Okay. Welcome everyone to our chat with Design Therapeutics. I'm Joe Schwartz from the Biopharma Equity Research team at Leerink Partners. It's my pleasure to be joined by Pratik Shah, CEO at Design. Thanks for joining us.
Joe, thank you so much, and thanks to Leerink for the invitation to the conference. It's terrific to be here. As you all are aware, I'll be making forward-looking statements in this discussion, and please refer to our SEC filings for risk factors and other important information about the company.
You've made several changes to the FA program, and you've been focused on execution as you get back on track. As you see the program today, what do you view as the single most important data milestone that will define the next phase of development?
Well, Joe, the single most important thing in FA is that the disease is caused by low levels of normal endogenous frataxin. The therapeutic goal in this area has been to try and increase levels of normal endogenous frataxin. As we are running our RESTORE-FA study in patients with FA, which is a multiple-dose study, what we're looking forward to is generating a data set that, hopefully we will be able to see an increase in the level of normal endogenous frataxin. If that could be achieved, it's something that's never been achieved before, and if that can be achieved, that would be a significant advance potentially in the field and the therapy for patients living with FA.
Great. When you talk about normal endogenous frataxin, how are you thinking about the relative importance of frataxin mRNA versus protein restoration in terms of demonstrating meaningful biological activity?
The mRNA is completely endogenous, and what we're measuring is the level of normal processed mRNA. That being said, because protein is made as a result of making normal endogenous RNA, we'll be measuring protein as well. We'll be measuring both mRNA and protein in cells from whole blood, but we'll also be measuring both of these in an affected tissue by muscle biopsy, although muscle biopsies are more limited in how you can sample them, so we'll be doing, you know, before and after dosing, and possibly a third.
Okay. Great. What work are you doing now to ensure that you can generate some robust reproducible frataxin measurements?
We've done a lot of work in this area. The mRNA and protein assays are being run , in a highly validated fashion, and we've also been running in the background reference studies so that we can understand the level of frataxin seen in a group or population of FA patients, and also what those measurements look like in healthy carriers. That'll provide some context on the response, knowing that the bar in the field continues to be any increase in endogenous natural frataxin, could have a meaningful consequence on the clinical status of a patient.
Truly, any increase or
Well, certainly from commentary from other sponsors in the field, we have heard about pivotal negotiations from other sponsors where, for example, a co-primary in terms of level of frataxin increase, a success criteria there would be, again, any increase in frataxin. And so if that's applicable to an exogenously delivered frataxin, it certainly should apply to an endogenous frataxin, knowing that, there does come a point where if you're in the healthy carrier range, I think that would leave little doubt as to whether that is sufficient.
Okay. Can you recap for us what you saw pre-clinically that made you comfortable that the GeneTAC mechanism was selective?
Yeah. There are numerous cell types that one can derive from patients living with FA, and regardless of what cell type we look at, when we apply the GeneTAC molecules to these cells, what we observe is an increase in endogenous frataxin RNA, and then all of the subsequent things that occur as a result of normal endogenous RNA production, which is normalization of protein levels, downstream functions like cis-aconitate, and furthermore, cellular functions like cellular respiration is also restored. In that type of pharmacology, we see a selective effect.
The wild-type genotype. There's no impact on it when it is exposed to a FA GeneTAC molecule, and that's because the repeat number in a wild-type allele is very short, so there's really no functional consequence observed in seeing what happens when you apply a GeneTAC.
Okay. I guess where are you in terms of enrollment currently? You came off of clinical hold. That allows you to proceed, so what's the status?
Yeah, we've been running our multiple ascending dose studies in patients with FA. That was following single dose studies in healthy volunteers where we confirmed the two most important scientific questions. One is, of course, the safety, tolerability, and we confirmed there that any issues that we had seen in the old formulation appeared resolved. Secondly, we saw a dose to exposure relationship that was comparable to what we had seen in our non-clinical studies. Having done that, we set out to conduct multiple dose studies in patients. We had not determined from the outset exactly how many cohorts we would ultimately run. What we've been doing is essentially running our dose ascending studies cohort by cohort with safety being the key gating criteria for dose escalation.
