Right. I guess we're good. Welcome, folks, to the first day of the healthcare conference here at Cantor. My name's Yanni Souroutzidis. I'm one of the publishing biotech analysts, and today I have with me from Design Therapeutics, Pratik Shah, President and CEO. Would love to hand it over to you for a few opening remarks on the Design story, what's been going on over the last six months, and what do we have to look forward to over the next 12- 18, and can dive into Q&A from there. On a very unique approach to addressing a variety of monogenic diseases. The most advanced program we have currently is in treating Friedreich ataxia, which is driven by a monogenic mutation in a single gene called a frataxin gene, and it's a disease caused by low levels of normal endogenous frataxin. The patients produce normal endogenous frataxin despite the presence of this mutation. The approach we're taking is unique and, to us, very compelling because it is a small molecule that can directly recognize these unique long GAA repeats and dial up endogenous natural frataxin, which is sort of exactly the kind of thing one would wish for in approaching a disease of this kind with this sort of known causality. We've been in a mode in the past of looking for the first sort of clinical proof of concept, and we're very delighted to have received data that we announced in May that was an earlier than expected set of results that gave us what we believe to be a clinical proof of concept for DT-216 in the treatment of Friedreich ataxia. In that mode of signal finding, we were evaluating all kinds of endpoints in an attempt to hopefully think about how we can shift gears for this program to a more late-stage program. What we have done based on that data is, as we advance 216 for the treatment of FA, we have selected a particular primary endpoint, which is endogenous frataxin blood protein. Which we believe would be a reasonable, likely surrogate endpoint for predicting clinical outcomes in Friedreich ataxia, based on extensive natural history data in which endogenous blood protein is at the centerpiece of that natural history evidence. So having declared a primary efficacy measure of endogenous blood protein, all of the other endpoints are essentially supportive in nature and intention. Off that primary endpoint, we felt that we needed to increase the sample size to be adequately powered for that primary endpoint, and that sample size is approximately 10 patients for what is our plan to go forward dose, which is a 1 mg per kg weekly administration. With that comes clarity on what we're going to do as a next step. We are planning to dose these cohorts for about 12 weeks. We have a planned dosing extension beyond that, but the primary efficacy assessment is intended for 12 weeks, and we anticipate having that data in Q1 of 2027. We were waiting to generate the data from the four-week studies, which we did in order to engage with the FDA, and that's an opportunity for us to get feedback on this idea of using endogenous blood protein as the primary efficacy evaluation basis as a reasonable likely surrogate endpoint. We will have a chance to provide an update in Q4 about our kind of forward registrational plans to the extent we have clarity on that, and that will benefit from having had, by that time, an FDA interaction to support our thinking on what our future plans could be. In addition, we are tackling other monogenic diseases. We have an exciting program in treating DM1 that is currently in a multiple ascending dose phase in treating patients who have DM1, and that is data we're anticipating in 2027. We continue to learn from the work going on in the field from other sponsors. In DM1, we feel we have a very, very different approach. We have something that is not an oligo, that is not conjugated to anything. It's a small molecule that distributes widely, and instead of fighting continuously produced RNA, it's intended to directly work on the mutant DMPK gene, the allele itself, that is causative in DM1, and downregulate the actual production of the toxic RNA that is driving all of the pathology. The advantage of small molecules in general is they get into cells easily, and they distribute widely. With the DM1 molecule, it has shown remarkable pharmacology in model systems, in cells, myotubes derived from patients, where we get a striking effect because we believe that working upstream of the RNA, working directly at the DNA, could give an inherent pharmacologic advantage to this mechanism. That's something we're looking forward to learning more about in clinical development. We have other programs. We have a Fuchs' program, where we now anticipate data next year. Then we have a preclinical Huntington's program, which is exciting and shows the power of the approach that we're taking. Understood. Quite a bit going on. Maybe coming back to the 4-week data that we recently got from the RESTORE-FA program. Obviously, this was the second foray into the clinic for DT-216. I think a big kind of moment of success was really the clean safety that we saw. Maybe just recapping briefly what you guys were hoping to see there in that regard, what we know about the mechanism here that really is distinct and accurate to really uniquely elevate frataxin and not really any other areas genomically. Yeah. What we were looking for is to understand whether DT-216 can increase endogenous frataxin sustainably, and to understand that effect. What we observed was an increase in endogenous, fully spliced mature mRNA. That is normal mRNA. We