Good morning, everyone. Welcome to our Piper Sandler Healthcare Conference. My name is Yasmeen Rahimi. I'm a Senior Biotech Analyst here at Piper Sandler. Excited to have Design Therapeutics here. I've had the pleasure of covering Design Therapeutics since its IPO and really excited for a great 2025 that's ahead of us. So we have lots to cover, and let's just jump right into it. Would love to start off on, I think a lot of investors in the room are familiar with Design Therapeutics and its program in FA, right? I think you have been very clear that you guys worked really diligently on second generation DT-216. Could you kindly give us an update where you are with that candidate in terms of really ensuring that it's highly safe, there's no excipients, and where you are in terms of getting it ready for the clinic? Great. Thank you so much for the invitation to be here. It's exciting to be at this conference and to meet all of you. I will be making forward-looking statements. Please refer to our SEC filings for our detailed data and disclosures. On the FA program, we feel like it's in a very interesting place because the active ingredient DT-216 was in the clinic in patients last year, and we saw that the 216 molecule does in humans exactly what it does in vitro, which is to dial up the expression of endogenous frataxin. The issue we ran into in the clinic were twofold. One is the primary issue is the duration of exposure was shorter than we would have liked. And the second is that there were some injection site safety observations that were sporadic and infrequent but were attributable to the excipient. And so what we've been doing since those observations is trying to address both of those limitations. And we feel that with DT-216 v2, the new drug product, it has all the characteristics that we believe address those limitations. And so we're very excited to take DT-216 v2 back into the clinic. We have seen by going into proprietary novel excipient space that the exposure duration is significantly higher than what was achievable with the previous formulation. And that, we think, positions us very well to achieve the goal of creating a sustained increase in frataxin, which is what the whole field has been wishing for, as is the case in monogenic diseases like this. We had originally observed this and showed that preliminary exposure PK data in sort of March, April of this year. We spent the rest of 2024 doing the formal GLP studies to confirm all of those preliminary findings, and we're now poised to get back into the clinic, and our approach is going to be to go first into healthy volunteers. We feel it'll be an expeditious path to confirm that the PK duration exposure improvements we saw in non-human primates is in fact seen in humans, and we've actually been able to tee up the program to explore both routes of administration with the new drug product, both IV as well as subcu, and we'll be looking at the pharmacokinetics in humans with both routes, and it'll also allow us to confirm that the injection site safety issues that were seen with the prior formulation appear to have been solved with the new formulation in all of our non-clinical studies. And the human studies will allow us to confirm even further that that's the case in humans. And so that, if we're able to be successful with that first set of studies in the humans, then we'll be going into patients also in 2025. But just to, will the healthy volunteer study be a SAD and MAD? Will it have both? And will it then test, like you alluded to, both the subcu as well as the infusion? Is that correct? Or will it be SAD only? The goal is to do SAD only in healthy volunteers, which should be sufficient to allow us to confirm this PK and injection site safety, and then that will allow us to then begin to go into FA patients for multiple settings, those studies of sufficient duration. Did you have to follow new IND, or was the IND already in? These will be based on new regulatory filing. Yeah. Because the exposure profile is so different that it would be important to confirm the safety profile in a full new regulatory filing. And so the timing on the filing and being in the clinic is. We expect to be beginning our single dose studies in healthy volunteers in the first half of 2025. Okay. Will you announce IND submission or? No, I think. You want to announce it. Somebody getting into the clinic is the important thing. Yeah. I agree. That's good people, and then you alluded to that a key focus beyond optimization was also ensuring that the GLP tox was completed, so at the time that you start IND, your first in human studies, what will the tox cover? Like, would it give you a chance? Yeah. I mean, our focus has been to get back into the clinic, and so that's very much on track, and then there'll always be a level of non-clinical studies just ongoing throughout development, which is pretty typical. Welcome to the conference center. Once we get into patients, we're trying to work out the duration so we make sure that exposure durations are sufficiently long that the entire system can get to steady state. And