Design Therapeutics Inc Aktie

Good day, and welcome to the Design Therapeutics Conference Call. [Operator Instructions] Please note this call is being recorded. I would now like to turn the call over to Sean Jeffries, COO. Please go ahead.

I'm Sean Jeffries, COO, of Design Therapeutics. This presentation will contain forward-looking statements, including statements related to our development plans and other information that is not historical fact. Such statements are subject to risks and uncertainties and actual results may differ materially from those expressed or implied by such forward-looking statements. For more information regarding these risks and uncertainties, please refer to the press release we issued today and the risk factors in our most recent quarterly report on Form 10-Q. It is my pleasure now to turn the call over to Design Therapeutics CEO, Pratik Shah.

Thank you, on behalf of Design Therapeutics, I'm delighted to announce an earlier than anticipated read-out on our RESTORE-FA study, a multiple ascending dose study in patients with Friedreich Ataxia. The results we will share are based on 4 weeks of dosing from IV once weekly, conducted at 4 dose levels with a total of 16 patients in the study.

DT-216 P2, also known as DT216 for injection, was generally well tolerated. All adverse events were mild to moderate. There were no serious adverse events and no study discontinuations. We are very pleased to report that we are seeing significant increases in production of endogenous natural frataxin in both mRNA and protein and activity in both blood and muscle.

The frataxin increases are at levels that are potentially already providing therapeutic effects as measured by well-accepted clinical endpoints such as mFARS and upright stability score and also supported by patient-reported measures of fatigue. These data lead us to believe that DT216 for injection could represent a potentially best-in-disease profile in the treatment of FA.

To our knowledge, this is the first time, it has been possible to evaluate the clinical impact of increasing natural endogenous frataxin as a result of a therapeutic intervention, and it is gratifying to see what the potential of a small molecule genomic medicine can be. In the context of these data, we are now beginning to develop a plan for a potential registration path. We expect to have further clarity on these plans in the fourth quarter of this year.

FA is a debilitating condition that is caused entirely by a mutation in a single gene frataxin. This is a disease driven by low quantity of normal endogenous frataxin in production, starting with low levels of normal mRNA and therefore, low levels of protein resulting in downstream effects on the mitochondria and cellular function, and ultimately leading to dysfunction in a number of organ systems.

The approved drug called Skyclarys or omaveloxolone, target -- as the mitochondria, but does not impact frataxin. There are other companies pursuing approaches involving exogenous delivery of either frataxin infusion protein or by exogenous gene delivery by viral vectors. The mutation is a long GAA nucleotide repeat expansion tension in the first intron.

This causes low levels of mRNA production that can be readily measured as shown on the bar graph on the right. as compared to mRNA levels from a wild-type allele with very few GAA repeats. DT-216 is a heterobifunctional gene taxol molecule, that is designed to recognize these long GAA repeats, and crude epigenetic proteins to dial up the transcription of endogenous frataxin mRNA.

As a result, treatment of cells from FA patients resulted in a dose dependent increase in frataxin expression that does not exceed normal levels as shown in the blue bars. The pathogenic cascade is shown on this slide. As a reminder, the cause of the disease is in the DNA in the nucleus. And this is a disease of partexin quantity, not quality since the splice for taxinmRNA is identical between in patients and unaffected individuals. The assay employed in the clinical trial is specific for endogenous -- mRNA, as shown in step 3 and frataxin protein as shown in step 4.

We have previously demonstrated in pre-clinical studies that treatment with an FA gene tech molecule increased mRNA, which translated to protein and that the protein increase resulted in downstream effects, like increases in cis-aconitase activity as well as increases in cellular respiration and oxygen consumption, thereby restoring cellular function to levels comparable to unaffected cells.

To assess clinical impact on the Restore study, we have used multiple clinical measures. Today's update is based on the 4-week IV dosing cohorts of the RESTORE EF study looking at both biomarker and standard clinical endpoints like MAR or the modified Friedreich Ataxia rating scale, which was used by the approved drug as a primary endpoint in their pivotal study, upright stability score USS, a component of MRs which the approved drug is now using as a primary endpoint for the ongoing pediatric brave study.

Since fatigue is an important complaint for patients living with FA, we have used a well-established disease-agnostic fatigue scale called PROMISE that has been used in many other drugs. As a reminder, these are some of the salient observations reported by others on MRs in the FAA therapeutic landscape. The approved drug in the MOXY study demonstrated a 1.56 improvement in mFARS change from baseline over 48 weeks, and there was a 1.6 point improvement seen at 4 weeks.

Placebo group improved by 1 point at 4 weeks and worsened by 0.85 points by week 48, resulting in a group difference of 2.4 points. Lexio and Lamar have reported data from their open-label studies. Lexia observed an improvement of 2 points with an F16 and Larimar reported an MFR change of 2.25 points with an INNOVATE. Our 2-point changes thought to represent approximately 1 year of progression.

On frataxin levels, the natural history data demonstrate that endogenous frataxin blood protein is a surrogate marker for predicting clinical benefit and that any significant increase would likely be therapeutic. We had wanted to understand how DT216 would fare while key biomarker criteria. First, whether DT216 would increase mRNA, Second, whether there was evidence that this induced mRNA would result in protein increases; and third, whether DT216 had evidence of activity in both blood and muscle. We are delighted that the results show that we have met all 3 biomarker success criteria and further that the measured increased levels of frataxin in this study already show clinical impact at a level that would potentially place DT216 as a best-in-disease profile.

Here are the patient demographics. This was an all-comer study. the functional staging of ataxia or FA core4 indicates that the patient would require the use of a walking device like a cane or walker and an FA C score 5 indicates we'll chair dependence. Ten of the 16 patients were on background omaveloxolone therapy for an average of over 5 years. Now for the salient clinical and biomarker observations.

We are extremely pleased to have observed a 6.4 point improvement in mFARS at the 1 MPK IV dose. On Upright Stability Score, we observed a 2.7 point improvement. Placebo effect on MRs in the MAX study at 4 weeks was a 1 point improvement Amir effects in previous FA studies have not exceeded 3 points and on a USS, a 1 point improvement would be beyond the 95th percentile confidence interval of any placebo study seen previously in FA.

