Good day, and welcome to the Design Therapeutics conference call. At this time, all participants are on listen- only mode. After the speaker's presentation, there'll be a question- and- answer session. To ask a question, you will need to press star one one on your touchtone telephone. Please note this call is being recorded. I would 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 am delighted to announce an earlier than anticipated readout on our RESTORE-FA study, a multiple ascending dose study in patients with Friedreich ataxia. The results we will share are based on four weeks of dosing from IV once weekly, conducted at four dose levels with a total of 16 patients in the study. DT-216P2, also known as DT-216 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 DT-216 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 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, targets the mitochondria but does not impact frataxin. There are other companies pursuing approaches involving exogenous delivery of either frataxin fusion protein or by exogenous gene delivery by viral vectors. The mutation is a long GAA nucleotide repeat expansion 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 GeneTAC small molecule that is designed to recognize these long GAA repeats and recruit 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 frataxin quantity, not quality, since the spliced frataxin mRNA is identical between patients and unaffected individuals. The assay employed in the clinical trial is specific for endogenous spliced mRNA, as shown in step three, and frataxin protein, as shown in step four.
We have previously demonstrated in preclinical studies that treatment with an FA GeneTAC 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 in the RESTORE-FA study, we have used multiple clinical measures. Today's update is based on the four-week IV dosing cohorts of the RESTORE-FA study, looking at both biomarker and standard clinical endpoints like mFARS 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 mFARS, 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 PROMIS that has been used in many other drugs. As a reminder, these are some of the salient observations reported by others on mFARS in the FA therapeutic landscape. The approved drug in the MOXIe study demonstrated a 1.56- point improvement in mFARS change from baseline over 48 weeks, and there was a 1.6- point improvement seen at four weeks. The placebo group improved by one point at four weeks and worsened by 0.85 points by week 48, resulting in a group difference of 2.41 points.
LEXEO and Larimar have reported data from their open- label studies. LEXEO observed an improvement of two points with an N of 16, and Larimar reported an mFARS change of 2.25 points with an N of eight . A two-point change is thought to represent approximately one 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 DT-216 would fare on three key biomarker criteria. First, whether DT-216 would increase mRNA. Second, whether there was evidence that this induced mRNA would result in protein increases. Third, whether DT-216 had evidence of activity in both blood and muscle.
We are delighted that the results show that we have met all three 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 DT-216 as a best in disease profile. Here are the patient demographics. This was an all-comer study. The Functional Staging for Ataxia or FSA score of four indicates that the patient would require the use of a walking device like a cane or walker, and an FSA score of five indicates wheelchair dependence. 10 of the 16 patients were on background omaveloxolone therapy for an average of over five years. For the salient clinical and biomarker observations. We are extremely pleased to have observed a 6.4- point improvement in mFARS at the 1 mg/kg IV dose.
On upright stability score, we observed a 2.7- point improvement. Placebo effect on mFARS in the MOXIe study at four weeks was a one- point improvement. mFARS effects in previous FA studies have not exceeded three points and on a USS, a one- 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 mFARS and USS changes to the placebo groups in the MOXIe study, as shown in the footnote, show comparative significance in an exploratory ad hoc cross-study comparison. The observed effects are add-on benefits in patients already on standard of care. These graphs show the data from all of the dose levels. mFARS is a composite score and contains a number of subdomains and therefore tends to be more variable.
The upright stability score component of mFARS is less placebo responsive and less variable. USS on the right evaluates balance, stance, and gait. It is the least variable component of mFARS, and the dose response relationship is particularly striking. On fatigue, an important complaint for patients, at 1 mg/kg , we see a greater than six point improvement in the PROMIS fatigue scale. You can see that the 0.1 mg/kg low dose group is acting like a placebo. We see a magnitude of improvement that far exceeds the three- 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 five- point improvement in the PROMIS scale. We also observe that the impact appears to be somewhat persistent at two weeks post fourth dose. Let's look at the biomarker response.
