On the first day of RBC's Global Healthcare Conference, we're really excited to kick this off with Design Therapeutics, represented by Pratik, who's their CEO. Thanks for being here.
Thank you so much for the invitation. Great to be here.
Maybe just starting off, a little bigger picture. Can you remind us and walk us through what a gene tag is and how that molecule has special properties that maybe make it a little like an ASO, a little like a small molecule?
Happy to do that. Thank you. Before I go into the discussion, I just wanted to remind the audience that I will be making forward-looking statements about our business, our R&D activities, and our financial condition. The actual results are very important factors and really important reasons. To understand those, please look at our recent NP file. Gene tag molecules stand for gene-targeted chimera, and this is a new class of small molecules that do something pretty remarkable, which is they dial up or down the expression of an individual gene in the genome. The reason this is so exciting is that we have developed a way that we think we can address the root cause of monogenic disease. I think there are many, but we know exactly what the driver is.
The therapeutic goal is to either dial up or dial down the expression of the causative gene without requiring any gene editing, without requiring gene therapy, working with somebody's natural gene. That is particularly important because with these types of small molecules, they can do what no other genetic medicine can do, which is to widely distribute into all cells to get into all of the pieces of the body. That is a very exciting possibility because it gets at the true reason for which genetic medicine in general has generated so much excitement and hope for patients. If we can show that this type of approach works to address the root cause of monogenic diseases, there is little doubt this would be the genomic medicine of choice. That is why gene tags are so exciting. They are not oligonucleotides.
They don't require the DNA to be opened up. They recognize sequences in double-stranded intact DNA, much like a natural transcription type.
Right. That's a really exciting technology. Maybe moving on to one of your lead programs, DT-216, and Friedreich's ataxia. Some time ago, you presented data from DT-216 showing some changes in expression. Since then, you've optimized that molecule into DT-216P2. Maybe you can start by talking about how you sort of optimized that and how the excipients you've added or changed produced the dramatic effects on PK, AUC, and potentially even intracellular mRNA.
DT-216 was taken into clinical studies in 2022 and 2023. What was very exciting about those results is that they demonstrated that in patients with FA, the mechanism that I just alluded to does upregulate endogenous protective expression in cells from patients in those clinical studies. The issue we ran into in the clinic was that the duration of exposure was short and that we were limited by injection site thrombophlebitis event. While on one hand, it validated that the approach that is so exciting that we have generated very nice clinical results for worked in humans, we needed to figure out if we could solve that problem. What DT-216P2 is, is the current generation product that we believe addresses the limitations that we saw with DT-216 in the clinic previously. We were able to overcome, we think, those limitations based on formulation alone.
We didn't change the molecule. The active ingredient is still DT-216, but the new drug product is a new formulation that we call DT-216P2. The key features of DT-216P2 are that we believe based on going outside of sort of traditional off-the-shelf excipients space, we were able to address the injection site thrombophlebitis event based on data from pre-clinical studies. We were able to get an exposure profile that we believe gives us the duration of exposure, eluted, and also allows for potentially increased frequency of injection if need be in order to achieve that sustained exposure we're looking for to reach our real goal, which is to see if we can get a sustained increase in endogenous protection. If that can be done, that would be a significant advance in the field and very exciting for patients.
Got it. You recently started up phase one study of DT-216P2. Can you maybe talk about what we should expect in terms of data readouts this year in FA and maybe just bigger picture, what we should be looking for in terms of PK safety and when we might see any hints of efficacy potentially?
We are very excited that DT-216P2 is now in the clinic. We are conducting a single ascending dose study in healthy volunteers currently. Our goal and objective is to then be able to hopefully take this forward into patients. We anticipate that being possible mid this year. If we make such an announcement, it would indicate that the data from the single ascending dose study are encouraging enough to support that type of advancement. There are a number of questions that we will continue to try and understand in the context of the single ascending dose study. We are evaluating multiple routes of administration with the same drug product. We are looking at IV weekly. We are looking at subcu, both injection and infusion. All of that is being done so that it can inform the optimum dose regimen to take in the patients.
Our goal is to look for a sustained protection expression in those studies, which we expect to only report with 12 weeks of DT-216P2 dosing. In terms of the single ascending dose phase I study in healthy volunteers, that will likely continue and have some overlap with the possible multiple ascending dose study in patients. What we plan to do is only report data from the single ascending dose study when we feel that we have enough information to both be reliable and meaningful. We have not given any formal guidance for that. We are going to wait and see what the results are in order to collectively interpret and report them.
Got it. You mentioned a few different ways of potentially administering DT-216P2. Can you talk more about what that enables and maybe the hope of the profile that you'll achieve, how you're thinking about IV versus subcu and maybe how that relates to the original formulation, which I believe was an IV push?