Although no head-to-head study was conducted, the results are striking and a comparison between the MFRS and USS changes to the placebo groups in the MAX study is shown in the footnote show comparative significance in an exploratory ad hoc cross-study comparison. The observed effects are add-on methods in patients already on standard of care. These graphs show the data from all of the doubles. MFRS is a composite score and contains a number of subdomains and therefore, tends to be more variable.

The upright stability score component of MRs is less placebo responsive and less variable. USS on the right evaluates balance, stance and gate. It is the least variable component of MFRS and the dose response relationship is particularly striking. On fatigue, an important complaint for patients had 1 MPK a greater than 6-point improvement in the promised fatigue scale. You can see that the 0.1 MPK dose group is acting like a placebo. We see a magnitude of improvement that far exceeds the 3-point change, which is considered a minimal important change.

The responder table on the very right column, shows a dose-dependent increase in the number of responders with greater than 5-point improvement in the promised scale. We also observed that the impact appears to be somewhat persistent at 2 weeks post fourth dose. Now let's look at the biomarker response. Dose-dependent increases in endogenous frataxin were observed following treatment with DT216 P2 across Rituxan mRNA and protein assays in whole blood as well as frataxin in mRNA measurements in affected muscle tissue, demonstrating activity in both blood and muscle.

Following 4 weeks of treatment at 1 MPK Whole blood for tax in mRNA levels increased by 65% from baseline. Whole blood frataxin-M and frataxin-E-protein levels increased by 22% to 27% from baseline 2 weeks following the last dose. Muscle for tax in mRNA levels increased by 42% from baseline. Together, these findings provide comprehensive biomarker activity with meaningful increases in frataxin mRNA and protein as well as activity in both blood and muscle caused by DT216 P2 treatment. The dose-dependent biomarker data provide mechanistic support for the observed dose-dependent clinical improvements in FA patients.

The observed increases in both isoforms off frataxin protein, measured by different assays provide conclusive evidence that the increases in mRNA from DT216 treatment resulted in increases in frataxin protein. Protection M is predominantly membrane bound inside the mitochondria matrix. And Protexin E is largely found in mature red blood cells. Further, the protein has been described in the literature to have a half-life of over a week, and the persistence of protein levels 2 weeks after the last dose. This is consistent with the expected behavior of endogenous natural for tax in protein. The mRNA has a shorter half-life and it also makes sense that it would go back to baseline 2 weeks after the last dose.

Mature red blood cells have no nucleus and therefore, no target sequences for DT-216 and have an average lifespan of approximately 4 months. Therefore, the observed frataxin E increases can only come from erithrosic precursors in the bone marrow that were exposed to drug in the few weeks since the beginning of dosing. And we estimate that Protexin protein increases are coming from the quarter to 1/3 of newly produced mature red blood cells that have been produced since the beginning of dosing.

It further confirms that DT216 is widely distributed. The individual responses in clinical measures by USS were best correlated to blood frataxin protein levels. DT 216 is generally well tolerated with serious adverse events or treatment discontinuations reported. All adverse events were mild or moderate. Adverse events considered possibly or probably related to DT216 occurring in more than 1 patient or mild-to-moderate transient ALT elevations observed in 3 patients, all of whom were asymptomatic with no associated increases in bilirubin. All 3 were on background omaveloxolone. As indicated, for example, in the KOL note from an analyst report, and I quote LFT increases with Sky Claris appeared to correlate with response in the clinical trial and may reflect an on-target metabolic effect rather than liver toxicity.

The broader implication is that AST/ALT elevations could potentially appear with other agents that restore fitaxin in the liver. Based on these data, we believe we have identified a suitable dose and route of administration had 1 MPK IV weekly to advance toward a registration path. The timing and venue of future data updates is TBD because of the shift in focus to registrational planning. We anticipate providing an update on registration plans in the fourth quarter of this year.

We want to sincerely thank the patients, the FA community and all of the people that have supported design for your part in pioneering these efforts to advance small molecule genomic medicines. Thank you very much.

[Operator Instructions] Our first question comes from Leonid Timashev with RBC.

Congratulations on the data. Just wanted to clarify something on the biomarker slide, it says that the statistical significance was against untreated individuals. Does that mean that this was the patient baseline? Or was there another cohort being compared to? And then maybe just a follow-up on that. Can you just help contextualize for us some of the benefits that you saw across these functional endpoints, maybe but the variability on a normal MFAR might be in the significance of that 6 points.

Yes, in relation to the biomarker, as is typical when a value of frataxin, all of these values are normalized to patients baseline, and so you're observing kind of increase over baseline or percent of baseline. The comparison was done to values measured in untreated individuals over time to understand the typical longitudinal variability in the FA patient population.

And on the second question, your second question about MFAR variability. The variability is shown in the data in the graph. It's a striking effect. These levels of changes that are far beyond anything ever observed in FA studies. And if you look at the applicability score component of the fires that is known and acknowledged to be the least variable component of mFARs. And in the upright stability score, there are published papers showing that across all previous studies in FA, the placebo groups don't really move very much and that a 1-point improvement in U.S. would be beyond 95 percentile confidence interval of any previous study seen.

And so that gives us a sense of how these data map, and that's actually 1 reason why we conducted some of these post Hawk statistical evaluations to confirm that these changes are striking as we can see.

Next question comes from Costas Valaris with Oppenheimer.

Congrats on the strong data. Maybe a couple of questions from us. The first 1 is, given these impressive clinical effect you observe -- would you say that some of this effect comes from drug penetration and effect in other tissues beyond the blood and the muscles that you measure? And the second question is although you touched on a little bit on that, can you talk a little bit about the individual level correlations between biomarkers and clinical endpoints. Thank you and congrats again.

Thank you so much, Costas. I think on your first question, yes, we have observed in preclinical studies the DT 26 is widely distributed across all affected organs and throughout the body. And we think it is quite plausible and very reasonable infer that based on these clinical effects observed that these may well be coming from the wide distribution properties of DT 216 beyond the specifically measured organ systems where we can generate direct evidence of target engagement.

And we know that from preclinical studies, the DT216 is CNS penetrant. On your other question, it's interesting. This is probably the first time that 1 can actually go back and see if the predictive surrogate markers from the natural history studies, how they actually fared in regard to having a relationship with observed clinical effects. And we have done an analysis on individual responders in the clinical measures or responses in clinical measures by U.S. and they were best correlated to blood frataxin protein levels, which is exactly what has been at the center of the natural history studies that concluded or demonstrated that blood protein would be a good surrogate. And as long as it's endogenous blood protein.