so once we have more clarity on the design of the patient studies informed by the healthy volunteer data, then we'll be in a position to lay out a more clear calendar for the patient studies and ultimately the FA readout, which is what everyone's very excited about and looking forward to. Thank you. And then, team, another question also that was when you reported the first human data was understanding the measurement of Frataxin. I think measuring RNA DNA levels are clear, but the variability of protein Frataxin levels is quite variable in patients. So we'd love to kind of understand what work has been ongoing in Design to really ensure optimizing those assays perfectly so that by the time you have data, it's a plug and play. We've continued to work on that and have sought the help of the opinion leaders in the field. There's a lot of academic experts who've optimized the measurement for frataxin. We've shown that we have very robust assays for measurement of mRNA and now also protein, so all of that, every assay is going to have some degree of inherent variation within a population, but we don't think that that's really a dominant issue. I think at this point, measurement of frataxin has been well worked out by various folks in the field, and there's publications as recently as this year that show robust techniques using LC-MS for protein measurement, so we'll be leveraging all of that knowledge, so we don't think that measurement of frataxin is a particularly confounding issue. Okay. And then, team, how do you think about sort of expected trial design? I mean, I think the SAD is pretty straightforward, healthy volunteers testing various doses of both subcu measuring frataxin levels, right? Yeah. We'll be looking at safety. Yeah. Yeah. We'll be looking at safety and exposure. So because the duration of drug exposure was the primary limitation with the previous formulation and the new formulation looks like it gives us a really nice both increase in levels and exposure, the key in the healthy volunteer study is to confirm that what was seen in non-human primates on PK is in fact seen in humans. So that remains. Your participation in this conference has been terminated by the host. Goodbye. phase one study. So we'll confirm those. And because we have the option of two different routes of administration, we'll use that exposure data to help inform the conduct of the patient study, both in terms of exploring dose levels, how many cohorts would you need, what route do we take, et cetera. So we're going to use the data from the phase one study to help inform the particular design and duration and conduct of the patient study. Welcome to the conference center. We're now in a place where we're very close to being able to hopefully do something that the field would view as incredibly exciting and important, which is to increase endogenous frataxin levels. Yeah. Team, what has changed in the regulatory landscape of FA, right, over the last year and a half, right? So let's fast forward. You have human data. We know what the doses are that you're moving forward. We know Frataxin measurements are going to be key, but would love to have your thoughts around sort of fast forward and regulatory approval on Frataxin levels. Right. So I think that the first is that with the approval of Skyclarys, there's now a treatment option, which is great. I think it validates that having something in the Friedreich's ataxia space as a commercial product has enormous value and can drive enormous return for shareholders. Having said that, Skyclarys doesn't really do anything to frataxin. So the fundamental opportunity to go after dialing up levels of frataxin, which is the monogenic known single driver of disease, remains the goal for the field. We think that in general, the regulatory landscape remains, I would say, favorable. Now, no one's really been able to increase endogenous levels of frataxin protein. I think that's something that we're uniquely positioned to be able to do. It's with that type of evidence set that would be the right time to engage with regulators about how that can play a role in an ultimate registration pathway and package. We've seen the agency be sympathetic to the unmet need, sympathetic to the idea of this being a monogenic driver. Until those conversations are had, I would say we're going to be cautious on expecting too much from regulatory concessions, knowing that in general, it appears to be a favorable landscape. Okay. And, team, I think we have time before we get into the favorite question of all times that you would have gotten, and I think Sean remembers that too before your data read out, is like what type of changes do we want to see in frataxin levels? I don't know if your thoughts have changed over the last few weeks and months of what we know about the natural history of the disease and. Yeah. There's been a tremendous amount of work done by the Friedreich's ataxia community, FARA, in looking at natural history, right? There's an incredible level of participation by patients. There's probably close to 2,000 patients in the natural history