get the carrier levels, I think it would leave little doubt as to whether the frataxin levels have been increased to a point where cellular function can be restored.
That makes sense. How much are you measuring the run-in of patients in this study? And when are you doing the biopsies?
There's a baseline measurement before treatment and then one after the treatment. If possible, we would like we'd try to get one additional. I think it's very hard to do more than two or three biopsies in an individual.
Yeah. That makes sense. And I guess I'm thinking beyond frataxin expression also as we look at the host of clinical outcomes like mFARS, quality of life, et cetera. Do you think we could see any of those measures move in this early study?
Our initial focus is very much on frataxin because that'll allow us to use an important disease causative marker to select a route of administration, a dose level, and a possible dosing interval. And I think once we have that information, we can focus on how. There's many, many opportunities to look for the clinical impact in this patient population as shown by both natural history studies as well as the kinds of endpoints other sponsors are measuring.
Yeah. And just going back to the frataxin expression, when you mentioned hopefully getting to carrier levels, which would be a great outcome, are you looking more in the muscle or more in the PBMC side of things?
We're actually going beyond PBMCs this time. We're looking at all cell types in whole blood. And that has been the most widely studied measure of frataxin in the literature. And so that would be the one important system to look in. Muscle is a logical thing for us to explore because it's an affected tissue, but it's not the only affected tissue.
Yeah. And all right. So let's switch gears. Let's go over to the Fuchs' side of things. I think the way that you're measuring splicing here is actually really interesting. Maybe you can just kind of walk through the trial design and what's a good outcome on splicing.
Yeah. There was no biomarker available in Fuchs in the field. And so we actually ended up developing for the first time a possible biomarker because a very small fraction of Fuchs patients at very late stages do undergo corneal transplant. And we asked, I mean, that's typically a discarded tissue. It's considered medical waste. We were able to obtain those samples from late-stage patients. And taking a sort of page from the DM1 playbook, looked at splicopathy. And we were able to see very consistent differences between the splice patterns in a Fuchs corneal tissue versus an unaffected donor. And that created for the first time an opportunity to look at splicing in Fuchs corneal dystrophy. So what we're doing in this study is taking patients who are already scheduled for a corneal transplant, having them take eye drops for four weeks or longer before their scheduled surgery.
Because the tissue would be discarded anyway, we can then take hold of that and look at whether the 168 is getting to the corneal endothelium and fixing splicing. Now, it's not a perfect experiment because you can't do a pretreatment baseline. So the effect size would have to be large enough that it could be picked up across a reference standard of unaffected or sort of placebo-treated cornea versus healthy. So if we see any impact on splicing, it would leave little doubt that 168 is actually doing what it was designed to do, which is to get to the corneal endothelium and fixing splicing. That would set us up for a clinical study looking at slowing or stopping progression.
Yeah. That makes sense. What are your expectations for how, I guess, a control or placebo arm would do on splicing?
We're collecting that information on untreated eyes so that we have a sense of what the splicing looks like. We've published in our deck a version of that we presented at the accelerator meeting before our vote this year.
Yeah. Are you planning to put out more of that data before the Fuchs data or kind of concomitant?
It's all targeted for the second half of 2026. Yep.
Awesome. What do you think about speed of onset of efficacy or, I guess, kind of speed of onset of the mechanism in general?
When we take corneal cells that are typically discarded and we treat them with 168 ex- vivo, you could see these toxic foci vanish in anywhere from six to 14 days, which is a very exciting result. And so that gives us some sense of what the time course is if you had direct exposure of the drug to those cells.
Yeah. All right. Let's switch. Let's go over to DM1 since you're actually going to be starting dosing patients in the first half of next year.
Yep.
Probably just worthwhile to explain kind of the mutant DMPK versus wild type dynamic.
You know, it's a disease that's caused by mutant RNA. There's a CTG expansion. It creates this RNA tangle. It really is visually visible as a sort of an RNA hairball trapped in the nucleus of cells. The wild type DMPK has no repeats. It goes to the cytoplasm and makes protein. And so our goal here was to see if we could develop a potentially best-in-category compound. And we've learned a lot from the other companies in the space. They're all oligonucleotides. And because oligonucleotides don't get into cells easily, they're all conjugated to something, whether it's a monoclonal antibody like Avidity or Fab fragment like Dyne or other sponsors have used other systems. And we developed a small molecule that just naturally gets into cells broadly. It goes beyond muscle. And perhaps that alone could be a driver.
The other thing I think is not well appreciated is that the repeat length that's reported in patient demographic, or if you ask a patient, is actually much shorter than the actual repeat length in an affected tissue. We're talking about muscle, for example, has 3,000 repeats on average. So it's 10 times longer. And so you need a modality that can actually work just as well in long repeats as short repeats. And so we've generated data showing that the mutant RNA, which is synonymous to the mutant or to the foci that you can visualize, we see an over 90% reduction in the mutant RNA. And we have no impact on the wild type protein expression. And that data is in our deck. And so that selectivity could be useful, although there's three other features, right? There's going beyond muscle.
There's the possibility of having it work just as well in long repeats or short repeats. And then the third is if we can get an even better splice impact in patients, that could drive adoption and differentiation. And so there's lots of different avenues by which we could potentially develop a best-in-category in a very significant category with a lot of unmet need and some exciting developments that have occurred from other companies.
Yeah. That makes sense. Do we know how much, at baseline, if you do a baseline biopsy for DM1 patients, how much would be, I guess, long repeat DMPK versus shorter repeat, whatever threshold you want to kind of use?
In an affected tissue, the mutation tends to be very long. And so if you do a Northern blot of RNA from an affected muscle, you see a big smear in the thousands of repeats.
Yeah. That makes sense. Do you think, I guess this is kind of a more fundamental DM1 question as we're looking to kind of cross-compare versus a lot of siRNA and PMO data. Do you think that your total DMPK, especially the long repeat DMPK, do you think that you'll see a divergence from splicing as we cross-compare?
You know, total DMPK is a confusing measure because it combines wild type and mutant. And so we think that the appropriate way to do it is to actually look selectively at mutant DMPK or correspondingly splicing.
Yeah. That makes sense. Awesome. I don't think we have time to touch on the Huntington's today, but maybe you can just kind of wrap up with cash runway and executive ordinances.
Yeah, well, we have a strong cash position. We ended last quarter with over $200 million, and that gives us runway into 2029 with a chance to get clinical data and at least hopefully one of these very significant conditions with unmet need and an opportunity to create a lot of value, so thank you so much for the invitation.
Awesome. Thanks for joining, Pratik.
Thank you.