Our next question comes from Adam Vogel with Craig Hallum.

Congratulations team on the solid data. So given FA is typically a slowly progressive disease, what's the biological rationale here for seeing this degree of improvement after only 4 weeks of dosing, and then just maybe quickly on durability and long-time longer-term dosing. Should investors expect continued improvement with longer treatment or stabilization after initial dosing or maybe even some attenuation over time?

Thank you so much. I mean the biological rationale has always been that in a monogenic disease, where we know exactly what the root cause is and its low quantities for tax in we've taken the approach of having a molecule that engages the GA repeat expansion, increasing frataxin expression, that's endogenous, and the prediction had been that this type of biomarker activity would translate to clinical benefit. So this mechanistic chain where you have the target, the biomarker and the clinic that's exactly the thesis that we've been building towards.

And we have seen in medicine that when one can provide a therapy that directly replaces something that might have been missing naturally or can cause the body to produce the natural missing quantities of protein that it is actually precedented in a sense that those types of interventions can have significant therapeutic effects.

I think on your question about duration, of course, it remains to be determined. It is a progressive disease, you know, mitochondria are expected to rapidly respond, but our goal remains to try and provide a best-in-disease profile therapy as we continue to develop this program, and it remains to be seen exactly how that plays out. But in the case of the approved drug, the response is also seen early at 4 weeks and essentially sustained through the duration of the pivotal study period at week 48. So we consider that to be encouraging.

Our next question comes from Joe Schwartz with Leerink Partners.

And congrats on the exciting results I was just wondering how uniform are the clinical benefits that you've seen in the 1 mg per kg cohort. Were all patients clear responders? Or was the mean 6.4 point benefit driven by any outliers? And then given upright stability score is part of mFARS, I'm just wondering how much of the total 6.4-point benefit was explained by the 2.7 point improvement and how much might have come from the other components like ballbar upper limb and lower limb components?

Yes, Joe, the -- on the mFARs, all of the patients in the 1 mg per kg cohort showed improvement. So this was, I think, broadly observed. You can see from the numbers that the USS is 2.7 versus the 6.4 million points improvement, so that's slightly less than half of the improvement in mFARs, but we also saw improvements on the other scales. Additionally, in the promise actually, again, all 4 of those patients saw improvements on promise and 3 of those 4 saw improvement above 5-point improvements, which is certainly well above the 3 points typically thought of for minimal important change using this measure.

And then if I could just squeeze 1 more in. Will you report any more data from RESTORE FA in the second half, such as more patients getting the IV or results from subcu or even response exposure analysis showing how to correlate the concentrations that patients are achieving and blood or muscle compares to what you thought you needed to achieve to get this kind of effect and maybe even correlations between for frataxin and functional changes?

Yes. The RESTORE FA study will continue to stay ongoing. -- for -- to support dosing for more extended periods than we've shared data from the timing, we will anticipate -- we do plan to share more data in the future, but the timing and the venue of future data updates is still to be determined. We believe we have an active dose and route of administration that we would like to advance toward registration.

And of course, during the ordinary course of development, it would be natural for us to plan to explore other parameters to understand the various variables, for example, maybe potential future regimens, potentially less frequent dosing intervals, subcu administration, we view all of those topics as not on the critical path.

Our next question comes from Ionnis Souroutzidis with Cantor Fitzgerald.

Folks, appreciate the time today, and congrats getting on the stellar data here. Two quick ones, I guess. One, could you maybe walk through a little bit more carefully how the baselines were, I guess, calculated with regards to the biomarker changes, as you mentioned, have been versus natural history. And was that same methodology applied for the functional endpoints as well? And then I have 1 quick follow-up.

I think I understand your question is just what were the baselines and the baselines of these patients, it is an all-comer study. So certainly a broad range but within expected values of the natural history study. And all of these values are normalized to baseline. This is typical for both the clinical and the biomarker endpoints in Friedreich Ataxia and really the best way to analyze this data is to look at change from a patient's own baseline. Does that answer your question, Ioannis?

I think so, but just to confirm, the changes we are seeing here are then directly tied back to the patient's own baseline or to a kind of cohort analysis of natural history and how those SP1 End points change over time?

No, this is all correlated with the patient's own baseline measured prior to the start of dosing.

Understood. Okay. And the follow-up was just between the M&E isoform, obviously, much more kind of time to blood cell turnover I guess, is there a particular reason you guys see such a congruence between the 2 versus maybe having larger increases in FX?

Well, they are both made from the same gene. And so that would explain the congruence because once you dial up the gene it would be natural for the RNAs to be made in all of the natural isoforms to be made. And so to us, this is all consistent with what the literature says.

And again, congrats, truly outstanding here.

Our next question comes from Faisal Khurshid with Jefferies.

I just want to ask a few quick questions on regulatory progress. So one, what does the time line look like for engaging with the FDA? Do you plan to seek breakthrough designation? And then lastly, is there any longer-term follow-up data from either the Phase I or from preclinical work that would be gating to a pivotal study?

Thank you. Well, with this recent data, this is the type of data we've been waiting for in order to develop a plan for advancing various things forward. Of course, as we think about the plans toward registration, it will involve all kinds of factors, including potential discussions with regulators. At this stage, given that we just got this information, we need time to kind of put all that together and put some thought into it. And so that's why we're planning to provide an update on these plans in the fourth quarter of this year. And I think yes, and all the things you mentioned are now on the table.

Our next question comes from Yasmeen Rahimi with Piper Sandler.

Congrats on the outstanding data. A few questions. One is were you able to within the cohort of patients to see that the patients who had an improvement in the most greatest for taxi levels across RNA protein model also exhibited sort of the greatest response in mFARS, sort of the correlation between these biomarkers as well as clinical end point Second question is I would appreciate, I don't know, 2 people have been paying us asking, what are the absolute free tax and protein levels at baseline and end of treatment.

And then the third one, is this validation is not only important for the FA program, but sort of big picture validation of the Gene Tap opportunity. Would love to hear your thoughts, how you're thinking about with this data set, what it means for building out the pipeline?

