Good afternoon, everyone. My name is Kostas Biliouris, and I'm one of the biotech analysts here at Oppenheimer. Thanks, everyone, for joining our healthcare conference today. It's a great pleasure to have here with us Design Therapeutics, and particularly the CEO of Design, Pratik, he will be walking us through the platform and some data. This is a very interesting company with small molecule genetic medicines, which I cover and I like, we are expecting a readout in the second half of 2026 that the CEO will be talking about. With that, Pratik, thanks for joining us today, and we look forward to your presentation.
Kostas, thank you, and thanks to Oppenheimer for this opportunity to talk about Design Therapeutics. I'm Pratik Shah, serving as the CEO. During the presentation, I will be making forward-looking statements. Actual results may differ materially. Please refer to our SEC filings for various risk factors that are relevant to this presentation and company. What makes Design unique and interesting is that we are attempting to treat diseases caused by single gene mutations in a new way. The idea is to design a novel class of small molecules to either dial up or down the expression of individual genes in the genome to address the root cause of genetic disorders. Typically, genomic medicines are, you know, large molecules and therefore have a difficult time getting into cells, getting broadly across tissues, and getting pan-cellularly into all the relevant cells.
Small molecules have this inherent advantage of being able to get into cells naturally, get into tissue naturally, and be pan-cellular. We are currently pursuing three clinical-stage programs, and the investment thesis here is that if we were to get positive clinical proof of concept in any one of these three programs, it could potentially drive significant advances in the treatment of these diseases and also create shareholder value. In FA, we are running a multiple ascending-dose trial in patients with FA. This is called the RESTORE-FA trial, and the goal of the trial is to see if we can increase the expression of endogenous natural frataxin. We anticipate having data from this trial in the second half of this year.
In FECD, we are running an exploratory biomarker study with DT-168 eye drops to see if we can impact splicing in patients with Fuchs' corneal dystrophy. In DM1, we anticipate starting dosing patients in the first half of this year in a multiple ascending-dose study with data expected next year. We're also working on a preclinical Huntington's program. All of these are large market opportunity areas with significant need. In FA, patients already make natural, normal, endogenous frataxin, but the levels of production are low, and that is what causes the cellular dysfunction and clinical disease. The levels are low because there is a genetic mutation in the nucleus. These are abnormally long GAA GAA repeats that cause low levels of expression of normal frataxin.
DT-216 is designed to directly recognize these abnormally long GAA repeats that are sitting in the frataxin gene that act like speed bumps, and DT-216 is designed to smooth the path so that the cellular machinery can read this gene without any gene editing or gene therapy or exogenous frataxin delivery, and dial up the expression of natural endogenous frataxin. Various preclinical data have shown that 10 nanomolar levels are enough to generate full pharmacology in cells taken from patients, and that's the data shown in the green bar. We had previously run a clinical trial in 2023 in FA patients, and in those studies, we were only able to get limited duration of exposure.
We were able to measure 8-10 nanomolar exposures in muscles for two days after dosing, as seen in the muscle biopsy levels shown in the right. These levels correspond to tens of nanomolar levels in circulation at day two, and after that, the levels dropped off. Despite being at 8-10 nanomolar in day two in muscle, what we observed was an unmistakable increase in frataxin expression. It confirmed that the in vitro pharmacology was validated in human studies. Since then, we've developed a new formulation with the same API, and what we see in this figure is a more sustained level of exposure with the new formulation called DT-216P2.
Now, whether this sustained level of exposure translates to sustained pharmacology or not is something that we are currently testing in a multiple ascending-dose study in patients with FA. What's the bar for success? Well, since no one has ever been able to create an increase in expression of normal endogenous frataxin in patients with FA, we believe that any increase in endogenous frataxin would be a win. We are measuring frataxin in whole blood, which is a well-studied marker in natural history studies, and also in muscle, which is an affected tissue. We're evaluating different routes of administration and have not predetermined the number of cohorts we will be running. We do expect to have data from this trial in the second half of the year. Moving to FECD.
There are 2 million diagnosed cases of Fuchs' in the United States, which, in which there is a progressive vision loss caused by loss of cells in the corneal endothelium. It's thought that losing these cells causes the cornea to get edema or swelling from excess hydration, and that interferes with corneal clarity and therefore visual clarity. Why do these cells die off? That's where the genetic mutation comes in. There is an abnormal CTG expansion in the TCF4 gene that is read by the polymerase to make a toxic RNA. The RNA contains tangles and traps splice proteins. Trapping splice proteins causes all kinds of other genes to be abnormally spliced, and this splicing defect is what causes the cells to get sick and eventually die off prematurely.
