Design Therapeutics, Inc. Common Stock 12th Annual Cantor Fitzgerald Global Healthcare Conference

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 4-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.

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 to 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.

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 7 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.