Thank you, everyone, for joining, those of you in the room and on the webcast. My name is Faisal Khashid. I'm one of the senior biotech analysts here at Jefferies. Really pleased to have with us here at Design Therapeutics. I have CEO Pratik Shah with me on the stage. Pratik, could you start by introducing the company?
Thank you for the invitation and for your attention and interest in design. Design is developing a new class of small-molecule genomic medicines. where we have a very unique approach, which is to have molecules that can recognize specific DNA sequences and by doing so can dial up or down individual genes in the genome. And as we think about monogenic diseases, there are many, many monogenic diseases where the root cause is well understood and is driven by a particular gene sequence. And so the promise of design has always been an ambitious mission, which is to take small molecule genomic medicines, which by their small molecule nature naturally distribute widely into the body, get into cells, get into organs, and have a pancellularity, and yet be able to dial up or down the root genetic driver of the pathology to ultimately have hopefully transformative therapeutic impact. And so it's been an ambitious mission, and we're really delighted that at this point we have our first sort of clinical proof-of-concept data in the Friedrich's Ataxia program.
Great. And then, Pradeek, if you don't mind me saying, I think the Friedrich's Ataxia data that you had was in some ways very encouraging and validating for the platform, but in some ways a little bit controversial among the investor community. Is that fair?
Well, I think from an objective perspective, you know, we believe that even based on the discussions we've had, there is broad agreement among those investors who are looking for investment opportunities with transformational medicines that this data set supports the fundamental investment thesis of the company. Certainly, it was earlier than anticipated, and we got answers to some of the key questions much earlier than we had thought. And as a result, we had a chance to accelerate our business plan. And as a result, there are certainly certain questions that we have that, you know, investors had and continue to have that are, in our view, no longer on the critical path. But because those haven't been answered, perhaps that's why you're describing it as controversial. But, you know, it's clear to us that we have the kind of evidence that we believe we needed to shift gears from sort of an early stage signal finding type of framework into a registrational later stage development type framework. And there are a number of decisions that go hand in hand with that. And I'm sure with the fullness of time, some of the ancillary questions, you know, will get answered.
Got it. And I think in a lot of my, like, dozens of conversations with investors since the data, the critiques, if you will, kind of fall into three buckets, one kind of being on just the nature of the disclosure, why it came when it did, and what's happening with the study, one category being the biomarker data, and one category being the clinical data. So I was hoping we could sort of maybe just tackle those one by one. Let's do that. So on the nature of the disclosure, can you just clarify why this data came when it did, ahead of a second-half expectation, and then also the sort of current status of the study? Right.
So in the second-half expectation, we had based our readout timing on a series of planned cohorts. and we had described in our prior quarters updates about kind of what the study cohort design was and we had achieved a PK predicted exposure level at that 0.6 MPK and then we had clearance to go to one MPK and we had begun both four-week and 12-week duration cohorts. We had chosen four weeks initially because it would allow us to get to those target exposures more rapidly than if we had used 12-week durations to get to the same exposures, right? So given that cohort setup, and I think it would have, it's fair to say that, you know, we would not have expected to have the kind of striking results that we observed as early as week four. And it gave us key answers to the questions of what is an active dose level? is what is the route of administration? Is a once-weekly administration regimen appropriate? What kind of endpoints might we have an effect on, both biomarker-wise as well as clinically? And therefore, what kinds of endpoints should be included in future larger cohort examinations? And so having answers to all of these questions from the four-week cohort was certainly earlier than expected. But does it change the fact that we have clarity on answers to all of these questions, which allows us to shift into activities that are typically reserved for later in development? And so the cohorts are ongoing. We continue to dose the patients in cohorts that are planned for either 12 weeks or longer. We believe we have an active dose at one MPK. We plan to explore additional dose levels, although it is not on the critical path. And so given that all of these activities are underway, certainly there could be additional data disclosures as we conduct the trial. But because we have an opportunity to accelerate the program and start to think about generating a registrational data set and explore as part of that solution set potential modifications to the existing protocol to support registration. We think that it is not appropriate to comment on the particulars of that until we determine what those will be, and we plan to provide that update in Q4.
Got it. So to confirm, so the study is enrolling in the 12-week cohorts, and it sounds like you're saying that there's a chance that that could become part of a registrational package, which is why you cannot commit to disclosing that data?
Yes, those studies are ongoing, and there's a number of things that we're exploring about what we can do with our ongoing studies in order to support registrational plans and because of that possibility, we're not commenting on the timing. But we will provide clarity on our plans in Q4.