Actually, you can see these toxic RNA in corneal endothelial cells taken out of a patient's cornea after a transplant surgery. Take a look at that middle upper panel, where you see these dots inside the nucleus, which are the toxic RNA foci directly visualized. We've designed DT-168 to recognize these abnormally long repeats in the DNA and dial down the production of the toxic RNA, and the effect is shown in the middle lower panel, where DT-168 causes a significant reduction in the toxic RNA foci. This is a potent molecule with low nanomolar IC50s. You can see that this reduction in toxic RNA is selective for the mutant allele, with the data on the left, and also improves the mis splicing across a wide variety of genes shown in the blue bars.
We completed a multiple dose healthy volunteer study to confirm the safety of the eye drops in healthy volunteers, and there were no clinically significant adverse events observed in the phase I study. Historically, there's been no biomarker available for evaluating mis splicing in Fuchs' corneal dystrophy. We developed, for the first time, a potential biomarker by using cells taken from discarded FECD corneal endothelium after a corneal transplant surgery. By extracting RNA from these cells and measuring splice events across a wide number of donor tissues from both Fuchs as well as corneal cells from non-Fuchs donors, shown in green, we were able to find gene events where there is separation between the splice events from diseased eyes and unaffected eyes.
The concept behind our biomarker study is that patients with Fuchs' who are already scheduled to have a corneal transplant surgery are given eye drops for several weeks before their scheduled surgery, and because their corneal tissue is going to be removed anyway, it gives us an opportunity to see whether DT-168 treatment could result in measurable changes in splicing. This study does have limitations in that it is both in late-stage patients, and the study does not permit measurement of splicing before dosing. There is a chance of a false negative, but if the study worked, it would leave little doubt that the molecule was doing what it was designed to do in the corneal endothelial cells. Let's now talk about our DM1 program. The disease mechanism of DM1 is shown in this video.
You see abnormally long CTG repeats in the DMPK gene, shown in red, and this causes the RNA polymerase to make a toxic RNA. These RNA cause tangles. The tangles trap splice proteins and cause these intranuclear foci. GeneTACs against the DMPK gene are created to recognize these abnormally long repeats and stop the production of the toxic RNA while leaving the wild type allele untouched. There are several programs in clinical development for the treatment of DM1. We've learned a lot from these programs. First, we've learned that the approach of targeting mutant DMPK can result in clinically measurable benefits in as little as 12 weeks after treatment. We also have the benefit of seeing what types of preclinical models better predicted the effects that were seen in patient studies, and these models fall into two categories.
One is where the mutation is in the DMPK gene itself, like it is in patients, and these are typically myotube models derived from patient-derived myoblasts. They have a similar spliceopathy and repeat length as an affected muscle in patients. The other category is where the mutation is in some other gene, such as in the mouse model, called the HSA-LR model, where the repeat is in the actin gene. This is used because repeat expansions in the DMPK gene in mice have very limited myotonia. Some companies have used wild-type non-human primates where there are no CTG expansions, but these models have been used for testing oligonucleotides that target non-CTG sequences.
A less appreciated phenomenon is shown on this figure on the right, taken from the paper cited below, and it turns out that while the repeat length either is reported by a patient as their repeat number or reported in a patient demographic reflects a repeat length from a blood test, and let's say it's, for example, 300 repeats. It turns out that the repeat length and affected tissue, like muscle, is way longer, often 10x longer, which puts it at, say, 3,000 repeats. This could be significant because oligonucleotides have a more difficult time targeting longer and longer repeats. This phenomenon could also explain why there is a heterogeneity in the tissue manifestation in various DM1 patients, because it's possible that the somatic expansion and lengths are different in different tissues.
This condition is 10x more prevalent than FA and is thought to be a very large market opportunity. This slide summarizes the programs that are currently in clinical development that are targeting the DMPK gene. These are all oligonucleotides, and because oligonucleotides have a more difficult time getting into cells naturally, they are all conjugated in some fashion to a moiety intended to facilitate distribution primarily into muscle. That makes all of these constructs quite large and therefore, naturally, have more limited tissue distribution.