data in the U.S. and probably another 1,000 ex-U.S., and the evidence set has been building, which supports the idea that frataxin is in fact a key contributor, which is not a surprise, and those measurements have been based on blood frataxin, and we know that healthy individuals and carriers have different levels of frataxin, so carriers have about half the level of frataxin as healthy individuals, but they are completely asymptomatic, and so they're healthy, and patients have another about half of the level of frataxin of carriers. So when you look at it in that context, if someone can be brought into the carrier range, I think no one would argue that that ought to have some sort of a therapeutic benefit. Having said that, it's still an open question, and there's reason to believe that any significant increase in frataxin levels for patients could have clinical value and clinical benefit. And so how much of an increase will result in a clinical impact is an unanswered question in the field. But I think we could take comfort in knowing that, gosh, if you can double levels of frataxin from patients and you get into carrier levels, if carriers are completely asymptomatic, that ought to have a positive impact on cellular health and ultimately, hopefully, some sort of a patient clinical benefit. Great. Team, we have 10 minutes, and I want to also spend time on the Fuchs program, which you already started the healthy volunteer study. So maybe just housekeeping, if you could just remind us sort of what is the. Your participation in this conference has been terminated by the host. Goodbye. Okay. So before I dive into that, just a quick summary of the Fuchs' opportunity. Fuchs is surprisingly common, and it's commonly diagnosed even at a community optometrist office. It's a slit lamp examination by just looking at abnormal deposits in the cornea, and that typically results in a Fuchs' diagnosis. While the epidemiology says widely published numbers are 4% of adults over the age of 40 have Fuchs, which works out to several million people. Even the IRIS Registry that the CDC hosts on its website describes prevalence of diagnosed Fuchs based on ICD-9, ICD-10 codes in the 2 million plus diagnosed individuals. In the U.S. Even though there isn't any real sort of fundamental disease-modifying therapy available, so you've got a large population of individuals who have diagnosed Fuchs, and what happens is there's a progressive loss of visual quality, and that is driven, interestingly, by a single layer of cells in the corneal endothelium, which gets sick, and they start to die off, which is why they deposit these extracellular deposits that show up as an abnormal cornea in a slit lamp examination, so why is it that these cells are dying off? They're dying off because, interestingly, it turns out in the last decade that there have been publications that show that this known family history of inheriting Fuchs is driven by 60%-80% of cases by a single mutation called CTG18.1, and that mutation is in the TCF4 gene, and it causes this cell layer to get sick. And it's a single allele that has an RNA hairball that you can actually see in these cells. So we asked surgeons who, in a very late-stage patient, they do a cadaveric corneal transplant, what they do with these sick cornea, and they typically discard them. So we got a hold of these cells from patients, and we were able to show that with DT-168, you could make these pathogenic RNA foci reverse and go away. And it's an allele selective effect, and that we've been able to make this into an eyedrop. And so that's a pretty remarkable opportunity because you have an allele selective that goes after the disease-causing mutation to restore cellular health. And so having done this, the objective of the first study in healthy volunteers is to confirm that these eyedrops are safe and well tolerated because that's information you can't really derive from an animal study. You don't really know how it feels and what is the patient experience with these eyedrops. So that is the first objective. And the study is of sufficient duration where the drug is expected to get to steady state. So it's about a week-long study. This is a BID eyedrop with dose escalation cohorts with placebo controls. And so once we confirm that the safety looks good, that would then position us to then begin studies in Fuchs patients. And so that, to us, is a very exciting milestone. In order to understand how to select the right patients and pick the right endpoints, what we've been doing is recruiting Fuchs patients in a study where they're not yet getting drug treatment. Getting that direct experience of recruiting patients allows us to understand patient characteristics. It also allows us to evaluate endpoints. What are the right endpoints? How do they behave? There's three different domains of endpoints. We're looking at various measures of visual quality because patients complain of contrast sensitivity issues or glare issues or visual acuity problems in particular low contrast conditions. Those are all visual assessments that are routinely done. We need