The goal has always been and remains to look at the frataxin response with 12 weeks of dosing, and that is data that we anticipate having in the second half of this year.
What kinds of concentrations do you think you need to achieve in order to deliver a meaningful frataxin increase?
Let me try to connect those dots. The foundation of that thinking is based on the potency of DT-216 in cellular systems. On that foundation, what we observe is that 10 nanomolar exposures give you full pharmacology as long as there is sufficient duration of exposure. Concentrations above 10 nanomolar certainly also work, but as long as you have long duration, 10 nanomolar gives you full activity. Well, that data point of exposure was, we believe, validated from the trials we ran in FA patients in 2023, where while we were disappointed that we saw only a very limited duration of exposure, we essentially saw 8-10 nanomolar of drug exposure at day 2, but the drug was almost all gone by day 7.
What was supposed to be a multiple ascending dose study, in hindsight, turned out to be a series of single dose studies one week apart. Despite only two days of exposure at about eight to ten nanomolar, at that time point, we saw an unmistakable increase in frataxin RNA expression, both in muscle biopsy samples as well as in peripheral blood cells. That provided, for the first time, validity in humans to that ten nanomolar exposure target that we had derived from our cellular studies. Now, the plasma concentrations corresponding to the muscle level is also in the tens of nanomolar. That created a hypothesis that if we could sustain that plasma exposure throughout the dosing period, that perhaps would give us sufficient exposure to see a sustained frataxin response.
The concept behind doing a study with 12-week duration is that it should give sufficient time for the drug to get to steady state and then the pharmacology to get to steady state since the frataxin protein is actually quite a long-lived analyte. It's about a 10-day to 2-week half-life. If one were to apply rule of thumb for any long-lived analyte, which is, say, about five half-lives to get from steady state to clearance or by corollary from , beginning levels to new steady state levels, then that is a several week period plus a few weeks for the drug to get to steady state. We believe that a 12-week dosing duration should get us to a steady state pharmacology.
Okay. Can you talk a little bit more about your confidence that DT-216P can drive sufficient frataxin protein expression in the tissues that matter most in FA?
I mean, the hypothesis is based on preclinical data, and we've seen in cell systems that as long as there is sufficient duration of sustained exposure, we see RNA increase and then subsequently protein increase. They have a different time course because protein is a longer-lived analyte. That hypothesis was further confirmed in ex vivo cellular treatment from cells we took from trial participants in the 2023 trial at baseline, where ex vivo you can sort of force the exposure to the trial participants' cells for a longer duration. Sure enough, in those settings we observed both an RNA increase and then a subsequent increase in protein. Having said all of that, we won't know whether we get the sustained RNA and protein increase until we get the results of the RESTORE-FA study.
Certainly from a pharmacology foundation and exposure analysis, you know, this is encouraging, but the proof will ultimately be, you know, determined when we get the RESTORE-FA results.
How did you choose the doses and the schedules that you're using in RESTORE-FA?
It was based on initially just a projected exposure from our non-clinical study results. We confirmed in the healthy volunteer studies that were run in 2025 that we were getting a comparable PK profile in humans as we had seen in non-human primates. With the conduct of the single dose study in healthy volunteers, we developed an understanding of the dose-to-exposure relationship. With that in hand, that gave us a basis on which to develop projections on what multiple dose study dose levels and exposures could be. As is very customary, we would start out at some, you know, low starting dose and then systematically increase exposure based on safety.
Okay. What kinds of patients are you enrolling in the trial? I know they have FA, but any particular profile of patient that you're targeting?
At this stage, it's a, I would say, a pretty permissive set of criteria. We have a really beyond a genetic confirmation diagnosis of FA. It's a pretty broad set of patients. Some are ambulatory, but some are wheelchair bound. Because at this stage we are most focused on, of course, safety, but to try and understand frataxin, this type of profile would allow us to address the level of frataxin and help us determine both a dose route, since we're doing both IV and sub-Q explorations in the current study, as well as a dosing interval and trying to understand the frataxin response as a foundation for future clinical investigation.