Okay. Thank you for the question. On your first question, yes, we did look at correlations across various clinical and various measurement approaches to the increases in endogenous for taxi. And interestingly, the individual responses in clinical measures really show up most clearly in U.S. That's because that's the least responsive to placebo. And of all the different ways of measuring frataxin perhaps as predicted by the natural history study, it's the blood of frataxin protein that best correlates the clinical responses at an individual level to the blood frataxin protein responses.

So I think that's a learning from that type of analysis. I think on your other question about the platform. Certainly, for the first time, seeing validation of the platform clinically is very exciting. And it certainly strengthens our conviction in the GeneTAC molecule approach. We have other programs, as you know, in various other monogenic conditions.

On the other hand, of course, every program's molecule is unique. And so each program has its own considerations, but certainly, a very exciting day for design to have this type of clinical validation. Sorry, I think you may have 1 more question that I missed, you want to...

Absolutely. Just a question around absolute changes in the...

So on that point, the we've described in the past and as most thoroughly in the last quarter's update, that because there are no agreed normalization quantitative standards in the FA protein measurement field. It is not possible to provide a cross-company comparator common Y axis, okay? So that's just not -- that's work that's just not been done and not possible. However, One thing that we've done a lot of work on is we ran studies in untreated patients and healthy individuals to understand the performance of these various assay systems to not only look at the assay variability, but also the relative levels in different settings.

And one of the conclusions we shared from those studies is that it's the whole blood mRNA assays that are the tightest and have the least overlap between patient levels or frataxin and healthy carriers. And so maybe to just -- you've seen, I think, in this biomarker data, a 65% increase in that parameter in whole blood frataxin mRNA. And just to share some benchmarks from the reference studies we ran, the 90th percentile increase in FA patient population untreated was about a 24% higher level than average, that's within the patient population and that the healthy carrier range in that assay system began at about a 46% increase relative to the patient population.

So I think that gives you a sense as a matter of context, and those numbers are different across different assays and different levels of variability, but we believe that the whole blood frataxin mRNA assay is best suited to understand the 216 induced frataxin in the context of the broader population.

Thank you. I'm showing no further questions at this time. I'd like to turn the call back over to Pratik Shah, CEO, for closing remarks.

Thank you very much. Well, we are Again, very appreciative of everyone joining us this morning and for your questions. Before we close, I just want to thank the patients, the families and the investigators in RESTORE FA. You made this morning possible, and the FA community is the reason that this work matters. We look forward to updating you in the months ahead. Have a good day. Thank you for your participation. You may now disconnect.

I'm Pratik Shah, CEO of Design Therapeutics. During this presentation, we will use forward-looking statements with regards to our business, R&D activities and financial conditions, which are subject to known and unknown risks and uncertainties. Actual results may differ materially due to various important factors, including those described in the Risk Factors section of our most recent Form 10-Q filed with the SEC.

Given the nature of the interest in the FA program and the design of the RESTORE-FA trial, we're delighted to provide a general update on our FA program, the key objectives of the RESTORE-FA study and the multiple biomarker endpoints being evaluated. And we're using this quarter's update to provide further context on how we're thinking about the study. The trial is proceeding well, and we're looking forward to data in the second half of 2026.

As a reminder, FA is a debilitating condition, which is caused by mutation in a single gene called the frataxin gene. The mutation causes low levels of production of frataxin, which causes all kinds of downstream dysfunction in multiple organs. There is an approved drug for FA called omaveloxolone, which targets Nrf2 and not frataxin. The mutation causing FA is a GAA-GAA repeat expansion in the first intron of the frataxin gene, which causes the level of normal mRNA to be low and therefore, levels of protein to be low. DT-216 is a heterobifunctional gene-targeted chimera or GeneTAC small molecule that is designed to recognize these long GAA repeat expansions and dial up normal frataxin RNA transcription.

Cellular data suggests a hypothesis that 10 nanomolar levels may be sufficient to increase frataxin as long as there is sufficient duration of exposure. So the green bar is 10 nanomolar of drug on iPSC, patient-derived terminally differentiated neuronal cells, and it shows that these levels increase mRNA and protein. The orange bar shows 100 nanomolar. While 100 nanomolar looks better initially, as long as there is sufficient duration, 10 nanomolar appears to give full pharmacology in cells.

What do we know about what drug levels may be sufficient in humans? So from our previous clinical studies from 2023, plasma exposures at day 2 are approximately 40 to 75 nanomolar and correspond to approximately 8 to 10 nanomolar drug levels in muscle. Our day 2 response data show that this results in an unmistakable increase in frataxin RNA expression. The frataxin levels drop off after day 2 because the drug is gone.

And what we see here is a single-dose pharmacokinetic profile from the current drug product, DT-216P2. And in the purple curve, approximately 40 milligrams gives us sustained levels of 40 to 75 nanomolar all the way till the end of 1 week, supporting weekly dosing, in which, with multiple doses, it would be expected to build to a higher steady-state level. So based on these exposures, we started a multiple ascending dose study in FA patients called RESTORE-FA. The trial is proceeding well, and we are looking forward to data in the second half of 2026. Accordingly, with this quarter's update, we're using the following slides to walk through additional elements of the trial design ahead of sharing data in the second half of this year.

So this is the dosing design in the RESTORE-FA study in patients with FA. So when we began the study, we had 4 weeks of non-clinical tox coverage. This was mid last year. And for both that reason and in order to get to the target exposures more quickly that we showed 2 slides ago in the purple line, the escalations go from 0.1 mg per kg to 0.3 mg per kg to 0.6 mg per kg in the 4-week context. And as a reference, the approximately 40-milligram single-dose PK from the single ascending dose trial in healthy volunteers is the 0.6 mg per kg dose level.

In order to generate additional exposure, we have started a 1 mg per kg group in 4 weeks, and to enable 12-week data update in the second half, we have also incorporated 12-week treatment cohorts, including the 1 mg per kg group. We expect additional cohorts in the 12-week dose group, because the PK projections do support additional dose levels within the non-clinical safety exposures.

