Welcome, everyone. I'm Joe Schwartz from the Biotech Equity Research Team at Leerink Partners, and it's my pleasure to host this fireside chat with Design Therapeutics. Welcome to Pratik Shah, CEO, who's here to give us an update today. Maybe we can start by having you give us a quick overview of the company's latest progress and highlight for us the goals that we have to look forward to over the next year or so. Great. Thank you, Joe, and thank you to Leerink for hosting Design. It's a pleasure to be here. I'll be making forward-looking statements. We actually filed our 10-K this morning and press release, so you can review that for more details on our updates. Design Therapeutics is developing a new class of small molecules that do something we think is very interesting, which is to dial up or down the expression of an individual gene in the genome. We're pursuing potential treatments for significant monogenic diseases. We have a program in Friedreich ataxia, a different program in Fuchs endothelial corneal dystrophy. We have a program in Myotonic Dystrophy and one in Huntington's disease. In each of these large areas, we have an opportunity to either be first in class or best in class with the approaches that we're taking. In terms of updates, we're delighted that we are now back in the clinic with DT-216 for Friedreich ataxia. This is with our new drug product, DT-216 P2. Our initial study is in normal healthy volunteers in order to understand safety, injection site safety, and pharmacokinetic properties of DT-216 P2. If we get successfully through this portion of the development program, our goal is to begin patient studies in mid-2025, so later this year. We're very excited about that possibility. Our goal there is to see if we can restore endogenous frataxin levels to those that would be therapeutically beneficial to patients living with FA. That would be a significant advance in the field if that can be achieved. Our previous program showed that this pharmacology is working in patients with Friedreich ataxia, but the duration of exposure with our previous drug formulation was too short, shorter than we had liked. We have developed DT-216 P2 to overcome all of the shortcomings we learned about in the clinic. We are very much looking forward to progressing the Friedreich ataxia program. We expect to have data from the multiple ascending dose portion of the study ready to report based on 12 weeks of dosing sometime in 2026. That is the update on the Friedreich ataxia program. In our Fuchs endothelial corneal dystrophy program, we are happy to report that we have completed dosing in the phase I portion of the Fuchs endothelial corneal dystrophy program. That was also done in healthy volunteers in order to confirm the tolerability of the eye drops and the safety of the product. We expect to have that data to report next quarter in the first half of this year. We have been thinking hard about what the next study would be. We would like the next study to be in FECD patients. We are in the process of designing that study should the phase I be supportive of further advancement of the program. Separately, we have been enrolling patients with Fuchs in an observational study. What we also reported is that we have now completed our target there for enrollment in the observational study. We have completed baseline visits on approximately 250 patients with Fuchs. Based on their baseline characteristics, we have chosen approximately 100 Fuchs patients for long-term follow-up and for progression so that we think that data will continue to help us understand the endpoint performance and gather data to inform the long-term development for the Fuchs program. In myotonic dystrophy, we are anticipating selecting our development candidate this year. We believe there we also have the possibility of being a best in class in the myotonic dystrophy treatment landscape. Our Huntington's study continues to progress. Our next milestone there is also the selection of a development candidate. Okay. Great. Thank you. Let's continue with 216P2. I'd love to actually start with having you tell us what you saw with DT-216 and what were the limitations of that formulation. How has that led you to enhance your chances of being able to see what you hope to see with 216P2? When we took DT-216 into the clinic in 2022 and 2023, what we saw was, on one hand, the duration of exposure of the drug was much shorter than we had wanted or anticipated. What was intended as a once-weekly administration led to observation that we were only getting 8-10 nanomolar of drug for about out to day two. By the time we got to day seven, in time for the next dose, the drug was essentially almost gone. Interestingly, despite this short duration of exposure, what we observed was that there was an increase in frataxin RNA expression in the patients as measured by both frataxin levels in peripheral blood cells as well as in muscle biopsies. While the duration of exposure was short, we were able to observe the pharmacology in patients at comparable exposures as we had seen were needed and sufficient in our preclinical studies in cellular models. That was very, very encouraging. It was not clear at the time whether we could increase