Does that mean that you're less focused on functional assessments or are those being done too?
There's less of a focus on it, but anytime you have a clinical trial in patients with FA, it is, you know, customary and expected to assess their clinical status using the standard clinical measurements that are used in FA. Yes, those are being looked at, but the study's goal is to look for a frataxin response.
What factors would influence whether we see RESTORE-FA data earlier or later in the second half of the year?
It's really mostly operational. We have some set of possible planned cohorts, but exactly, you know, where we end up getting sufficient information to get clear conclusions is undetermined as of yet.
Maybe we'll come back to FA, but I wanna make sure we talk about the rest of your pipeline. Can you give us an update on the ongoing Phase 2 biomarker study in FECD?
Sure. We are conducting an exploratory biomarker study in patients with late stage Fuchs' corneal dystrophy. Now, before I get into that study, I'll just describe the goal of the therapy. The eventual product profile that we're targeting is to have hopefully an eye drop that would slow or stop progression of Fuchs' corneal dystrophy, which means that , if somebody's diagnosed with, let's say, mild or moderate Fuchs', and that diagnosis tends to occur early in the disease state, it would be really terrific to have something that could slow or stop progression and help people keep the visual quality that they have at the time of diagnosis. Now, because no one's ever done anything like this, we asked ourselves if we could develop any kind of indicator or biomarker that would provide evidence of target engagement.
That's been a very challenging strategy to develop, but we did develop actually for the first time a possible biomarker by measuring splicing from what would have been discarded corneal tissue after a corneal transplant surgery in very late stage patients. Since those tissues are typically discarded anyway, it gives us a chance to actually isolate RNA from those corneal endothelial cells and look at the spliceopathy. The limitation of the study that we're conducting is because you cannot take a pre-drug treatment corneal tissue, you don't really know where the spliceopathy was before giving the eye drops. That's certainly a limitation. It's also a much later stage population that's essentially , gonna have a scheduled surgery in a few weeks after dosing commences. It's possible that this type of approach could lead to a false negative.
On the other hand, if we saw any impact on splicing relative to a reference set of splice data, that would, to us, give clear evidence that the eye drops are doing what they were designed to do and having an impact on the pathogenic spliceopathy in these corneal tissues. If we had that confirmation of target engagement, it would provide further confidence that the drug is doing what it was designed to do. What we're doing currently is providing these eye drops for several weeks to patients who are already scheduled for their surgery and comparing those splice results to that of a reference set of either samples taken from Fuchs'-affected corneal tissue or non-Fuchs' donor tissue. In those splice events where you see a clear separation, that's the backdrop in which we can see if DT-168 creates a splice improvement.
What do we know about the degree of spliceopathy that exists between patients and healthy individuals currently?
We've run for the first time a broad panel of mis-spliced events across various genes that are expressed in the corneal endothelium, and from that have identified , a handful of splice events where you see a separation between a group of donors from Fuchs' cornea and a group of donors with unaffected. Those splice events that have the most separation in the group results provide the backdrop in which to assess whether DT-168 affects splicing in a way that gets us closer to the unaffected levels of splice events.
Okay. Do you have a sense yet about the magnitude of improvement that would be meaningful?
No. It's a ongoing exploratory study, and we'll assess the results when we have all the samples done.
Okay. What's the status of that effort?
That is also expected in the second half of this year.
Okay. Great. Moving to DM1, you have a different approach there from a lot of other sponsors upstream, maybe also can penetrate more tissues. Can you talk a little bit about what makes your approach for DT-818 different?