The subcu infusion dosing details are still being determined. Because the IV is fully bioavailable, we preferred using the IV first to determine dose levels ahead of subcu cohorts. As we have mentioned before, we are evaluating endogenous frataxin levels in both blood and muscle by looking at mRNA and protein. As is customary in clinical trials involving patients, we have included clinical exploratory endpoints, including mFARS or the Modified Friedreich Ataxia Rating Scale, which is commonly used in studies with FA patients, and was used by the omaveloxolone trials for initial approval. Upright Stability Score, or USS, is a component of mFARS, that's being used by the approved drug as a primary endpoint in the BRAVE study.

Fatigue is an important complaint for patients living with FA, and in particular, we're using a PROMIS Fatigue Scale, which is considered a validated patient-reported outcome and has been used in a variety of disease areas and multiple regulatory submissions.

The purpose of the RESTORE-FA study for us is, you know, threefold. One, to provide a go, no-go on the FA program. Two, to hopefully establish a clinical proof of concept. And three, to inform the regulatory path and probability of a potential future approval. Now in general, there are two broad regulatory frameworks. Under an accelerated framework, a particular single frataxin biomarker measurement is chosen as a primary endpoint, which would be based on potential future regulatory alignment.

So our goal with RESTORE-FA is to take the data from four measures across blood and muscle and mRNA and protein and zero in on a single biomarker as the potential primary surrogate reasonably likely to predict clinical benefit. Further, since observing clinical benefit would be expected under either framework eventually, it would be helpful to understand possible clinical endpoints that could be used to support a potential accelerated path and provide the basis for eventual full approval.

So the pathogenic cascade is shown here with the disease starting with an intronic mutation in the frataxin gene in the DNA. Now because the pre-mRNA made from the mutant gene is different, but the spliced mRNA is identical to the wild-type mRNA, just lower in quantity, our assay is specific to the spliced wild-type mRNA. Once the spliced mRNA is made, the rest of the cascade is intact in patients with FA. So patients make protein normally, lower in quantity, and both mRNA and protein are measured in the clinical trial.

Now we've reported in the past that the protein made in cellular systems by treating with an FA GeneTAC molecule is functional, as measured by increases in downstream effects like cis-aconitate levels, and that's in the science paper, and by increasing mitochondrial function as measured by cellular respiration and oxygen consumption by the cells. This was reported by us at a scientific meeting. And as shown in this cascade, clinical effects would be downstream of the cellular effects, and they are being assessed in the clinical trial.

Now an area to spend a moment on is our choice of various measures of frataxin as a biomarker. The first point to address is, why we selected whole blood and muscle to measure frataxin response. Well, endogenous whole blood protein was chosen, because it is the tissue and biomolecular analyte that is at the center of the natural history data, which has been generated to establish frataxin as a reasonably likely surrogate for predicting clinical effects in the literature, and therefore is the most robust biomarker from a future regulatory alignment point of view.

Now there is some data using whole blood RNA, and unfortunately, very little information about muscle RNA or protein in the literature. So eventually, when a single analyte is chosen, we believe, for purposes of regulatory alignment, it would potentially need to bridge to blood protein to directly reference the natural history studies. But the muscle biomarkers were chosen, partly because we had the assay from our previous studies, and it is another affected tissue.

The second question is, do we know how these different assays perform with regard to longitudinal variability and assay variability? In other words, if one were to measure the same analyte in the same tissue at 2 different time points, how do these assays perform? As we had mentioned previously, we've been running studies in the background with the biomarker assays in untreated patients and healthy individuals to assess both assay performance and intra-patient variability. In general, these assays perform acceptably, although blood assays are tighter than the muscle biopsy-based assays.

As far as how to think about evaluating frataxin responses, for reasons noted both in the footnote and the cited paper, it's noted there's no normalized standards in the FA field, and because of things like assay variability and other such factors, change relative to baseline is considered the more robust readout in interventional trials rather than absolute frataxin thresholds. You can see that in the quote below. So we plan to report data in the second half based on change from baseline.

Now a third question we get on the biomarkers is, well, which of these assays can be best used to determine whether the drug effect gets into a carrier range? And to answer that question, we have compared levels by each of these assays to find the best one to answer that question, and the blood mRNA assay has the least observed overlap between patient and carrier levels, making that assay, in our opinion, best suited to make such a determination.

Well, how much frataxin do we believe is enough? No one really knows the definitive answer to this question yet, because no one has increased endogenous frataxin production. The answer will ultimately come from correlations between therapeutic clinical effects and frataxin levels. The natural history studies suggest that differences in frataxin levels between patients correlate as a continuous variable with all major clinical outcomes like age of onset, when is loss of ambulation, disease severity, disease progression. And further, based on commentary from other sponsors like Lexeo, it appears that they have alignment on the accelerated development pathway with frataxin expression as a co-primary endpoint to be evaluated for any increase from baseline rather than a numeric threshold.

So for the biomarker readouts, there are three central questions that we are attempting to answer with the RESTORE-FA data. Does DT-216 increase frataxin mRNA using either tissue? Does 216 increase frataxin protein using blood or muscle? And does it have activity in both blood and muscle using either mRNA or protein? The biomarker data scorecard is therefore on the right. The data readout will inform whether DT-216 checks zero, one, two, or all three criteria.

While it's not expected in the study at this stage to observe any clinical benefit, any clinical trends, if observed, could be useful for designing future clinical studies. Ultimately, correlations of these clinical measures with frataxin levels will have to be used to understand how much frataxin increases are indeed therapeutic.

To that end, this is a summary of the clinical observations that have been seen with mFARS, which is a clinician-administered tool used to measure neurologic dysfunction and disease progression in FA. mFARS was used by omaveloxolone in their pivotal study, which is called the MOXIe study, as a primary endpoint. And approximately 2.4 point group difference between treated and placebo at 48 weeks was observed.

This reflects a change from baseline of 1.56 points against a worsening placebo, which worsened by 0.85 points over 48 weeks. The 1.5 or 1.6 point change from baseline was observed at week 4 and 12, but the placebo had improved by approximately 1 point at those time points. Therefore, over 48 weeks, the treated arm maintained its change from baseline against a worsening placebo group since this is a progressive disease. And to our knowledge, thus far, Lexeo reports a 2 point improvement change from baseline with an N of 16 at 6 months, and Larimar has reported 2.25 point improvement over baseline with an N of 8 at 1 year. The approved drug uses upright stability score, a component of mFARS, as a primary endpoint in the BRAVE study. USS is considered the most objective, least variable component of mFARS.

