Great. Thank you everyone for joining, those of you in the room and on the webcast. My name is Faisal Krishnan and one of the senior biotech analysts here at Jefferies. Really pleased to have with us here Design Therapeutics. I have CEO Pratik Shah with me on the stage. Pratik, could you start by introducing the company? Sure. Thank you for the invitation and for your attention and interest in Design. Design is developing a new class of small molecule genomic medicines where we have a very unique approach, which is to have molecules that can recognize specific DNA sequences, and by doing so, can dial up or down individual genes in the genome. As we think about monogenic diseases, there are many monogenic diseases where the root cause is well understood and is driven by a particular gene sequence. The promise of Design has always been an ambitious mission, which is to take small molecule genomic medicines, which by their small molecule nature, naturally distribute widely into the body, get into cells, get into organs, and have a pancellularity, and yet be able to dial up or down the root genetic driver of the pathology to ultimately have hopefully transformative therapeutic impact. It's been an ambitious mission, and we're really delighted that at this point we have our first sort of clinical proof of concept data in the Friedreich's ataxia program. Great. Pratik, if you don't mind me saying, I think the Friedreich's ataxia data that you had was in some ways very encouraging and validating for the platform, but in some ways a little bit controversial among the investor community. Is that fair? Well, I think from an objective perspective, we believe that even based on the discussions we've had, there is broad agreement among those investors who are looking for investment opportunities with transformational medicines that this data set supports the fundamental investment thesis of the company. Certainly, it was earlier than anticipated, and we got answers to some of the key questions much earlier than we had thought. As a result, we had a chance to accelerate our business plan. As a result, there are certainly certain questions that we have that investors had and continue to have that are, in our view, no longer on the critical path. Because those haven't been answered, perhaps that's why you're describing it as controversial. It's clear to us that we have the kind of evidence set that we believe we needed to shift gears from sort of an early-stage signal-finding type of framework into a registrational later-stage development type framework. There are a number of decisions that go hand in hand with that. I'm sure with the fullness of time, some of the ancillary questions will get answered. Got it. I think in a lot of my dozens of conversations with investors since the data, the critiques, if you will, kind of fall into three buckets. One kind of being on just the nature of the disclosure, why it came when it did, and what's happening with the study, one category being the biomarker data, and one category being the clinical data. I was hoping we could sort of maybe just tackle those one by one. Let's do that. On the nature of the disclosure, can you just clarify why this data came when it did ahead of a second-half expectation, and then also the sort of current status of the study? Right. In the second half expectation, we had based our readout timing on a series of planned cohorts. We had described in our prior quarters updates about kind of what the study cohort design was, and we had achieved a PK predicted exposure level at that 0.6 MPK, and then we had clearance to go to 1 MPK, and we had begun both four-week and 12-week duration cohorts. We had chosen four weeks initially because it would allow us to get to those target exposures more rapidly than if we had used 12-week durations to get to the same exposures. Right? Given that cohort setup, I think it's fair to say that we would not have expected to have the kind of striking results that we observed as early as week 4. It gave us key answers to the questions of what is an active dose level? What is the route of administration? Is a once-weekly administration regimen appropriate? What kind of endpoints might we have an effect on, both biomarker-wise as well as clinically, and therefore, what kinds of endpoints should be included in future larger cohort examinations? Having answers to all of these questions from the four-week cohort was certainly earlier than expected. Does it change the fact that we have clarity on answers to all of these questions, which allows us to shift into activities that are typically reserved for later in development. The cohorts are ongoing. We continue to dose the patients in cohorts that are planned for either 12 weeks or longer. We believe we have an active dose at 1 MPK. We plan to explore additional dose levels, although it is not on the critical path. Given that all of these activities are underway, certainly there could be additional data disclosures as we conduct the trial. Because we have an opportunity to accelerate the program and start to think about generating a registrational data set and explore, as part of that solution set, potential modifications to the existing protocol to support registration, we think that it is not appropriate to comment on the particulars of that until we determine what those will be, and we plan to provide that update in Q4. Got it. To confirm, the study is enrolling in the 12-week cohorts, and it sounds like you're saying that there's a chance that that could become part of a registrational package, which is why you cannot commit to disclosing that data? Yes, those studies are ongoing. There's a number of things that we're exploring about what we can do with our ongoing studies in order to support registrational plans. Because