Dose-dependent increases in endogenous frataxin were observed following treatment with DT-216P2 across frataxin mRNA and protein assays in whole blood, as well as frataxin mRNA measurements in affected muscle tissue, demonstrating activity in both blood and muscle. Following four weeks of treatment at 1 mg/kg , whole blood frataxin mRNA levels increased by 65% from baseline. Whole blood frataxin-M and frataxin-E protein levels increased by 22%-27% from baseline two weeks following the last dose. Muscle frataxin 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 DT-216P2 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 of frataxin protein measured by different assays provide conclusive evidence that the increases in mRNA from DT-216 treatment resulted in increases in frataxin protein. Frataxin-M is predominantly membrane-bound inside the mitochondrial matrix, and frataxin-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 two weeks after the last dose is consistent with the expected behavior of endogenous natural frataxin protein. The mRNA has a shorter half-life, and it also makes sense that it would go back to baseline two 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 four months.
Therefore, the observed frataxin-E increases can only come from erythrocytic precursors in the bone marrow that were exposed to drug in the few weeks since the beginning of dosing. We estimate that the frataxin-E protein increases are coming from the quarter to a third of newly produced mature red blood cells that have been produced since the beginning of dosing. It further confirms that DT-216 is widely distributed. The individual responses in clinical measures by USS were best correlated to blood frataxin protein levels. DT-216P2 is generally well-tolerated with no serious adverse events or treatment discontinuations reported. All adverse events were mild or moderate. Adverse events considered possibly or probably related to DT-216P2 occurring in more than one patient were mild to moderate transient ALT elevations observed in three patients, all of whom were asymptomatic with no associated increases in bilirubin. All three were on background omaveloxolone.
As indicated, for example, in the KOL note from an analyst report, and I quote, "LFT increases with SKYCLARYS appeared to correlate with response in the clinical trial and may reflect an on-target metabolic effect rather than liver toxicity." And quote, "The broader implication is that AST/ALT elevations could potentially appear with other agents that restore frataxin in the liver." Based on these data, we believe we have identified a suitable dose and route of administration at 1 mg/kg 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.
Thank you. As a reminder, to ask a question, please press star one one. If your question has been answered and you'd like to move yourself in the queue, please press star one one again. Our first question comes from Leonid Timashev with RBC. Your line is open.
Hey, guys. Congratulations on the data. Just wanted to clarify something. On the biomarkers slide, it says that the statistical significance was against untreated individuals. Does that mean that this was the patient baselines, or was there another cohort being compared to? Then maybe just to follow up on that, can you just help, you know, contextualize for us some of the benefits that you saw across these functional endpoints, maybe what the variability on a normal mFARS might be and the significance of that 6 points? Thanks.
In relation to the biomarker, as is typical when evaluating frataxin, all of these values are normalized to a patient's 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.
Great. Thank you. On the second question, your second question about mFARS' variability.
The variability is shown in the data, in the graphs. It's a striking effect. These levels of changes are far beyond anything ever observed in FA studies. If you look at the upright stability score component of mFARS, that is known and acknowledged to be the least variable component of mFARS. In the upright stability score, there are published papers showing that, you know, across all previous studies in FA, the placebo groups, you know, don't really move very much, and that a one-point improvement in USS would be beyond the 95th percentile confidence interval of any previous study seen. That gives us a sense of how these data map.
That's actually one reason why we conducted some of these, you know, post-hoc statistical evaluations to confirm that these changes are, you know, striking as we can see.
Thank you. Our next question comes from Kostas Biliouris with Oppenheimer. Your line is open.