Got it. And then with respect to dose, I know you are saying that you believe one mg per kg is an appropriate pharmacologically active dose based on what you're seeing so far. Could you clarify, based on the biomarker data especially, the extent to which going beyond one mg per kg is a priority?
So we think one MPK is active, and actually if you think about the program in the context of a larger plan for eventual submission, one of the factors that weighs into that is to begin to collect longer-term safety data and exposure data. And so establishing what you believe is an active dose is really helpful to start to build that long-term safety database. So that's, to us, a critical path-type item. We will continue to explore other dose levels. We actually have clearance to go above one MPK, and that will be part of our future plans. It doesn't seem like that is on the critical path because we don't have data from those dose levels yet, and we don't think we need it in order to advance what we believe is an active dose got it so some of the investor pushback here is
that can't understand why they're not going beyond one make per keg it's not like they're doubling for taxing that's that's what I hear from investors I'm
curious your point of view on that yeah and and you know we think that in terms of getting to an understanding of the possible future effects I certainly would not be surprised if with extended duration we continue to see a perhaps significant further increase in the biomarkers right the pharmacology basis supports that notion and that will all mature as we continue to run this study and we generate additional information. And so that's, duration is a lever, and dose is a lever, and both are available to us, and we have clearance to do both, and we're going to keep understanding the nature of the effects as we, you know, continue our cohorts.
Great, okay. I think that's fair on, let's say, topic one. And by the way, I do really appreciate and respect you kind of being willing to engage and like all of these questions. So let's shift over the topic to the biomarkers. So I've heard two big questions on biomarkers. One being how the biomarkers that you're seeing and the frataxin increase that you're seeing both in RNA and in protein relate to a potential therapeutic goal, which I know is a debate, but a potential therapeutic goal of achieving carrier levels of frataxin. That's one question that's come up. And then the other kind of big topic of a question is the ability to see fritaxin protein expression in muscle. So those are the two things I kind of want to dig in on. But maybe can we start with the first one?
So on the issue of, you know, how much fritaxin would be considered therapeutic, Certainly from a genetics perspective, it makes sense that since there are carriers who are healthy, that there's essentially genetic evidence that carrier levels of fritaxin cannot possibly lead to disease because there are no carriers with F.A. And vice versa, if you have, you know, FA as a disease and a biolelic mutation, that whatever fritaxin levels are produced in those patients, you know, do lead to FA, right? So that's clear. But, in fact, the natural history data, which is an extensive data set that establishes endogenous fritaxin as a reasonably likely surrogate for predicting clinical benefit, looks at fritaxin levels within the patient population. And what the data demonstrate is that patients who have more fritaxin than other patients do better on all major clinical outcomes. Whether it is age of onset, when is there loss of ambulation, what is the rate of disease progression by MFARs, what is the rate of disease progression by USS, really by every metric, patients who have more frotaxin do better. And that has led to a conclusion that this is a biomarker that's a continuous variable, not driven by a threshold effect of carrier levels. And because the natural history had concluded that, we believed that any increase in endogenous natural fritaxin could be therapeutic. But it wasn't until we received this data, which for the first time shows an agent that's a pharmacologic agent that can increase endogenous fritaxin and already is showing measurable clinical impact. and so essentially it allows us for the first time to actually see the whether the natural history reasonably likely surrogate prediction was potentially correct and so I think with that type of evidence you know we believe that what we're seeing is is make sense but to the carrier levels comment let's go to if If you look at the biomarker data, the blood RNA assay is the tightest, most robust assay. And in that assay, there is essentially no overlap between patient levels of fritaxin and carrier levels of fritaxin. And that's a reflection of reality, that the levels in patients lead to FA and the levels of fritaxin in carriers. don't lead to FA. And so by using that assay, what you see in studies we've run, which is reported on our corporate deck, if you download that and look in the footnotes on the biomarker side, you can see these numbers, that the 90th percentile of an FA patient has 24% more RNA production than the average FA patient. So that gives you a sense of how the frotaxin levels are within the patient population. The carrier range begins at a 46% higher level than an average FA patient. Well, in our one-make-per-kick group, the treated population showed a 65% increase in frataxin to their baseline. And so I think you're already starting to see pharmacologic evidence that the magnitude of frataxin response in the one-make-per-kick treated group you know to us is quite significant um and so god just to clarify i think this is an important
point that wasn't that i think was missed a little bit on the day that you had the data so you're saying that at least on a blood mrna basis your one make per keg and even your 0.6 make per keg are getting into the carrier range yes and then what about protein and on protein