Right. You know, all of the routes and regimens that we are evaluating are designed to all be commercially viable and appropriate for this patient population. There is really no commercial sort of profile reason to drive these. The reason to look at multiple routes is that in the previous clinical experience, we were limited in what we could do in patients because of the nature of the drug product and the studies that were done to support going into patients. This time around, to maximize the likelihood that we would get the sustained exposure of drug that we believe we need in order to get to our goal, which is a sustained frataxin expression, we are trying different routes of administration and different frequencies so that we maximize our likelihood of getting to the ultimate profile that we are looking for.
That makes sense. I guess, you know, what's your sense of the enthusiasm for DT-216 and maybe additional treatment options for Friedreich's ataxia, just given the sense given that there have been approved agents now? You know, some clinicians may have experience with DT-216. I guess, what are you seeing from both patients, from physicians, and how recruitment's going?
I believe the level of excitement for this is very high. You know, the reason for it is that even though there is now an approved medication for Friedreich's ataxia, it doesn't really address the low levels of frataxin, which is the root cause of Friedreich's ataxia. There is a general desire and need for medicines that can address this fundamental root cause. DT-216P2 represents probably the only agent that would increase endogenous frataxin. If one can do that, that's sort of the desired profile in the field. That's why the excitement level we believe is very high, in particular because the results from the previous study were very encouraging. I think that there is a strong sort of interest in both clinicians and the patient community to see if we can fulfill the original hope and promise of this approach.
Just to maybe clarify one point, with DT-216, this is a product that can make it into all tissue types or just certain tissue types. You know, there are certain other competitors out there that sort of target different tissue types. Is this something that's going to be broadly distributed to the body?
We expect so. The data that we have seen in non-clinical studies support that DT-216P2 distributes widely into every tissue that we've looked at. That is one of the points that, you know, I made earlier on, which is the beauty of having a small molecule genetic medicine is that it can distribute widely into a variety of tissues. Once it gets into a tissue, it can go into essentially all of the cells rather than some fraction of cells. I think in that sense, there are fundamental properties that support the idea that if this works, it would be the genomic medicine.
You know, maybe it's a little early to talk about commercial, but just curious how you're thinking about how the FA market itself has evolved. Related to that, I guess, is there a bar internally of efficacy you'd like to meet or you think about in terms of what you'd want to see either on mRNA expression or that pulse through protein expression?
We have always believed that there is a huge commercial opportunity in this field. I think with the approval of Skyclarys and the acquisition of Reata by Biogen for north of $7 billion and the subsequent good performance of Skyclarys has only confirmed in the investor community the commercial opportunity in the FA space. That is for a drug that does not really address the endogenous frataxin. In terms of the profile, the reason that we think this is so exciting is it is endogenous frataxin. No one has really ever been able to increase the expression of endogenous frataxin with a patient's natural means. You know, on one hand, the preclinical data are really exciting because they show a very nice increase in endogenous frataxin.
On the other hand, I think we are trying to be humble about what exactly we might see because no one's ever been able to do this. We know that carriers have about half normal protection and are clinically completely normal. There is, you know, a sort of a genetic benchmark out there that if an individual has 2x the amount of protection as an average protection level in a patient, that ought to be highly therapeutic. We think given the endogenous protection, you know, potentially any significant increase in protection could be clinically needed.
As you think about how best to understand changes in protection, are you thinking about mRNA? Are you thinking about protein? You know, I know with DT-216, there were questions about where is it best to measure these biomarkers. I guess if you coalesced around maybe the best way to actually gather evidence around this biomarker so that you can make that case either to investors or the FDA.
Yes. I think that's a pretty well-resolved issue at this point. We've shown in our previous studies that you can measure mRNA robustly in both blood and in muscle. And that's something that we've used before to see endogenous increases in frataxin. We plan to continue to use. In addition, on the protein, there have been, since we reported that data, additional reports in the literature from experts in the field who have used LCMS detection methods to have a robust examination of protein levels in both peripheral blood and in muscle. And we'll be looking at all of the issues and approaches to look at endogenous frataxin. The thing about blood frataxin is that's the biomarker that's most widely reported in the literature. The natural history studies have used blood frataxin as the marker and is sort of validated by clinical history and natural history.
We'll be looking at all of these to see what we're looking for.
I guess I also have a second program that's quite exciting, DT-168 for Fuchs' corneal dystrophy. I guess can you maybe talk about what Fuchs' corneal dystrophy is for those that aren't as familiar and why this indication is well-suited for a gene tag approach?
Fuchs' corneal dystrophy is a progressive vision disorder that leads to loss of visual quality and ultimately loss of vision. It has been known for a very long time. It is commonly diagnosed at the optometrist's office in a routine slit lamp examination. The IRIS registry, which is a CDC database, you can look it up on their website, indicates that based on claims data, there are probably approximately 2 million cases diagnosed in the United States. Unfortunately, the primary treatment approach is a watchful waiting, which essentially is a silent suffering for the patients until they progress to a point which is so bad that they would then require corneal transplant surgery or keratoplasty surgery, of which there are about 18,000-30,000 procedures done annually in the United States.