And lastly, fatigue is an important complaint for patients living with FA, and we're using a validated PRO scale called the PROMIS Fatigue Scale, which is disease agnostic and has been used for various regulatory submissions for other drugs. A 3 point improvement is cited in the publication below as an MIC or minimal important change.

Well, this completes our FA update. We look forward to the results of the RESTORE-FA study in the second half of this year.

All right. We're ready to get started. Welcome, everyone. I'm Josh Schimmer from the Cantor Biotech Equity Research team. I'm pleased to introduce from Design Therapeutics, we have Pratik Shah, Chief Executive Officer.

We're going back to some GeneTAC. So Pratik, thanks so much for joining. Why don't you frame Design Therapeutics and give us a quick overview of how the GeneTAC platform works?

What makes design unique and interesting is that we've developed a new class of small molecules that do something remarkable, which is that they dial up or dial down the expression of a single gene in the genome. And the way the molecules do that is they recognize DNA sequences through the minor group interactions, much like a transcription factor would. And they then recruit the appropriate transcriptional machinery to the locus to either dial up or down expression.

And so as you think about the role of individual genes in disease, there are many monogenic disorders where the single gene root cause is known, and we're working on several such monogenic conditions. One is Friedreich's ataxia. The other is Fuchs endothelial corneal dystrophy. The third is myotonic dystrophy and then Huntington's disease as our front-runner examples of monogenic diseases.

In Friedreich's ataxia, the problem is that the level of expression from the frataxin gene is low. and that's what causes the disease. And so what we've done with the GeneTAC platform is developed a molecule that can dial up the expression of normal endogenous frataxin despite the presence of the mutation that causes this disease, which is a very exciting prospect and goes after sort of the root cause of the condition. So if we can dial up frataxin expression in patients with FA, that could provide significant clinical benefit and value to patients and a value creation opportunity for investors.

In the case of the other 3 diseases, they are all caused by a toxic gene product derived from the mutant allele. And so the GeneTAC, in those cases, dial down the expression of the toxic RNA and/or protein, and that's how the GeneTAC is intended to create benefit. And so having an opportunity to do that in Fuchs corneal dystrophy, myotonic dystrophy and Huntington's disease is what we're looking to demonstrate hopefully with our clinical results.

And we're now in -- 2 of these programs are in clinical investigation currently, and we're looking forward to the results of those.

How do you get gene selectivity with this mechanism?

So one primary driver of selectivity is the ability to recognize the particular DNA sequence in the mutation. So in the case of Friedreich's ataxia, the molecules look for long GAA, GAA, GAA sequences, and there's generally a selective pressure against long repeat expansions in the genome because they drive genomic instability.

But in the case of Friedreich's ataxia, you have this GAA repeat expansion; where in a normal allele, you have a handful of repeats; but in a mutant allele, you have hundreds of repeats, sometimes over 1,000. And so that's an added layer or driver of the selectivity is when there are more binding sites all next to each other, that facilitates the localization of the molecule to the locus of interest.

And we've seen selectivity between the wild-type and mutant allele. In Friedreich's ataxia, we've seen this similar selectivity in the case of Fuchs corneal dystrophy where the wild-type allele is left untouched and -- in myotonic dystrophy as well as Huntington's.

What do we know about the frataxin expression in Friedreich's ataxia. I guess it's autosomal recessive, and so many patients have very minimal. There are actually some interesting clues because we talked to Alexion yesterday about what they're showing in the heart and actually how minimal enzyme activity might be required to start to normalize patients.

Yes. So when one looks at the literature of the level of frataxin expression, there are widespread reports that indicate that a carrier has approximately half the level of frataxin expression as non-effect -- as a non-carrier wild-type condition. And carriers are actually quite common, about 1 in 100 individuals are carriers of the Friedreich's ataxia mutation, but they're clinically unaffected. And so we know that there is some reserve capacity where you can go down to half normal expression and there have no clinical manifestation whatsoever.

Patients on average in the literature are reported to have about 20% to 25% of wild-type levels of frataxin. And it's a systemically expressed protein, and it's certainly encouraging to hear that any sort of increase in endogenous frataxin level could provide benefit. But that's really never been demonstrated. No one's ever really increased endogenous frataxin expression. And so we have an opportunity to potentially do that and see what level of increase might provide therapeutic benefit.

As a small molecule, are you able to address all aspects of Friedreich's ataxia? There's a neuro component, cardiac component. I'm not sure if there are any other components.

Yes. The small molecule naturally gets into cells and gets into the nucleus and binds to its target without any facilitation. These are not charged molecules. And so unlike other genomic medicine modalities, whether it's gene therapy, proteins, oligonucleotides, those all have to be either transfected in or somehow get into the cell.

So these small molecules, because they naturally get in, they distribute widely into a variety of organs, including all of the target organs you mentioned. And so there's simply an opportunity, more than one, target organ in which we might look for or potentially observe therapeutic benefit.

We're able to measure CSF concentrations with the first product iteration, and that will be a good segue into DT-216 and then ultimately 216P2.

Yes. We don't measure the drug level in CSF. In fact, it doesn't -- it really compartmentalizes more to the tissue. So it's not really -- readily observable. But in all of our nonclinical studies, we've looked at CNS levels of drug, and we believe we get adequate exposure in the CNS with a systemic administration to drive pharmacology.

And your next question was about 216?

216, yes.

Yes. So we had the opportunity to take our FA molecule, DT-216, into the clinic in 2022 and 2023. And in those studies, on one hand, we saw a nice demonstration that 216 actually can and does upregulate frataxin expression in patient studies. And that was seen in both peripheral blood mononuclear cells as well as in muscle as measured by a biopsy after treatment.

The issue that we ran into is that the previous formulation was not well-behaved, and there were 2 limitations that prevented that from continuing development. One was that we saw injection site thrombophlebitis that prevented us from considering increased dose frequency or dose levels because there were concerns around worsening of those reactions.