of that possibility, we're not commenting on the timing, but we will provide clarity on our plans in Q4. Got it. With respect to dose, I know you are saying that you believe one mg per kg is an appropriate pharmacologically active dose based on what you're seeing so far. Could you clarify, based on the biomarker data, especially, the extent to which going beyond one mg per kg is a priority? We think 1 MPK is active, and actually if you think about the program in the context of a larger plan for eventual submission, one of the factors that weighs into that is to begin to collect longer-term safety data and exposure data. Establishing what you believe is an active dose is really helpful to start to build that long-term safety database. That's, to us, a critical path type item. We will continue to explore other dose levels. We actually have clearance to go above 1 MPK, and that will be part of our future plans. It doesn't seem like that is on the critical path because we don't have data from those dose levels yet, and we don't think we need it in order to advance what we believe is an active dose. Got it. Some of the investor pushback here is that can't understand why they're not going beyond 1 mg per kg. It's not like they're doubling frataxin. That's what I hear from investors. Okay. I'm curious your point of view on that. Yeah. We think that in terms of getting to an understanding of the possible future effects, I certainly would not be surprised if with extended duration we continue to see a perhaps significant further increase in the biomarkers. Right? The pharmacology basis supports that notion, and that will all mature as we continue to run this study and we generate additional information. Duration is a lever and dose is a lever, and both are available to us, and we have clearance to do both, and we're going to keep understanding the nature of the effects as we continue our cohorts. Great. Okay. I think that's fair on, let's say, topic one. By the way, I do really appreciate and respect you kind of being willing to engage in all of these. Of course. questions. Let's shift over to topic two, the biomarkers. I've heard two big questions on biomarkers. One being how the biomarkers that you're seeing and the frataxin increase that you're seeing both in RNA and in protein relate to a potential therapeutic goal, which I know is a debate, but a potential therapeutic goal of achieving carrier levels of frataxin. That's one question that's come up. The other big topic of a question is the ability to see frataxin protein expression in muscle. Those are the two things I want to dig in on, but maybe can we start with the first one? Yeah. Sure. On the issue of how much frataxin would be considered therapeutic. Certainly from a genetics perspective, it makes sense that since there are carriers who are healthy, that there's essentially genetic evidence that carrier levels of frataxin cannot possibly lead to disease because there are no carriers with FA. Vice versa, if you have FA as a disease and a biallelic mutation, that whatever frataxin levels are produced in those patients do lead to FA, right? That's clear. In fact, the natural history data, which is an extensive data set that establishes endogenous frataxin as a reasonably likely surrogate for predicting clinical benefit, looks at frataxin levels within the patient population. What that data demonstrate is that patients who have more frataxin than other patients do better on all major clinical outcomes, whether it is age of onset, when is their loss of ambulation, what is the rate of disease progression by mFARS, what is the rate of disease progression by USS. Really, by every metric, patients who have more frataxin do better. That has led to a conclusion that this is a biomarker that's a continuous variable, not driven by a threshold effect of carrier levels. Because the natural history had concluded that, we believe that any increase in endogenous natural frataxin could be therapeutic. It wasn't until we received this data, which for the first time shows an agent that's a pharmacologic agent that can increase endogenous frataxin and already is showing measurable clinical impact. Essentially, it allows us for the first time to actually see whether the natural history reasonably likely surrogate prediction was potentially correct. I think with that type of evidence, we believe that what we're seeing makes sense. To the carrier levels comment, if you look at the biomarker data, the blood RNA assay is the tightest, most robust assay. In that assay, there is essentially no overlap between patient levels of frataxin and carrier levels of frataxin. That's a reflection of reality, that the levels in patients lead to FA, and the levels of frataxin in carriers don't lead to FA. By using that assay, what you see in studies we've run, which is reported on our corporate deck, if you download that and look in the footnotes on the biomarker side, you can see these numbers, that the 90th percentile of an FA patient has 24% more RNA production than the average FA patient. That gives you a sense of how the frataxin levels are within the patient population. The carrier range begins at a 46% higher level than an average FA patient. Well, in our 1 mg per kg group, the treated population showed a 65% increase in frataxin to their baseline. I think you're already starting to see pharmacologic evidence that the magnitude of frataxin response in the 1 mg per kg treated group, to us, is quite significant. Got it. Just to clarify, because I think this is an important point that I think was missed a little bit on the day that you had the data. You're saying that at least on a blood mRNA basis, your one mg per kg and even your 0.6 mg per kg are getting into the carrier range. Yes. What about protein? On protein, the