We wanted to look at the clinical splicing, which has been reported from these programs, and see that of the two categories of models we discussed, it appears that the preclinical human myotube foci are closer in predicting the human splice effect, potentially because these models have a mutation in the same gene that is seen in patients. Based on all of this background knowledge, what we set out to do was design what could be a best-in-disease program to have several potential differentiation properties. First, perhaps it's important to go beyond muscle, and we wanted to design a molecule that would distribute broadly into affected organs. Second, we wanted to develop a molecule that would work well in both longer and shorter repeat expansions, but do so in a way that would still maintain selectivity for the mutant allele.
Lastly, we wanted to target a greater pharmacologic effect on the production of the mutant DMPK RNA, as seen as nuclear foci, as well as a potentially greater improvement in splicing. This slide shows data from our development candidate, DT-818, which has low nanomolar potency with comparable pharmacology in both shorter or 330 repeats, as well as longer or 2,600 repeats, and corresponding improvement in splice effects in DM1 myotube systems. Now, this is visually what a 90%+ reduction in foci looks like. A foci are a direct measure of the mutant DMPK RNA. Immunohistochemistry with the antibodies to the splice proteins like MBNL1 co-localize to these nuclear foci, as seen in the upper panel. Treatment with DT-818 causes a reduction in the mutant DMPK RNA, resulting in a reduction in foci.
While it's not feasible to do a direct head-to-head study, it turns out that everyone in the field uses the same set of myotube lines, known as the DM1 line or the DM1 clone 5 myoblast line, differentiated into myotubes. Data from other sponsors' publications, which are shown on the left, you see approximately a 30%-55% reduction in the mutant RNA and resulting foci. On the right is the data from DT-818, showing why we are excited to observe a greater than 90% reduction in toxic DMPK RNA and foci in the same type of assay system. While the mutant allele results in an RNA that's trapped in the nucleus, the wild-type RNA has no CTG expansion, goes out to the cytoplasm, and is translated into the DMPK kinase protein.
The data on the right shows that DT-818 treatment has no observed effect on the wild-type kinase, unlike a control antisense oligo, which is expected to result in a reduction in wild-type DMPK RNA, as seen. We wanted to confirm activity of these molecules in vivo, so we've used a commonly used actin repeat mouse model, and as you can see in the video on the left, there is a pinch myotonia model in which a pinch in the rear causes the hind legs to splay outward, and they have a difficult time bringing these legs in due to the myotonia. On the right, you can see a treated mouse has improved myotonia upon this pinch test and also a reduction in the toxic foci in the muscle.
As we go to higher species, we see the plasma levels here observed in non-human primates at two illustrative doses. We like this pharmacokinetic profile, and while the ultimate dosing interval will be determined clinically, we're initially going to be dosing once weekly to look for pharmacologic effect. Like DT-216, DT-818 is also bioavailable by sub-Q administration, so we'll be evaluating that also in the clinic. If sub-Q works, that could be a differentiation over various intravenous products that are in clinical development. We plan to begin dosing DM1 patients in the first half of this year in a phase I multiple ascending-dose trial with DT-818. The initial results are focused on safety and an evaluation of the correction of missplicing. Those data are anticipated next year.
In summary, Design is conducting programs in three significant areas of unmet need with clinical studies: FA, FECD, and DM1, with data anticipated both in the second half of this year and next year. Success in any one of these programs could create a significant opportunity for advancement and creation of value. We ended the third quarter with $206 million, which gives us significant runway to conduct these programs and hopefully obtain a clinical proof of concept. We also continue to pursue Huntington's disease, as it also illustrates the potential of our GeneTAC small molecule approach. Thank you for your interest, and I have a few minutes left for some questions.
Thank you so much, Pratik. That's very interesting, and we look forward to the data. Maybe we can start with a couple of questions on Friedreich's ataxia. Just to clarify, you mentioned that any increase in frataxin levels would be a positive signal here for the study. When you say any increase, you mean compared to placebo or compared to baseline? How variable should we expect the placebo response to be? Is this a risk? If placebo is very variable, it may actually undermine the active response levels.
Okay, thank you for that question. We have done a number of measurements of frataxin in untreated individuals, and we see that really it's a biomarker that doesn't really move with placebo treatment. The comparison would be to a patient's own pre-treatment baseline level. When I say a significant increase in frataxin, it would be against a individual's own baseline. Now, having said that, we are also running in the background assessments of the frataxin levels seen in a population of untreated FA individuals, so that we have a clear understanding of what types of levels are observed in a population of untreated individuals to contextualize the magnitude of the response against an individual's own baseline.
Thank you. That's, that's very helpful. How should we be thinking about the frataxin levels in the plasma versus muscle? Should we expect a strong correlation there? Which one do you think is the best to focus on, if any?