Thanks for taking our question, and congrats on the strong data. Maybe a couple of questions from us. The first one is, given these impressive clinical effect you observed, would you say that some of these effect comes from drug penetration and effect in other tissues beyond the blood and the muscles that you measured? 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, Kostas. I think on your first question, yeah, we have observed in preclinical studies that DT-216 is widely distributed across all affected organs and throughout the body. We think it is quite plausible and very reasonable to infer that based on these clinical effects observed that, you know, 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. We know that from preclinical studies that DT-216, you know, is CNS penetrant. On your other question is, you know, it's interesting.
This is probably the first time that one 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. We have done an analysis on individual responders in the clinical measures or responses in clinical measures by USS, 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.
Thank you. Our next question comes from Adam Vogel with Craig-Hallum. Your line is open.
Great. Thank you. Congratulations team on the solid data. Given FA is typically a slowly progressive disease, what's the biological rationale here for seeing this degree of improvement after only four weeks of dosing? Just maybe quickly on durability and 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.
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 of frataxin, we've taken the approach of having a molecule that engages the GAA repeat expansion, increasing frataxin expression that's endogenous. The prediction had been that this type of biomarker activity, you know, would translate to clinical benefit. This mechanistic chain where you have the target, the biomarker, and the clinic, that's exactly the thesis that we've been building toward.
You know, we have seen in medicine that when one can provide a therapy that, you know, directly replaces something that, you know, 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, you know, of course it remains to be determined. It is a progressive disease. You know, mitochondrial energetics, you know, are expected to, you know, rapidly respond. You know, our goal remains to try and provide a best- in- disease profile therapy as we continue to develop this program. You know, it remains to be seen exactly how that plays out.
In the case of the approved drug, you know, the response was also seen early at four weeks and essentially sustained, you know, through the duration of the pivotal study period at week 48. We consider that to be encouraging.
Thank you. Our next question comes from Joseph Schwartz with Leerink Partners. Your line is open.
Thank you, 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 mFARS benefit driven by any outliers? Given upright stability score as part of mFARS, I'm just wondering how much of the total 6.4 point mFARS benefit was explained by the 2.7 point USS improvement and how much might have come from the other components like bulbar, upper limb, and lower limb components? Thanks.
Yeah, Joe, on the mFARS, all of the patients in the 1 mg per kg cohort showed improvement. This was, you know, I think, broadly observed. You know, you can see from the numbers that the USS, you know, is 2.7 versus the 6.4 points improvement, that's slightly less than half of the improvement in mFARS. We also saw improvements on, you know, the other scales. You know, additionally, in the PROMIS, you know, actually again, all four of those patients saw improvements on PROMIS, and three of those four saw improvement above 5-point improvements, which is, you know, certainly well above the three points typically thought of for, you know, minimal important change using this measure.
Great. That's super helpful. Thanks. If I could just squeeze one 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 subQ, or even response exposure analyses showing, you know, how to correlate the concentrations that patients are achieving in blood or muscle compares to what you thought you needed to achieve to get this kind of effect, maybe even correlations between frataxin and functional changes?
Yeah, the RESTORE-FA study will continue to stay ongoing for to support dosing for, you know, more extended periods than we've shared data from. The timing, you know, we do plan to share more data in the future, the timing and the venue of future data updates is still to be determined. We believe we have an active, you know, dose and route of administration that we would like to advance toward registration. Of course, during the ordinary course of development, it would be natural for us to plan to explore, you know, other parameters to understand the various variables, for example, maybe potential future regimens, you know, potentially less frequent dosing intervals, subQ administration.
We view all of those topics as not on the critical path.
Makes sense. Thank you.
Thank you. Our next question comes from Yanni Souroutzidis with Cantor Fitzgerald. Your line is open.
Hey, folks. Appreciate the time today and congrats again 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, at the, you know, versus natural history? Was that same methodology applied for the functional endpoints as well? I have one quick follow-up.