baseline protein levels in our 1 mg per kg group were not atypical, right? They were in the 1 MPK group, in fact, across the whole study were typical. In the 1 MPK group, they were slightly above average, right? An average FA patient baseline protein levels are maybe around half of the average of carrier levels, but the carrier range is broader than that. In that sense, the baseline protein levels in the 1 MPK group were not atypical. It's not a situation where they were some 0.1% or something, and that the observed protein increases couldn't possibly have any pharmacologic relevance, right? I think they are actually quite relevant. By showing that the induced mRNA in the blood translates to protein, both frataxin-M, which is a mitochondrial endogenous protein, as well as frataxin-E, which is largely in mature red blood cells, I think further confirms that the induced mRNA is functional as would be predicted. I think there's very little doubt at this point that the induced mRNA makes protein. There's no evidence of any kind from any literature or from any of our studies that the induced mRNA from our compound definitively makes protein. We know that the mRNA is increased in muscle by 42% in the 1 mg per kg group. That's an affected tissue. The evidence set all corroborates. I would not be surprised, as the dosing continues, for those protein levels to build up. In fact, that was our original expectation as we looked at the kinetics and half-life of the protein, which is a much longer-lived protein. The fact that we see sustained protein two weeks after the last dose, I think confirms that this is behaving like the predicted long half-life of endogenous frataxin, which is also very comforting. All of those pieces of biomarker evidence establish a very strong mechanistic and biologic foundation for the clinical effects. To see all of that together, along with early indications of patient experience like improvements in the fatigue as a patient reported, all of this paints a clear picture to us that we have an active dose at one MPK that deserves being advanced in a rapid fashion. Got it. Just to clarify, you're saying that on a blood protein basis, the Friedreich ataxia patients are on average 1/2 of the carriers? Yes. Got it. Okay. The patients in the 1 MPK group at baseline were slightly above average. Got it. Okay. At baseline. Got it. That means that to fully restore to the average on protein, you need to double. To get into the range would be presumably lower than normal. A less lower effect than that, yes. Got it. Okay. Just the last thing on the biomarkers is if you can explain, on blood protein, the relevance or importance of that and what your findings were or were not on that. Yeah. On blood protein, that has been at the center of the evidence set on the natural history. Anytime a topic comes up about a reasonably likely surrogate for predicting clinical benefit, that evidence comes from natural history studies. What do they teach us about the predictability of a clinical outcome based on a measured marker? The measured marker at the center of the natural history is endogenous blood frataxin. Because that's the centerpiece of the natural history, you would imagine that in any discussion about using a surrogate endpoint for a clinical study, that conversation would likely begin with the same thing that was used in the natural history studies, which is endogenous blood frataxin. By seeing it induced by 65% at the mRNA level and 22%-27% in the protein measurements at two weeks post last dosing, gives us confirmation that we're getting a pharmacologic effect on what we believe to be a reasonably likely surrogate for clinical benefit. By measuring protein two different ways, two different isoforms, one is frataxin-M, one is frataxin-E, kind of adds to the weight of evidence that the induced mRNA definitively makes protein. Got it. In terms of measuring protein in muscle, can you describe that? Yeah. That story's still being written. As we had begun in this conversation, this was an earlier than expected and planned readout. There were a number of things that I believe will still need to play out, and we have very little doubt at this point that the induced mRNA makes protein. We've shown that in multiple ways, and we've seen this 42% increase in frataxin mRNA in muscle. I think, with time, we'll complete that sort of data set on muscle protein. Whatever's going on, we know that the drug is widely distributed. It's having the clinical impact that it's having, and DT-216 goes well beyond muscle, right? It goes into really all of the affected organs. It distributes very widely. I can confirm once again that we have seen in non-clinical studies in both rodents and non-human primates, DT-216 at very good levels in tissues, including the brain, and CNS at levels that we believe would drive full pharmacology. Whatever's going on is completing the cascade from the drug target, where you're dialing up normal frataxin from the DNA and measuring it out to the protein, and then all the way to standard clinical measurements. Got it. Just to be clear on this, you're waiting to kind of conduct those analyses and get that data back? There's a number of things that are trickier with muscle biopsy assays than blood assays. The RNA results are very clear, and we're working on generating the protein evidence in muscle. Got it. Okay. Shifting gears to the clinical data, could you explain just overall the relevance of the magnitude of mFARS decreases that you are seeing, and also how this compares to just general variability in mFARS? Yeah. What convinces you that this is not a kind of chance finding seen in a short study? Right. There's quite a bit of literature on how mFARS does in previous studies in FA, and we've actually included the key figure from a recent