saw a very nice effect there in whole blood that, of course, induced mRNA as expected, translates to protein. We observed an increase in endogenous blood frataxin protein. RNA assays, in general, are more sensitive than protein assays. In the RNA assay results, you start to see an effect already at 0.3 and 0.6. For the protein assay, you need an adequately loud signal, if you will, for the protein assay to detect it, so we see a very clear response at the 1 mg per kg on protein, establishing that the induced mRNA does make protein as expected. We also confirmed that the drug was active in muscle. We see an endogenous frataxin expression increase as measured by RNA in muscle. That is a sensitive method. We think that confirms that what we are observing in blood as drug pharmacology is also occurring in muscle. In addition, we were exploring whether this could translate to any clinical impact and what clinical endpoints might look like. We had included assessment of the two commonly used endpoints in FA studies, mFARS, Modified Friedreich's Ataxia Rating Scale, and then Upright Stability Score, which is actually a component of mFARS. In both of those, we saw some striking results. Typically, other programs, both in clinical development and the approved product, have seen about a 1- 1.5 point change from baseline on mFARS. USS is typically not something that you see much of an improvement on with either the approved products and in previous placebo studies. USS is more objective, sort of hard to move endpoint. On mFARS, we observed a 6.4 point improvement, and then in the USS, we saw a 2.7 point improvement change from baseline. So it was pretty striking. Of course, we recognize that there is a lot of outcomes as we continue to explore this drug that would still potentially put 216 in a best-in-disease category, even if the data look different as we go forward. Our plan is to really initially focus on the now declared primary efficacy analysis of endogenous blood protein and then look for supportive evidence from all of these other assessments. That is helpful context. Obviously, with the four-week data, it was quite striking, the dose trends there, both on the biomarker side and the functional side. Maybe focusing first a little bit on the biomarker side, because I think that ties in a little bit to the kind of regulatory backdrop here. Walk us through what we have seen in natural history, how that does lend itself to what we are hoping to see clinically, and then what has been the current understanding of what regulators would hope to see to allow a drug of any sort in Friedreich's that increases frataxin to come to market. On your first question about what would you expect to see from the natural history. The natural history is actually quite an extensive data set. It is over 600 individuals worldwide with FA, with a follow-up period of as long as 10 years. It is a very extensive data set. And the results have been published as recently as 2026. And what those data demonstrate is that individuals within the FA population that have higher levels of frataxin do better than those individuals who have lower levels of frataxin, and do better clinically by a number of measures. If somebody has a very long GAA repeat mutation, it is likely that those individuals would have very low levels of frataxin expression. And as a consequence, you might see an age of onset of maybe seven years old, right? Individuals who have higher levels of frataxin would have a later age of onset. In some cases, it could be in their teens, in some cases, it could be someone who is 30. And so the age of onset is an example, and then of course, it also is a predictor of when someone might end up with a loss of ambulation or end up being in a wheelchair. And so these are very significant clinical consequences of having had a particular level of frataxin. And those frataxin levels in an individual are essentially unchanged over a period of time, but they can remain disease-free for a certain period, depending on what their level is. And the other learning from the natural history is that this appears to be a continuous effect variable. In other words, there is no particular threshold that is determinant of their outcome and that those who have more do better. So that creates a therapeutic opportunity or goal to say, can one increase someone's endogenous frataxin relative to their baseline? And that creates the therapeutic opportunity and the chance to do something unprecedented, which is to increase endogenous frataxin. And so that is what the natural history data show. Now, there is this genetic observation that people who are heterozygous are still healthy, and it confirms that if somebody has a certain level of frataxin deficiency, you can still be completely healthy. But that is a general observation on averages on protein. But for a variety of reasons, it is the change from baseline that is the therapeutically useful way of looking at a frataxin increase. Now, in terms of what is clinically considered meaningful, we know from the drug that has been now approved for the treatment of FA, that that program ran a trial with mFARS as a primary endpoint, and the group difference was about 2.4 points at 48 weeks. And this supported approval on the basis we believe that about two-point change in mFARS represents approximately one year of progression. So the therapeutic expectation in FA is that the goal is to try and slow the progression of a progressive disorder. And so that approval, I think, signifies that a