So the baseline protein levels in our 1-mig per K group were not atypical, right? They were in the 1-MPK group. In fact, across the whole study were typical. But in the 1-MPK group, they were, you know, slightly above average, right? So an average FA patient's baseline protein levels are maybe around half of the average of carrier levels, but the carrier range is broader than that. And so in that sense, the baseline protein levels in the 1-MPK group were not atypical. So it's not a situation where they were like some 0.1% or something, and that the observed protein increases couldn't possibly have any pharmacologic relevance, right? I think they are actually quite relevant. And by showing that the induced mRNA in the blood translates to protein, both for taxin M, which is a mitochondrial endogenous protein, as well as for taxin E, which is largely in mature red blood cells, I think further confirms that the induced mRNA is functional, as would be predicted. And so I think there's very little doubt at this point that the induced mRNA makes protein. There's no evidence of any kind from any literature that, or from any of our studies, that the induced mRNA from our compound, you know, it definitively makes protein. We know that the mRNA is increased in muscle by 42% in the 1 mic per K group. That's an affected tissue, so the evidence set all corroborates. and I would not be surprised as the dosing continues for those protein levels to you know build up in fact that was our original expectation as we looked at the kinetics and half-life of the protein which is a much longer lived protein the fact that we see sustained protein two weeks after the last dose, I think confirms that this is behaving like the predicted long half-life of endogenous frataxin, which is also very, very comforting. And so all of those pieces of biomarker evidence establish a very strong mechanistic and biologic foundation for the clinical effects. And so to see all of that together, along with early indications of patient experience, like improvements in the fatigue as a patient reported. It's like all of this paints a clear picture to us that we have an active dose at one MPK that deserves being advanced in a rapid fashion.
Got it. And just to clarify, so you're saying that on a blood protein basis, the free disc ataxia patients are on average half of the carriers? Yes.
And the patients in the 1-MPK group at baseline were slightly above average at baseline.
Got it. So that means that to fully restore, like, to the average on protein, you need to double. But to get into the range would be presumably lower than that. A lower effect than that, yes. Got it. Okay. And then just the last thing on the biomarkers is if you can explain on blood protein the relevance or importance of that and what your findings were or were not on that?
So on blood protein, that has been at the center of the evidence set on the natural history. So anytime a topic comes up about a reasonably likely surrogate for predicting clinical benefit, that evidence comes from natural history studies. What do they teach us about the predictability of a clinical outcome based on a measured marker? And the measured marker at the center of the natural history is endogenous blood for taxon. And so because that's the centerpiece of the natural history, you would imagine that in any discussion about using a surrogate endpoint for a clinical study, that conversation would likely begin with the same thing that was used in the natural history studies, which is endogenous blood for taxon. And so by seeing it induced by 65% at the mRNA level and, you know, 22 to 27% in the protein measurements at two weeks post-last dosing gives us confirmation that we're getting a pharmacologic effect on what we believe to be a reasonably likely surrogate for clinical benefit. Now, by measuring protein two different ways, two different isoforms, one is for Texan-M, one is for Texan-E, kind of adds to the weight of evidence that the induced mRNA definitively makes protein.
And then, but then in terms of measuring protein and muscle, can you describe that?
So that story is still being written. You know, as we had begun in this conversation, this was an earlier than expected and planned readout. So there were a number of things that, you know, I believe will still need to play out. And we have very little doubt at this point that the induced mRNA-mix protein, we've shown that in multiple ways, and we've seen this 42% increase for taxon mRNA in muscle. And so I think, you know, with time, you know, we'll complete that sort of data set on muscle protein. And, you know, whatever's going on, we know that the drug is widely distributed. It's having the clinical impact that it's having. And 216 goes well beyond muscle. And it goes into really all of the affected organs. It distributes very widely. I can confirm once again that we have seen in non-clinical studies in both rodents and non-human primates 216 at very good levels in tissues, including the brain, and CNS at levels that we believe would drive full pharmacology. And so, you know, whatever is going on is completing the cascade from the drug target where you're dialing up normal for taxin from the DNA and measuring it out to the protein and then all the way to clinical, standard clinical measurements.
Got it. And just to be clear on this, so you're waiting to kind of conduct those analyses and get that data back?
There's a number of things that are trickier with muscle biopsy assays than blood assays. The RNA results are very clear, and we're working on generating the protein evidence in muscle.
Got it. Okay. So then shifting gears to the clinical data, could you explain just overall the relevance of the magnitude of MFARs decreases that you are seeing, and also how this compares to just general variability in MFARs and what convinces you that this is not a kind of chance-finding seen in a short study?