the duration of exposure of DT-216. That was one challenge we wanted to address and see if we could overcome. The second issue we ran into is that there were sporadic and infrequent injection site thrombophlebitis events, which prevented us from dosing either more intensively or more frequently. That was a second issue that we wanted to see if we could resolve. What we learned as we investigated this further is that it appears that the excipient that we were using in the DT-216 formulation was likely driving the injection site safety issues. In an effort to try and address both of these limitations, we did quite a bit of exploratory work. Through that work, we developed DT-216 P2. We were delighted that we were able to address both of these limitations in nonclinical studies without changing the active ingredient, without changing DT-216. The way in which we ended up creating DT-216 P2 is to change the excipient. We went outside of the off-the-shelf excipient space and identified a novel and proprietary excipient, which gave us a remarkable improvement in the duration of exposure. We have seen very good injection site tolerability in all of the nonclinical studies that have led to us going back into the clinic. We are very excited to now see if we can confirm that these promising properties of DT-216 P2, in fact, hold up in our first human studies. If we're able to get supportive evidence, then we can move into patients and go after our original goal of a sustained increase in frataxin in patients with FA. Okay. Great. Thank you. Can you talk about how the preclinical data for 216P translated from animal models to humans? How do you think about the potential for the preclinical data for 216P2 to translate into humans? With the prior formulation, we had seen something that's relatively unusual for small molecule drugs, which is we saw a disconnect between the pharmacokinetic profile in plasma versus tissue. That was why the company felt that there was a possibility that we would see a sustained exposure duration in tissue. What we learned, of course, in the human studies is that DT-216 and its previous formulation behaves like every other small molecule drug, which is that the plasma levels are more or less concordant with tissue levels. With DT-216 P2, we've seen in general a better-behaved injection product. In doing so, we see both availability by IV administration as well as now by Sub-Q administration, which the old formulation was not. We also see a nice concordance between plasma levels and tissue levels. Really everything about DT-216 P2 looks more in line with typical injectable small molecule products. It is on that basis that we think that sustained exposure in plasma is the desired profile. We are going to look to confirm that in our human studies. Okay. Great. Thanks. What should we expect to see from the phase I SAD Healthy Volunteer study? What time frame will this be? I'm wondering how informative would this be? Where does this fit into the overall constellation of what we're talking about in terms of the final product profile? The key things that we are looking for from the single-dose study is supportive evidence to move forward into patients. If we're able to get that supportive evidence, I think that would be a really wonderful step forward. In particular, we're evaluating both routes of administration in the single ascending dose study. We are looking at an IV route of administration as well as a Sub-Q route of administration. Knowledge of the pharmacokinetic profile will allow us to design the appropriate route and dose regimen for the patient studies. All of that will collectively inform the next phase of the program. We will be looking to hopefully hit that milestone of getting into patients. We will report the single-dose data in due course. Okay. How do you think about the muscle concentrations or CNS concentrations that are going to be required in order to see activity based on what you've seen in animals? How do you think that aspect might translate? What kind of exposures do you hope to be able to achieve? One of the key insights we got from our previous patient studies in 2023 was an answer to the question you asked, which is what is the level of exposure needed in order to see pharmacology in patients? What we learned in those studies is that the predicted exposure from cellular assays, which was about 10 nanomolar, is consistent with the exposure that drives pharmacology even in patients. The issue was that the duration of exposure we achieved in the clinic was just too short. Working off of both of those data sets, we think that a sustained exposure to get to that sort of 10 nanomolar level is the likely target. We're going to know directly by measuring frataxin in the patient studies. I think that gives us a goalpost or a benchmark. What's interesting about this pharmacology is that in all of the preclinical models, having more than that at a sustained level over time doesn't really drive more pharmacology. You get essentially full pharmacology in these cellular systems at about 10 nanomolar as long as you sustain it over time. I think what we're looking for here is just to see if we can achieve that sustained exposure level, which