two-point change in mFARS or approximately a one-year delay of progression is a clinically meaningful therapeutic impact and has been an example of what FDA has considered clinically significant. Understood. As it relates to the primary here for the 12-week data and increasing frataxin in whole blood, we have seen some precedents from other competitors, or I would not even say competitors, but other players in the space attacking the disease differentially, that are kind of focused on the biomarker as a means for accelerated. I guess, yeah, maybe bringing that element into the story here as well, considering the changes we already have seen from baseline. No one is really increasing endogenous frataxin. There are these other attempts, as you mentioned, to use either a gene therapy in the heart or a frataxin fusion protein to try and provide exogenous frataxin. The fact that both of those programs are pursuing an accelerated pathway is encouraging to us, and we believe sets some precedent for frataxin to potentially be considered a reasonable likely surrogate endpoint. We certainly think that the endogenous frataxin measurements are. We know they are biologically relevant because we are measuring something that the patient's cells are naturally making. In particular, if you think about frataxin-M, frataxin-M is produced in the mitochondria through proteolytic cleavage by an enzyme that is in the mitochondrial matrix. So whatever frataxin is produced by the cell, translated in the cytoplasm, goes into the mitochondria, and you can only get M if it is proteolytically cleaved in the mitochondria. By directly measuring frataxin-M, we believe we are getting a measure of something that is a mitochondrial natural active protein. We think that that is disease-relevant and functional and important. Understood. So coming back, I guess, to the four-week data and looking forward to the 12, you did mention those improvements on mFARS and upright stability and saw some pretty substantial dose-dependent trends there. I guess, generally, how do you think that might kind of translate to the 12-week data, knowing kind of what we have seen so far on a PK/PD basis? I guess, bigger picture, are you starting to be more focused on the function, on the biomarker, how to think about these things as it relates to being able to access the markets and have a commercial product? Yeah. The four-week data was very informative to us because it allowed us to pick a dose. It gave us comfort that our weekly administration was appropriate, because we saw in the four-week data that at two weeks after the last dose, you could see a continued sustained frataxin protein elevation. That is consistent with the known long half-life of the protein. In that sense, it was very helpful to help us choose an endpoint and select that. Our focus on the 12-week data is on the endogenous blood protein. The study is not powered for clinical effects. All we are really looking for is some supportive evidence. In that sense, the goal of the 12-week data is not to say, "Okay, how does it look relative to the four-week?" But that does it meet a prospectively defined primary efficacy endpoint? Is that reasonable as a likely surrogate for clinical? Do all of the other data provide supportive evidence? Does this allow us to then advance DT-216 to registration as we think about how that fits into an overall registration plan? Understood. You also had mentioned that you guys added a higher dose cohort as well. I do not believe the dose has been disclosed quite yet. Then in tandem, you also kind of increased the sample size up to 10 patients. Maybe just for the 12-week data that we are getting next quarter, is it both cohorts together? Is it the full 10 patients at that point? Just high level, kind of what we should expect. We do anticipate the full 10 patients of data for the 1 mg per kg planned go-forward dose in Q1. We could go higher than one, which is why we are exploring that. We just don't have any data yet on anything higher than 1 mg per kg. We are planning to also have data from the higher dose level in Q1 of 2027 as well. Okay. But not necessarily the full 10 patients or both. Yeah, we haven't quite. If there's. decided how many we will end up having with the higher dose level. But certainly, the 10 with the 1 mg per kg is Understood is the goal. Understood. In terms of reasonable next steps, it seems like you are engaging with regulators. This would be kind of the first opportunity for formal feedback on the four-week data. It seems like the RESTORE-FA program obviously has a lot of flexibility for the protocol to be amended. Maybe just kind of walk us through what you think base case feedback is or what kind of answers you are hoping to get or questions that you are asking and how that might evolve the remainder of the study or might lead to a separate new effort. Yeah. We have declared the endogenous blood protein as the primary efficacy analysis. That is something we would like to get some feedback on. Is that an appropriate way to assess efficacy for DT-216? That would potentially make us eligible for an accelerated framework. That is something we would love to know. The alternate framework for pursuing registration would be a traditional approval with a clinical endpoint. That is certainly available to us as well. We will try and get an understanding of whether the way in which we are planning to analyze the response to DT-216 by using frataxin, is it okay for it to be a reasonably likely surrogate? That will then inform how we think