I mean, I think, Now, frataxin by itself is not actually free-floating in plasma. It's expressed intracellularly and taken into the mitochondria. What we're doing is measuring frataxin from cells taken from whole blood, and that is a measurement approach that is most widely studied in the literature, and the natural history studies actually use whole blood frataxin as a measure to establish frataxin, not only as the monogenic root cause by definition, but also that, you know, frataxin levels have a established relationship to look at clinical status of an individual. Because muscle is an affected tissue, and we developed a muscle frataxin assay for our 2023 trials, we'll be looking at frataxin level in muscle as well.
I think, in a muscle, you know, you're limited in your time points of assessment. You can essentially do, you know, one pre-treatment muscle biopsy and one post-treatment, maybe two. I think that will give us a picture, a broader picture of what is the pharmacodynamic response to DT-216.
Perfect. Maybe one last question here. There are some debates around the size of the Friedreich's ataxia market, given that Biogen's approved drug sales are about $130 million per quarter. Any thoughts around the size of the market and whether the Biogen sales are not representative of the actual size?
Well, I mean, I think that the unmet need in this population is enormous. While it is, you know, a positive that there is some treatment option available for these patients, the approved product does not really address the genetic root cause of FA or have any impact on endogenous frataxin levels. It's understandable that there would be still an enormous need here for something that could address the root cause of FA. We know, based on essentially the prevalence and the magnitude of medical need, that the market opportunity here is significant.
Thank you. Makes sense. Maybe we can pivot to the DM1 program, which is of high interest, and your preclinical data are unique here. Are there any data, either preclinically or a correlation between preclinical and clinical data now that we have from many companies, to directly link the foci level in the body to functional outcomes or even splicing correction levels?
Right.
How should we be thinking about that? Clearly, you have a very differentiating data set on the foci, toxic foci removal. Here, up to 90%+ , if not 95%+ , compared to 50% and lower for everyone else. Any thoughts around the potential clinical translation of this effect?
Right. The root molecular pathology is driven by these toxic RNA tangles. This type of assay system using myotubes gives us a direct visualization of those toxic RNA tangles. In a sense, these foci are directly looking at the level of the tangle caused by the genetic mutation. Now, it makes mechanistic sense that if you have an impact on these particular levels of the toxic RNA tangles, that it ought to result in a improvement in splicing, and some improvement in splicing has now already been observed to result in clinically measurable improvements in myotonia in as little as 12 weeks in the video of a hand opening test, as an example.
It also makes sense, therefore, that if in the clinical studies thus far, there has been very encouraging clinical response, but still leaves a lot of medical need on the table to be addressed, that it makes sense that there could be a lot of different contributing reasons for that. One could be that you just need to go beyond muscle, and that the splice correction is sufficient, you just need a broader tissue distribution. An alternative, perhaps, a hypothesis, is that if one could get a more profound impact on that root cause RNA tangle, then that could result in a greater improvement in splicing and potentially a greater impact clinically. All of these possibilities are on the table.
I don't think a definitive answer is currently available to that question, but because DT-818 has multiple potential avenues to deliver additional clinical benefit, we look forward to generating data in our multiple ascending-dose study to address that question, hopefully more clearly.
Thank you. That's very interesting. We look forward to that. Maybe one last question. Let's assume you deliver data in Friedreich's ataxia in the second half. They look great, investors like it, they are convinced. What read-through does this have to your DM1 program, which will potentially have data in, let's assume, in the first half of 2027? My estimation doesn't come from you. You said 2027, but I assume first half.
I mean, I think that we are still at a stage where the GeneTAC small molecule approach has not established a definitive clinical proof of concept, even though we have very encouraging human data providing some evidence from 2023. If we had a definitive clinical proof of concept, I think in general, it would create, for the first time, evidence that this approach works. That being said, these are different molecules with the same sort of architecture and general platform. They bind to different repeats. The FA is a dial up, the DM1 is a dial down, so there are certainly, you know, molecule-specific factors at play.
Certainly, Kostas, we hope that you're right and that we see, you know, very good data and allows us to move a program forward to advance medicine in this field.
Perfect. This is very helpful, very interesting. We are on top of the 30 minutes, I believe. Thank you so much, Pratik, for joining us today. Thanks, everyone, for attending the Oppenheimer Healthcare Conference. We look forward to your data in the second half of this year.
Thank you for this opportunity and your interest.
Bye.
Bye-bye.