we think would position us for the kind of ultimate pharmacology we're looking for. We're going to be able to measure it directly. We're going to measure it in blood. We're going to measure it in muscle and see if we're achieving that goal. We'll have that data in 2026. I heard you say that you saw RNA increases, although they were short-lived. What about protein? At what point do you think once you get into patients, it's reasonable to expect that frataxin protein increases might be detected? We would like to make sure that we let the system get to steady state. In order to give the system time to get to steady state, we're planning on analyzing the frataxin data after about 12 weeks of dosing. That's, we think, the right duration of study to conduct before we know whether we've achieved our goal. When you go back to the cellular data, it's very interesting because we've had this data in our presentation all along before we ever ran any of our previous trials as well. When you go back and look at that information, it's remarkable because even in cells, if you only expose the cells to drug for about three days, you get RNA, but you don't yet get protein. It is just the inherent kinetics of the frataxin system to require sustained exposure before the protein levels can build up to get to a new steady state. It makes sense because the protein is a very long-lived protein. The literature reports the protein to have a half-life of anywhere from several days to a couple of weeks. When you think about any long-lived analyte, whether it is on the way up or the way down, the rule of thumb people use for any long-lived analyte is about five half-lives, right, to either clear it out or to get to a new steady state level. By that logic, having a 12-week study with a protein that is, let's say, two-week half-life, that is about 10 weeks. You need maybe two to four weeks to get the drug to steady state. All of that points to the direction of doing a 12-week study to look for that frataxin protein effect that you asked about. I remember at the time that you were developing 216P in patients, it wasn't clear whether or not you could quantify the protein accurately. How do you feel now about the ability to do that? Is this a biomarker that could be? I'm going to hold the second part of the question until you answer it. We looked at that issue in some depth. We asked the key opinion leaders who have published numerous papers with frataxin measurements in the literature. I think it's very clear that these are well-established approaches. There's a relatively recent paper last year in the Journal of Neurology showing that if you use triple quadrupole LC mass spec as the measurement for frataxin protein, that's a reliable measure. That's a lesson we've incorporated into our frataxin measurements. We feel that the marker is readily measurable. There's also natural history data generated by the opinion leaders in the field that look at frataxin levels by blood test and creating a relationship between those levels and the progression of the condition. We think that there's quite a bit of good evidence on the measurability and the relevance of frataxin as a measure. We feel well-positioned to measure it in the clinic. Okay. Great. I know you're still fairly early in development with this formulation, but you've gone further with the prior one. FDA has been leaning into collaborating with other sponsors in FA in this area. I'm wondering, have you had many interactions with the FDA? Can you spend a minute or two talking about how you think they're thinking about this space, which has helped other sponsors get a significant amount of traction? Right. You know, it's encouraging to hear what we're hearing from the other sponsors, interactions with the FDA. It sounds like there's some appreciation at the agency for the relevance of frataxin. However, I think no one's really been able to generate an evidence set that you can increase endogenous frataxin levels. And so what we'd like to do is first see if we can achieve that objective and gather that kind of data before engaging with the agency on the applicability of that kind of information for the overall development program. It sounds from what other sponsors are saying that there's an openness at the agency. That's to be determined. Okay. Makes sense. Can you talk a little bit about the route of administration that you foresee 216P2 taking? I know you're evaluating Sub-Q as well as IV and maybe a couple of different IV formats. What's your take there? Yeah. Both IV weekly and a variety of Sub-Q routes would be suitable for the long-term administration of 216P2. We think both routes are acceptable. There's many examples of commercial products that are given IV weekly, EXONDYS being one example. That's clearly an avenue we have. Sub-Q is something we're exploring. Either route would be fine from our perspective long-term. We're going to let the data from these studies inform that long-term decision. I think the first is what does the PK look like? What does safety tolerability look like? What do the injection sites look like? Frankly, any one of these answers that we could land on would have long-term potential as long as the exposure and the duration