about the overall registration plan. Got it. I guess maybe just briefly, if you can give us any additional color on the higher dose. There was obviously a bit of a formulation reengineering that occurred from the first generation to the current. It seems like the dose selection was based on kind of what was known about the drug at the time between PK and PD. Knowing now what we know in terms of what we've seen so far from the recent four-week data, conceptually, how should we be thinking about any higher doses? Is it similar magnitude? Is it really trying to go back to dose levels that we saw with the first kind of clinical decline? I see. No, I think this is a new sort of dose-to-exposure relationship with DT-216P2. We have chosen the 1 mg per kg as our planned go-forward dose based on the profile and the activity we've seen with it in the overall package. We just didn't have any data on a higher exposure, so we're exploring that. There are a number of things that we can start to do from a long-term planning perspective with our planned go-forward dose that allows us to be better prepared for late-stage development. So I'm looking at the higher exposure as purely an exercise in exploration and curiosity. Understood. Okay. I did want to shift a little bit to the DM1 program. just given the recent updates the field saw this week. Yeah. But just wanted to check in if there was anything else on FA that you feel like we haven't No. Okay, perfect. Maybe then touching on DT-818, obviously a bit earlier stage, but now kind of in the clinic and dosing patients. Maybe just give us a bit of a recap here how mechanistically this is different from anything else really in the clinic for DM1, and certainly different even than 216 in its approach. Yeah. 818 has been designed to recognize these unique long CTG repeats in the DMPK gene that drive DM1. The mutant allele creates a toxic RNA, and 818 is designed to not only recognize those sequences but actually dial down the production of that toxic RNA itself at the DNA level. That's a very unique mechanism. It's not an oligonucleotide. It isn't trying to block or degrade already manufactured RNA. In that sense, it's a very differentiated profile. The way that it has manifested itself is in these cell systems that are derived from patients, which to us appear to better predict what has been observed in human studies than what was seen with the actin repeat models or with non-human primate wild type DMPK assessments, is the pharmacology is quite striking in that we see essentially +90% elimination of those toxic RNA. You can visualize it. You can see it in the form of intracellular, intranuclear trapped RNA foci. You can directly visualize this by fluorescence immunohistochemistry. We also noticed that the DT-818 approach works just as well in very long repeats as short repeats. This is important because patients' reported repeat length is from blood, but their actual affected tissue, like muscle, has repeats that are often 10x longer than what is reported in a patient demographic in a clinical trial. We know that trying to improve the cellular state is important to do even when there are super long repeats. We see with DT-818 just as good a potency and just as good an RNA reduction in 2,600 repeats as 330 repeats. That has been a very distinctive observation. DT-818 being a small molecule distributes widely. There is no transferrin receptor conjugation, so perhaps all we would need is to have something that distributes more broadly than to muscle. There are a number of features of DT-818 that could drive a best-in-disease profile. We are in a multiple ascending dose study, and we are learning from the field as to what kinds of endpoints might be suitable for long-term clinical development. I think it is pretty clear that the video hand opening time is proving to be a challenging endpoint for a variety of reasons. We do not know definitively as a field how big an impact on the mutant RNA might be required to translate to a clinical effect. We know there is a tremendous amount of unmet need. There is a lot of heterogeneity. There is a lot of opportunity to have clinical impact in DM1. As we advance DT-818, we will have an opportunity to learn about endpoint performance from other sponsors. We will have an opportunity to learn about what is known about the relationship between how much of an impact you can have on the gene or the RNA and how that translates to clinical effect. As we think about our 2027 readout, our first focus is to help us choose a dose level on some rational basis, and then by that time have a better understanding of how that can translate to a true clinical impact assessment. Maybe briefly last one for me because I know we are coming up on time, but how should we think about that readout? Is it going to be very akin to what we have seen from others in the field? Is it going to be more like RESTORE-FA with regards to a focus on biomarkers and different dose levels? Maybe just a high-level framework of what you are hoping for. Yeah. We are still trying to determine that. We know that there are a number of other readouts that are anticipated between now and then. We would like to learn as much as we can from what occurs in the field before we more sharply define what we are going to be reporting against. Understood. Well, that is all for me. If there is any other messages you want to broadcast here at the conference. Otherwise- No, this is a terrific opportunity to talk about Design. Thank you for your questions and for hosting us.