I think I understand your question is just, you know, what were the baselines. You know, the baselines of these patients, it is an all-comer study, so, you know, certainly a broad range, but within, you know, expected values of the natural history study. All of these values are, you know, normalized to baseline. This is, you know, typical for both the clinical and the biomarker endpoints, you know, in Friedreich ataxia. Really the best way to analyze this data is to look at, you know, change from a patient's own baseline. Does that answer your question, Yanni?
I think so, 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 endpoints change over time?
No, this is all correlated with the patient's own baseline measured prior to the start of dosing.
Understood. Okay. Thank you. The follow-up was, you know, just between the M and E isoform, obviously E, you know, much more kind of tied to red blood cell turnover. I guess, is there a particular reason you guys see such congruency between the two, versus, you know, maybe having larger increases in FXN M?
Well, they're both made from the same gene. You know, that would explain the congruence. Because once you dial up the gene, you know, it would be natural for the RNAs to be made and all of the natural isoforms to be made. You know, to us, this is all consistent with what the literature says.
Understood. Okay. Thank you. Again, congrats. I mean, truly outstanding here.
Thank you. Our next question comes from Faisal Khurshid with Jefferies. Your line is open.
Hey, guys. Thanks. Great question. If it's okay, I just want to ask a few quick questions on regulatory progress. One, what does the timeline look like for engaging with the FDA? Do you plan to seek Breakthrough designation? 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.
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, you know, all kinds of factors, including potential discussions with regulators. At this stage, given that we just got this information, you know, we need time to kind of put all that together and put some thought into it. That's why we're planning to provide an update on these plans, you know, in the fourth quarter of this year. I think, you know, all the things you mentioned are now on the table.
Got it. Thank you.
Thank you. Our next question comes from Yasmeen Rahimi with Piper Sandler. Your line is open.
Good morning, team. Congrats on that 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 frataxin levels across mRNA protein muscle also exhibited sort of the greatest response in mFARS, sort of the correlation between these biomarkers as well as clinical endpoint? Second question is, would appreciate, I don't know, a few people have been pinging us asking, what are the absolute frataxin protein levels at baseline and end of treatment? The third one is, this validation is not only important for the FA program, but sort of big picture validation of the GeneTAC opportunity.
Would love to hear your thoughts, how you're thinking about, you know, with this data set, what it means for building out the pipeline.
Okay. Thank you for the question. On your first question, yeah, we did look at correlations across, you know, various clinical and various measurement approaches to the increases in endogenous frataxin. Interestingly, the individual responses in the clinical measures really show up most cleanly in USS because that's the least responsive to placebo. Of all the different ways of measuring frataxin, perhaps as predicted by the natural history study, it's the blood frataxin protein M that, you know, best correlates the clinical responses at an individual level to the blood frataxin protein responses. I think that's a learning from that type of analysis.
I think on your other question about, you know, the platform, certainly it, you know, for the first time seeing validation of the platform clinically is very exciting. You know, it certainly strengthens our conviction in the GeneTAC small molecule approach. We have other programs, as you know, in, you know, various other monogenic conditions. On the other hand, of course, every program's molecule, you know, is unique. You know, each program has its own considerations, but certainly it's a very exciting day for Design Therapeutics to have this type of clinical validation. Sorry, I think you may have had one more question that I missed.
Oh, absolutely. Thank you, Pratik. Just the question around absolute change of interest.
Yeah.
Then from.
Okay. On that point, you know, 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.
That's work that's just not been done and not possible. However, you know, one thing that, you know, we've done a lot of work on is we ran studies in untreated patients and healthy individuals to understand the performance of these, you know, various assay systems to not only look at the assay variability, but also the, you know, relative levels in different settings. 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, you know, patient levels of frataxin and healthy carriers. Maybe to just you've seen, I think, in this biomarker data, a 65% increase in that parameter in whole blood frataxin mRNA.
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, you know, and that's within the patient population, and that the healthy carrier range in that assay system, began at about a 46% you know, increase relative to the patient population. I think that gives you a sense, as a matter of context. You know, 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 so much.
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 wanna 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.
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