and the safety look good. Yep. Okay. Great. Switching gears to yet another formulation. You have a Fuchs Endothelial Corneal Dystrophy program with an eye drop formulation. Can you talk a bit about what you've seen preclinically so far, both on the safety tolerability as well as any efficacy signals? Yeah. The Fuchs program is based on a molecule that dials down the expression of mutant TCF4. Mutant TCF4 is described in the literature as a CTG18.1 mutation, which is a CTG repeat expansion in one allele of the TCF4 gene that causes the corneal endothelial cells to dysfunction and get sick and die off over time. The therapeutic hypothesis here is that if you can dial down this sort of disease-causing toxic RNA, that ought to have therapeutic benefit. What's remarkable is that we've been able to achieve that sort of selective downregulation of mutant TCF4 in a way that spares wild-type TCF4. The way in which we can assess that is in a number of models. The most relevant one, we think, is looking at the human endothelial cells directly. Some of these patients, about 0.5% of them, progress to the point where they have to get a corneal transplant. We asked surgeons what they do with these diseased corneal cells. They typically discard them. We asked if we could actually obtain these samples from patients with Fuchs. What you get is a desiccated membrane with the corneal endothelial cells on it. When you visualize these cells, when you look under a microscope, you can actually see the mutant toxic RNA if you put a fluorescent probe with a tag that identifies the RNA. These show up as dots inside the nucleus that are called foci. You could imagine our delight when we were able to see that the DT-168, when you apply it to these human corneal endothelial cells, these intranuclear foci, which is the hallmark of the pathology of this disease, vanish. They disappear. As a consequence, the genes that are misspliced as a result of this toxic RNA, that splicing gets corrected. That to us was very, very encouraging. What is even more remarkable is that we were able to formulate this into an eye drop so that with a topical administration in animal studies, we see a very nice distribution to this target cell layer, to the corneal endothelium. Those two things combined created the evidence set to advance this into the clinic. We also actually announced in our 10-K that we have completed chronic tox studies in animals with DT-168 successfully. Based on those findings, the molecule appears well tolerated with what we think would be a very nice therapeutic window. We think the next step is to, in fact, confirm in patients that the topical eye drop is a viable formulation and path to take forward. As we're waiting for that data, we're planning our first Fuchs patient studies and determining what we should measure, why we think that would be a clinical de-risking event. Stay tuned for that, likely to be articulated once we get the data and are ready to report on that from the phase I studies. Okay. You get phase I healthy volunteer safety tolerability data. Right. Will there be anything else out of that that's helpful? We would not expect much systemic exposure from an eye drop. That is another thing to confirm in the studies just to understand what we are dealing with in terms of systemic exposure and safety risk. Okay. Where does the observational study fit in? Do you need some results from that, some analyses? Do you talk to regulators after you formulate a plan to track different functional or anatomical or both kinds of endpoints? How do you see the order of operations in this program? The observational study has already been very helpful because we're getting experience in recruiting Fuchs patients into an investigational study, even though there's no treatment arm. We're understanding the patient characteristics through various domains of evaluation. We're looking at visual quality measures. We're looking at other high-precision instruments that are now available in ophthalmology to see things like subclinical edema, for example, which is measured by Scheimpflug tomography. That is a type of instrument. Part of it is to understand patient characteristics. The other part is to understand endpoint performance. How do these endpoints behave? How does the picture look over time as we follow these patients for long-term progression? We think no matter what the observational study results are, it will be useful as we engage with the agency on what we believe would be an appropriate set of things to measure in patients with Fuchs in a trial context. I think that'll continue to inform development. Independently, we've been thinking about what would be the right type of study to do after a healthy volunteer study to de-risk the program and gain confidence in DT-168 as a viable product. Okay. Very interesting. Just in closing, cash resources in order to fund all of this activity? Yeah. We ended the year with $245 million. We've structured our business so that it gives us runway into 2029 sufficient to get to a de-risking event on at least one of these various programs we talked about. Excellent. Thank you so much, Pratik. Appreciate the update. Thank you. Really appreciate it. Thanks, everybody.