paper in our corporate deck. You can look at that on our website. What you see in that figure is that mFARS has been seen in placebo groups, in various FA studies to show anywhere from a one-point improvement to a two-point improvement, in some cases, even a three-point improvement, right? We know that other companies that are pursuing exogenous delivery of frataxin in an open-label study where patients are being told that they're given exogenous frataxin, either by gene therapy or by protein fusion. All of the mFARS responses in those types of studies, even in an open-label setting, have been in the neighborhood of two points or two and a quarter points. Given the placebo responses and the experience of other companies to see a 6.4 point improvement at the 1 mg per kg dose. Admittedly, it's N of four, but if you even combine that with the 0.6 mg per kg group and you average their mFARS improvements, it's still a 5.2 point improvement with a sample size of eight, which is half the study so far. I think that the response in mFARS is striking. To your second question, which is what would give us confidence? I think the thing to do there is, it is well known in FA that the upright stability score component of mFARS, which contributes to the points of improvement, is the least placebo responsive. In fact, in that same figure, in the same publication, a one-point improvement in upright stability score component of mFARS would be beyond the 95th percentile confidence interval of an improvement seen in any prior study. For us to see a 2.7-point improvement in upright stability score, and by my earlier logic, even if you average out the 0.6 and the 1 MPK and you get to a sample size of eight, you've still got about a two and a quarter point improvement in upright stability score, which is a more objective component of mFARS, and is less placebo responsive. When you see that type of behavior in the USS, that combined with the dose response in USS, and in fact, when we look at the individual responders, the USS clinical response also best correlates with the predicted natural history biomarker, which is frataxin blood protein. When one looks at the totality of evidence, I think it, again, is consistent with the reason for the company to exist, the predicted basis for a therapeutic effect, and now for the first time, we can actually see that the idea of restoring frataxin can in fact give you therapeutic impact. We're excited to advance this, to increase our sample size, and to do a number of things to shift into later stage development and generate more data. Yeah. This is something that every time I've heard this thesis of the mFARS potentially being some chance finding, I think you can't really fake the dose response, right? Can you clarify, this was a blinded study? No, this is an open label study, but on USS, we know that even with placebo, you don't get changes in USS. We know that because both other companies delivering exogenous frataxin are also running open label studies. Yeah. We're not unique in that regard, and those are actually presumably being used for registrational purposes. If other companies are using these type of study format for registrational purposes, certainly it's appropriate to evaluate the data at this stage and say, "Okay, what is it objectively telling us? Yeah. Thanks. We're very encouraged by it. Yeah. Can you comment on, so under the next kind of major milestone that you've guided to definitively is in the fourth quarter, providing an update on what the path forward is, which is dependent on your regulatory discussions. What is the kind of next steps in engaging on that? I presume you have to request the meeting, prepare for that, et cetera. Right. Can you just give us a sense of what the time scale for that looks like? Yeah, it's all of the usual things. I think that we had been waiting to generate data to understand what questions to engage with regulators on, and we certainly have a number of questions that we'd like to get clarity on. That will all be a part of. Often these topics can take multiple conversations. It's something that we'll keep working on. We'll make a determination of our plans going forward in Q4. Because we have an ongoing study, on one hand that could generate other interesting data or relevant data. On the other hand, we certainly want to preserve our ability to use any future information for potential submission as part of a registrational package. Yeah. Just to clarify with respect to the FDA discussions, is there like a singular big Type C meeting where you expect to get formal feedback, or is this more of a correspondence back and forth type of thing? It's to be determined, but we'll do the best we can to have all the information we need to make our plans clear in the fourth quarter. Got it. With respect to this possibility of making the 12-week portion of the study, morphing that into a pivotal study, I'm just wondering honestly, strategically, right? It's like rightfully or wrongfully, I believe wrongfully, investors have kind of en masse spoken and said, "We want to see more data before being really convinced." Does that feed into your decision-making on this as well, where in order to convince investors, you might want to not convert that to a pivotal study and show us that data? This is where drug development meets Wall Street. We're very focused on what is right for patients and what is right for the program. That remains the guiding principle for how we advance things. If along the way additional information is generated that doesn't compromise that might be interesting and relevant to investors, we'll certainly be prepared to inform folks about things as we learn them. Got it. Well, that's all that we have time for. Thank you so much, Pratik, for joining us. Thank you. Appreciate it.