And the other is that the duration of exposure was very short. And so what was supposed to be a multiple-dose study with an increased expectation of steady-state levels, in hindsight, turned out to be a series of single-dose studies 1 week apart because the drug exposure was seen only for about 2 days. But despite that very short exposure at that day 2 time point, both in peripheral blood and in muscle, we saw an unmistakable increase in frataxin RNA expression. And that occurred at exposures of about 8 to 10 nanomolar which match nicely with our preclinical cellular exposure experiments that suggested that 10-nanomolar exposure was sufficient to drive full pharmacology as long as the duration of exposure was sufficient.

And so on one hand, we had validation that the mechanism works in humans. On the other hand, we realized at the time, we needed to figure out how to address both of these limitations. And I'm really pleased to see that here we are 2 years later and that we were able to create a new formulation of the same molecule that showed activity in humans and address both of these limitations.

So we've recently showed data from our single-dose studies in humans with the new formulation that we call DT-216P2. And that data shows that the exposure is -- the profile is more favorable. We like the PK, and we've published that. And we also have now sufficient evidence to support the view that this injection site thrombophlebitis that issue we had run into has now been resolved.

How did you solve it with formulation?

Originally, we had used sort of off-the-shelf excipients. And we took those forward into the clinic with the expectation that it would be fine. But after having the clinical experience that we did where we were surprised to see the short duration of exposure in the tissue, we went back and looked more broadly at novel-excipient space. And because this is a new chemistry and a new modality, we now have developed a different set of formulations that actually are much better behaved and allow us to progress into the clinic.

We know what the half-life of frataxin protein is as a guide to, like, ultimately accumulating protein with successive dosing?

It's a pretty longer protein. So the literature reports generally guide to a multi-day, potentially 2-week half-life. And once the protein is made, it is thought to be stably incorporated into the mitochondrial matrix, and that might explain why it has a long half-life.

And the consequence of having a long half-life protein is that like any long-lived analyte, it takes, as a rule of thumb, several half-lives for an analyte to clear and by -- corollary, it takes, say, 5 half-lives to also get to steady state. And so if we think about the time course in which a protein might get to steady state, that takes you into the sort of several week time frame, as a rule of thumb. And you layer on top of that, that DT-216 has a half-life that supports, we think, about a once-weekly administration. And that will take a few weeks to get to steady-state exposure. And so I think those factors have led us to target about a 12-week treatment duration for our final analysis for frataxin impact of 216.

So what are the next steps for the program now?

Well, we're in Phase II studies. It's the RESTORE-FA trial, where we're doing multiple ascending doses in patients with FA. And we're excited to be in that phase of the program, and we look forward to analyzing the totality of 12-week data sometime next year.

What doses are you exploring? And how do this compare to the exposure you achieved with the original formulation?

So we published some early PK recently with approximately 40-milligram dose that showed a very nice exposure relative to what was a comparable dose of P1. And so that data gives us comfort that we have in DT-216P2 a formulation that gives us the kind of PK profile we like.

Now we are in a dose-escalation study. And so we haven't yet determined all of the dose-escalation levels. We have a lot of flexibility in terms of both frequency and duration. So we're exploring various routes. We're doing an IV route as well as now we have subcu route of administration available. So we're exploring that in some cohorts.

And so we're working through that whole dose escalation schema, and we'll have more clarity on the timing of our readouts as we finish up planning our operational study execution.

And what do you expect you need to bring to the FDA to contemplate a registration trial and [design]?

Our focus right now is on generating data to see if we can restore endogenous frataxin, and that's our current objective. In terms of registration, we're just looking -- we're following, with interest, the conversation, reports from other sponsors in the FA space, and we find the reports from those sponsors to be encouraging, both in terms of the FDA's appreciation for the level of unmet need in this population as well as potentially what looks like there might be an openness to considering surrogate endpoints for potential registration. But until we have endogenous frataxin data, we won't really have an opportunity to engage with the agency on those conversations.

On the clinical side of the development path, are you thinking more cardiac symptomatology or neurosymptomatology to kind of guide that registration strategy?

We have an opportunity to look at a variety of potential impacts. So right now, our focus is on seeing what sort of a frataxin [registration] we're able to get. And then either of those avenues could be fruitful.

Would the mechanism, in theory, be complementary to gene therapy by getting even further expression of frataxin, whether it's in the heart or -- I think there are program -- gene therapy programs targeting the CNS as well?

Yes. I mean I think the goal of the GeneTAC approach is to increase endogenous frataxin. And so until we know what the impact is of exogenously delivered frataxin on patients clinically, it's hard to say. But our hope is that by addressing endogenous frataxin production for the patient's own cells under natural regulatory control that, that we hope would be sufficient to address the need. But sure, there are certainly scenarios in which it could be complementary to other therapies.

SKYCLARYS from Biogen now annualizing around $500 million a year. Do you think that kind of generally defines the market? Or is it likely to be much bigger with either -- for whatever reason, broader penetration and/or global expansion?

Yes. I mean I think the -- it's wonderful to have an approved therapy for patients living with FA and both the acquisition of Reata as well as the performance of SKYCLARYS, I think, has sort of validated the value creation opportunity in FA. But SKYCLARYS doesn't really go after the root cause of Friedreich's ataxia. And so I think in general, the field is very much looking forward to a therapy that goes after sort of the fundamental root cause of FA and believes that, that can create enormous value for patients.

Maybe we can turn to the Fuchs endothelial corneal dystrophy program that you mentioned initially. You recently had some Phase I data for DT-168. Remind us what this condition is, what causes it and how you're solving it?

Yes. So Fuchs corneal dystrophy is a progressive corneal disease. And it's actually diagnosed relatively early and readily, often in annual eye exam at an optometrist office. And it's thought to be quite frequently diagnosed. The Centers for Disease Control has an IRIS Registry that estimates approximately 2 million diagnosed cases of Fuchs corneal dystrophy in the United States.

And unfortunately, there are no real disease-modifying treatments for Fuchs corneal dystrophy. So patients are unfortunately in a situation of sort of subject to a progressive loss of visual quality until the disease is so advanced that the treatment at that point would be to get a cadaveric corneal transplant surgery.

And so patients are in this situation where you kind of suffer through this progression until it's so bad that it justifies a surgical procedure. And so that's the current state of affairs in Fuchs corneal dystrophy.