Yes. DT-818 is a small molecule, and it's not an oligo. In that sense, it is a very different approach than all of the sponsors that are in clinical trials currently targeting DMPK for the treatment of DM1. The molecule does distribute naturally across all of the affected tissue systems, and so in that sense, it's also quite different from oligo approaches, which have often to be conjugated to some sort of a carrier to try and get into the target muscle tissue. Perhaps going beyond muscle would itself create a clinical differentiation. The pharmacology itself is also very interesting because it's targeting a level upstream of all of the oligonucleotides.
By going after recognizing the pathogenic CTG repeat expansions, DT-818 is designed to dial down the expression of the mutant DMPK allele while being selective and therefore sparing the wild-type kinase. By targeting the mutant allele, we see over 90% reduction in the expression of the toxic, DMPK RNA as visualized by RNA foci, 'cause you can see these toxic RNA tangles in the microscope, with a fluorescent CUG probe. Seeing that type of profound reduction in mutant DMPK RNA toxic nuclear foci explains why we see a corresponding improvement in the splice index. All of that pharmacology is very exciting.
Plus, the situation in the disease is that the repeats are way longer in the affected tissue than what is reported in, say, the patient demographic in a clinical trial or what a patient might report as their repeat number. For example, somebody with 300 repeats would, in their muscle or affected tissue, have somewhere closer to 3,000 repeats. That's notable because oligonucleotides in general have a more difficult time the longer the repeat gets. What's exciting about the DT-818 observed pharmacology is that we get a comparable pharmacology whether you have 300 repeats or 2,600 repeats. That could end up being an important factor in seeing the clinical effect down the road.
Furthermore , certainly IV is our main focus for a route of administration, but like DT-216, DT-818 is also bioavailable by sub-Q administration. It's possible that if the sub-Q administration pans out clinically, that could be an additional factor to drive adoption versus many of the clinical investigational stage therapies that are all IV.
Right. Interesting. What can you learn from the work with two one six, and two one six P, and one six eight that you can apply to eight one eight?
W e've learned a lot about how to take this class of molecules and develop them into what we believe are pharmaceutically suitable injection products. All of the lessons on how to create a drug product from two one six have been applied to the eight one eight program. We've also learned a lot about how to you know run and manage biomarker studies with rigorous measurements, so we're applying that. This is yet another example of us being able to go after a root cause monogenic condition by. In FA, it's dialing up, and in DM1, it's a matter of dialing down the toxic gene product.
How are you able to find ligands that can do each of these unique functions and leverage the other two components of the GeneTAC technology, namely the DNA minor groove binder and the linker like-
Right. Well, this is what we're all about. This is why, you know, we call the company Design Therapeutics. We, have been now at this for almost 10 years, pioneering a new class of bifunctionals so that we can create molecules that have the desired pharmacology. What we have found is that there is a significant role of not just the medicinal chemistry, but also it is highly gene specific. Every locus has its own particulars that guide the design of the molecules. What we're guided by is ultimately the desired selectivity, pharmacology, and of course the pharmaceutical property. It's been on one hand a broad platform, but also with very program-specific implementation factors.
We've been able to find ligands that, in the case of DM1, in the case of FECD, are, able to provide repressive effects on transcription, whereas in FA, we're relieving a transcriptional elongation block. Yes, they are two different sides of the same platform.
Is it harder to do one versus the other?
Like, it's often easier to knock down.
Right
With conventional biotech approaches. Is that the case here, or is it agnostic?
I would say it's very sort of gene driven. On one hand , everything that we do , is hard in the sense that no one's ever done it before.
Makes sense. Okay. With over $200 million in cash and that taking you into 2029?
That's right. Our business plan has been focused on trying to generate positive clinical proof of concept in at least one of the various large areas that we're working in, knowing that, each of these areas are of great unmet need, and positive clinical data could create a meaningful advance in therapy. The cash runway and the business plan was designed to get us to hopefully at least one positive POC. With that plan in mind, our current cash position does take us into 2029.
Okay, great. Well, we will stay tuned and look forward to.
Thank you so much.
The updates that you have later this year for us.
Really appreciate being here, Joe, and thanks for your attention.
Thanks for the update.
All right.