Right. So there's quite a bit of literature on how MFARs does in previous studies in FA. And we've actually included the key figure from a recent paper in our corporate deck. So you can look at that on our website. And what you see in that figure is that MFARs has been seen in placebo groups in various FA studies to show anywhere from, you know, a one-point improvement to a two-point improvement, in some cases even a three-point improvement. We know that other companies that are pursuing exogenous delivery of fritaxin in an open-label study where patients are being told that they're given exogenous fritaxin, either by gene therapy or by protein fusion, All of the MFAR's responses in those types of studies, even in an open-label setting, have been in the neighborhood of, you know, two points or two and a quarter points. And so given the placebo responses and the experience of other companies, to see a 6.4-point improvement at the 1 mg per kg dose, admittedly it's N of 4, but if you even combine that with the 0.6 mg per kg group and you average their MFARs improvements, it's still a 5.2-point improvement with a sample size of 8, which is half the study so far. And so I think that the response in MFARs is striking. But to your second question, which is what would give us confidence? And I think the thing to do there is it is well known in FA that the upright stability score component of MFARs, which contributes to the points of improvement, is the least placebo responsive. In fact, in that same figure, in the same publication, a one-point improvement in upright stability score component of M4s would be beyond the 95th percentile confidence interval of an improvement seen in any prior study. And so for us to see a 2.7-point improvement in upright stability score, and by my earlier logic, even if you average out the 0.6 and the 1 MPK and you get to a sample size of eight, you've still got about a two and a quarter point improvement in upright stability score, which is a more objective component of MFARs and is less placebo responsive. So when you see that type of behavior in the USS, that combined with the dose response in USS. And in fact, when we look at the individual responders, the USS clinical response also best correlates with the predicted natural history biomarker, which is for taxid blood protein. So when one looks at the totality of evidence, I think it, again, is consistent with the reason for the company to exist, the predicted basis for therapeutic effect, and now for the first time we can actually see that the idea of restoring fritaxin can, in fact, give you therapeutic impact. And, you know, we're excited to advance this, to increase our, you know, sample size and to do a number of things to shift into later stage development and generate more data.
Yeah, and this is something that I've been, every time I've heard this thesis of the MFAR potentially being like some chance finding, I think you can't really fake the dose response, right? And can you clarify, this was a blinded study?
No, this is an open-label study, but on USS, we know that even with placebo, right, you don't get changes in USS, right? And we know that because both other companies delivering exogenous frataxin are also running open-level studies. So we're not unique in that regard. And those are actually presumably being used for registrational purposes. And so if other companies are using these type of study format for registrational purposes, certainly it's appropriate to evaluate the data at this stage and say, okay, what is it objectively telling us? We're very encouraged by it.
And then can you comment on the next kind of major milestone that you've guided to definitively is in the fourth quarter providing an update on what the path forward is, which is dependent on your regulatory discussions. What is the kind of next steps in engaging on that? I presume you have to request the meeting, prepare for that, et cetera. Can you just give us a sense of what the time is?
Yeah, it's all of the usual things. I mean, I think that we had been waiting to generate data to understand what questions to engage with regulators on, and we certainly have a number of questions that we'd like to get clarity on. That will all be part of, and often these topics can take multiple conversations, so it's something that we'll keep working on, but we'll make a determination of our plans going forward in Q4 and because we have an ongoing study on one hand that could generate other interesting data or relevant data. On the other hand, we certainly want to preserve our ability to use any future information for potential submission as part of a registrational package.
Yeah, and just to clarify with respect to the FDA discussions, is there like a singular big type C meeting where you expect to get formal feedback, or is this more of a correspondence back and forth type of thing?
It's to be determined, but we'll do the best we can to have all the information we need to make our plans clear in the fourth quarter.
Got it. And then with respect to this possibility of, you know, making the 12-week portion of the study, morphing that into a pivotal study, I'm just wondering, honestly, like strategically, right? It's like rightfully or wrongfully, I believe wrongfully, investors have kind of en masse spoken and said, we want to see more data before being really convinced. Does that feed into your decision-making on this as well, where in order to convince investors, you might want to not convert that to a pivotal study and show us that data?
I mean, this is where drug development meets Wall Street. We're very focused on what is right for patients and what is right for the program, and that remains the guiding principle for how we advance things. and if along the way additional information is generated that doesn't compromise that that might be interesting and relevant to investors, we'll certainly, you know, be prepared to inform folks about things as we learn them.
Got it. Well, that's all that we have time for. Thank you so much, Rajiv, for joining us. Appreciate it.