If you think about the gap between 18,000-30,000 category corneal transplants and the 2 million diagnosed cases, there's clearly a very large population of patients who undergo progressive vision loss until they're so bad that they have to elect for surgery. There is a huge opportunity for a potential pharmaceutical that could slow or stop the progression of Fuchs. Fuchs is caused by a dysfunction in the corneal endothelial cell layer. We've known for a long time that there's a family history component for Fuchs. Actually, it turns out there's a single mutation called the CTG18.1 mutation in the literature, which is a CTG/CTG repeat expansion in a single gene called the TCF4 gene that's responsible for this family history. 60%-80% of patients with Fuchs have inherited this CTG18.1 mutation.
That mutation causes the endothelial dysfunction because it produces a toxic RNA. That RNA causes splice dysfunction and causes general loss of cellular health and cell density over time, which is what explains the progressive vision loss. What DT-168 is, is a gene-targeted chimera that's been designed to go to that specific CTG18.1 mutation in the corneal endothelial cells and turn off the production of the toxic RNA, which is a remarkable thing in particular because the data that we published show that it's selective. In other words, the normal copy of the TCF4 transcript is unaltered. It is very exciting to have a molecule that can go to the root cause mutation and turn off the production of the toxic RNA, which causes the endothelial cell dysfunction, which then causes the progressive cell loss.
What is more remarkable is that we were able to create a molecule that can be administered as an eye drop. We have recently completed our phase one studies with DT-168 in healthy volunteers. It confirmed what we believed could be possible based on our non-clinical studies, that it was very well tolerated and there were no clinically significant adverse events. The data support us progressing with DT-168 in the phase two studies.
Got it. You're running actually a couple of studies in parallel, a natural history study that you're hoping to learn more about the disease and continuing the phase one and phase two transitions. Can you maybe talk about what you're hoping to learn from the natural history study, how that's going to inform future development plans, and maybe we can get into sort of the potential biomarker design for the next clinical study?
We've been running this observational study to understand the patient characteristics that would best be suited for further development. We're looking at a variety of endpoints in the natural history study or the observational study. We're looking at visual quality instruments. We're looking at basically what is subclinical and clinical edema. That edema is the intermediate step between cell dysfunction and visual quality issues because the main function of the cell layer is to keep the stroma appropriately dehydrated to maintain clarity of the cornea. It's when the cornea gets hydrated that you end up with vision like a foggy and rainy windshield. The subclinical and clinical edema are now precisely measurable with newer specialty instruments like the Shyam Patil tomography approach. We're employing that in this study to see how good that instrument is and those measures are for clinical effect.
We're also borrowing a page from the back of the eye in the geographic atrophy drugs where they've used imaging. It turns out that you can image a fraction of these corneal endothelial cells using specular microscopy. That's another endpoint that we're assessing, a tool that we're assessing rather than relying entirely on the literature for the appropriateness of endpoints. The goal of all of this was to know how to best measure drug activity. In the meantime, we kept getting questions, including Leo from you in the last fireside we had, where you said, "Hey, is there a biomarker that can be used to look at whether DT-168 works?" In parallel to the phase one study, we conducted a reference study comparing the tissue from donors from Fuchs' cornea as well as unaffected eyes.
Remarkably, we were able to see a very nice difference in RNA biomarker and splicing from these tissues. That enables for the first time potentially a chance to look at biomarkers as a way to know whether DT-168 works the way it was designed to work. What we're doing is beginning a phase II study with DT-168 in patients who are already scheduled for a corneal keratoplasty surgery. Because the tissues from those cornea will be discarded anyway, it's an opportunity to provide drug in eye drop form for approximately a month or more before the scheduled surgery. At the time of surgery, to then retrieve that tissue and see whether the drug has activity. It's an exploratory study. It's never been done before.
If it works, I think it would be very, very exciting because it would confirm that DT-168 in fact does what it was designed to do. That combined with results from the observational study can help inform how we might then subsequently register a product like this.
You guys have a lot of other exciting programs as well. You guys have a whole pipeline behind the company. I wanted to ask on what you're doing in Huntington because you mentioned selectivity. In Huntington's as well has been a space that's becoming increasingly more interesting. I guess can you talk about your approach in Huntington's in the last minute that we have left?
Yeah, we have two exciting additional programs. We have the Huntington's program where we have a molecule that selectively downregulates mutant Huntington without touching wild type. And it's a small molecule, so it distributes very widely into the affected cells. Interestingly, with the somatic expansion that occurs in Huntington's disease, this molecule works even better with longer repeats. The cells that need it more would have an even greater effect naturally based on the mechanism. We also have a very exciting program in myotonic dystrophy or DM1, where we believe we have best-in-class pharmacology as evidenced by the effect that the DM1 gene tags have on intranuclear foci, which is a hallmark of the condition. With these four monogenic programs, we're very excited that success in any one of these could be value-creating for investors and for patients.
Thank you. I think that's all the time we have, but really appreciate you being here.
Thank you very much. Great to be.