Mechanistically, this is driven by a loss of cellular health of the interlayer of the cornea, which is the corneal endothelial monocellular layer. And the reason these cells are dysfunctional is they carry a single mutation. Now this has been known to have a big family history component. But it wasn't until maybe a decade ago that the specific gene was identified as the TCF4 gene that causes this cellular dysfunction, which then leads to Fuchs corneal dystrophy. And the mutation is called CTG18.1 in about 60% to 80% of patients with Fuchs corneal dystrophy.

And the reason this mutation causes the disease is that the single bad allele of TCF4 creates a toxic RNA. And that toxic RNA creates a foci, which you can see under a microscope. So if you take cells from -- that would be typically discarded from a corneal transplant, and you look under the microscope, you can see these RNA toxic foci in the nucleus.

And so what we've been able to do is create a GeneTAC molecule, which is DT-168, that dials down the expression of that toxic RNA. And you can see these foci vanish after drug treatment in cells taken from corneal transplant patients, ex vivo. And so the opportunity now exists to potentially modify the course of this condition, and we've been able to formulate this as an eye drop, which is remarkable. And so the exciting possibility here is to have an eye drop that would slow or stop the progression of Fuchs because if you can get rid of the foci and allow the cells to stay healthy and survive, there is the potential to change the course of the disease.

What can you learn from kind of an early Phase I study to inform next steps [to] maybe take us through that?

So the Phase I study that we conducted was primarily to confirm the tolerability and safety of the eye drop in healthy volunteers, and we're delighted to say that the study went well and that eye drops were well-tolerated. So our focus now is on trying to see if we can generate evidence that DT-168 does what it was designed to do in the cornea of patients with Fuchs.

And so we've been looking for whether a biomarker could exist for this type of a situation. And the literature really doesn't have any demonstrated biomarker. So we ran a study looking at whether you can detect splice defects as a result of these toxic RNA foci, and we were able to successfully identify splice markers that show a difference in corneal cells from Fuchs patients versus corneal cells from unaffected individuals. And those splice differences were large enough that we felt that it could potentially serve as a biomarker for the DT-168.

And so to conduct this type of clinical study, what we would be doing is taking patients who are already scheduled for corneal transplant anyway and treat them for approximately a month or more with DT-168 eye drops so that when those corneal cells are available, we can look to see if the splicing was, in fact, affected in a therapeutic fashion as a result of 168 eye drops.

And so that's a very exciting. It's a novel design. There's some limitations to this approach because you can't take a pretreatment baseline version. But if it works, it would be really a remarkable demonstration that DT-168, in fact, does, as an eye drop, what it was designed to do, which then sets us up for dose selection and a longer-term study looking for the ability to slow or stop progression of Fuchs.

So you might not have the benefit of a baseline, which might make the results very hard to interpret. On the other hand, if you had a comparator arm untreated, still a bunch of [noise that] it might start to give you...

Right, right. And we have that at this point. So we have the data for splicing from untreated individuals, and we have splice data from unaffected individuals. And so we can see that what a normal splice pattern might look like and what an untreated splice pattern looks like. So the idea here is, is the treatment effect large enough that it actually looks closer to the unaffected individuals than the untreated individuals.

What kind of -- how tight is that data? Or what kind of variability is it, which will kind of determine the sample size you might need to have a more precise answer?

Yes. We published that and presented it at the [Accelerator] meeting just prior to ARVO this year. And so that data is in our corporate deck. And you could see across several splice events that there is a nice separation between affected and unaffected splice levels. So our initial approach is to go in with a few dozen individuals as a sample size to start, but it's an exploratory study, and we'll find out as we go whether this approach gives us confirmation of the activity of 168.

What are approval endpoints you might contemplate for a registration trial?

That's something we're evaluating in a separate trial that we're running. It's the observational study, is how we're terming it. And there, we're looking at 3 domains of endpoints because no one's really run clinical studies with these endpoints in Fuchs corneal dystrophy.

So we're looking at visual quality measures to see how reliable they are, how do they -- how noisy are those endpoints. We're looking at a second set of domain, which is a measure of corneal edema, which is functionally the driver of the poor visual quality. And so we can now directly measure corneal edema with precision instruments. There is a Scheimpflug tomography approach to measuring corneal edema. So we're deploying that.

And then we've got a third domain, which is trying to borrow, if you will, a page from the geographic atrophy playbook, trying to look at imaging endpoints. And so we're looking at directly visualizing the corneal endothelial cells using specular microscopy. And so once we have results from our observational study, which is now fully enrolled and we have approximately 100 individuals that we'll be following up on, we will be able to choose endpoints and potentially patient enrollment criteria to inform a registrational trial.

Given the mechanism, would you generally expect a stabilization effect? Or is there any reason to think you might actually improve the [earnings]?

Well, from an unmet-need standpoint, anything that would slow or stop the progression of Fuchs would be highly welcome already. And so that's our base case target, is to see if 168 can improve that. Now of course, if, in any disease condition, one can actually reverse disease, that's always a remarkable thing. But at the moment, we've heard universally that anything that would slow or stop the progression of Fuchs would be welcome.

You also have a DM1 program. When do you expect to select a development candidate? And how quickly could that move...

We expect to select a DC this year. And then alongside the selection is when we'll be able to project a likely path to both getting in the clinic and potentially clinical data.

Again, like leveraging the advantage of a small molecule benefit to target beyond muscle components of the disease, how are you thinking about kind of the positioning of this relative to some of the other more advanced therapeutics that have already reached Phase III?

There's many opportunities for us to potentially be best-in-class. First is that the molecule has a mechanism that works upstream of all of the other mechanisms that are further along. And as a result, the pharmacology we've seen in cells from patients is much more profound than has been seen with the molecules that are further in development. And so that's, of course, the most exciting possibility.

In addition, we have selectivity for the mutant DMPK allele. We distribute very widely across a wide range of tissues and don't require any sort of transferrin receptor-mediated modality. We have also potentially a subcu route of administration option, whereas all the other therapies are intravenous. So between selectivity, distribution, inherent pharmacology, there's lots of opportunity here to be potentially best-in-class.

And do you have the resources to advance all the programs? Or do you think you're going to have to partner any?

We have -- we ended the quarter with $216 million. We feel that we have plenty of capital to execute on trying to get to hopefully a clinical POC on one of these.

We're looking forward to the updates across the portfolio.

Thank you so much.

Thanks so much for joining, and thanks, everyone, for tuning in.