to do those in a manner that's standardized that allows us to directly get experience of endpoint performance. There's two other domains. So when these cells start to get sick and die off, what that does is their primary function is to keep the stroma appropriately dehydrated so that the cornea remains clear. And so you can actually measure now with precision instruments how much corneal hydration there is. And that's called anterior eye tomography or Scheimpflug tomography. And so we're using those types of instruments to understand what kind of edema or subclinical edema measurements can be made objectively. And could that be used as an additional or as an endpoint for a drug effect? And then third is to borrow a page from the back of the eye playbook. In geographic atrophy, for example, we were asking, are there imaging instruments, high-precision microscopes? And there are now specular microscopes that allow you to directly image the corneal endothelial cell layer. And while that's been in practice, I don't think anyone's really done a systematic review of standardized conditions and specular microscopy measurements in Fuchs patients. And so we're gathering that data set so that we can get a direct understanding of that as a possible endpoint. So this is all important, systematic groundwork that we're doing so that when we design our phase two study, it's informed by our experience in recruiting patients, understanding their baseline characteristics, picking endpoints. And we're exploring, are there biomarkers that might be available? It's harder with the eye because, again, on one hand, it's very beneficial that you have a topical eyedrop where there's no real systemic exposure. On the other hand, it also creates a question of how do you actually measure the drug effect on the intended target in this population. So these are all questions we're addressing systematically with the observational study. But armed with our phase one results, which we expect to have in the first half of 2025, we could then position the program for an efficacy study in phase two, which will be very exciting. At the time that you report out the healthy volunteer study, would you be in a position to also share how you think about phase two consideration, just given there are so many factors to consider, or should we just, you obviously have to have a phase two decision? It's possible, but it's hard to predict exactly when in the observational study conduct we'll have sufficient information to zero in and declare a phase two design because we've been recruiting patients all year. We have a one-year and a two-year follow-up to look at progression, so exactly when in the conduct of the observational study we feel like, okay, we have enough data now, is hard to say for sure, but we're running the study, and certainly the way we've structured our cash runway in our business, it is part of our plan to be able to conduct a phase two study and get that data within the scope of our current cash runway. Okay. And then you are, as you alluded to, you're running this observational Fuchs study in 200 potential patients with genetically confirmed TCF4 mutations. So it's all listed on ClinicalTrials.gov, and you alluded to some of the endpoints that you're looking at. So will you be able then, at the time of the data, maybe share a little insight on how the observational study is going so we could learn? Even if we don't know what your study design is, you could just say, "Look, in this observational study, here's what we're finding. These are all considerations. Yeah, that's exactly. When we have a phase 2 design established, we will expect to explain why we think that's a reasonable design, and that'll all be informed by the conduct of the ongoing observational study. So that's part of our plan, yes. Great. And is there any other competitors developing therapies in Fuchs? There aren't any companies or wherever that are really going after this disease-causing mutation, which is the driver of Fuchs. Most of the pharmaceutical programs have been in the context of surgical intervention, which is, there's about 18,000-30,000 surgeries done a year in the context of several million people having this progressive condition. So yes, it's a wide open landscape for us. And that's exciting, but it also means we have to figure out the roadmap. I know that the stock has had quite a rebound over the last, what, six months or so. Do you think is it due to the excitement around the work that you're doing on FA, or is it Fuchs, or is it a combination of the optionality of both? I think it's the fact that we've got four different programs, any one of which could be first-in-class and best-in-class in clinical data, and any one of these could drive a tremendous return opportunity and impact on patients. So I think it's a recognition that this is a very attractive entry point from a stock price standpoint, and the upside potential is huge. Great. We have come to the end of the fireside chat. I want to take the time to applaud you and say thank you so much for being part of our conference. Thank you for.