Thanks for being here.
Thank you, Leo. Pleasure to be here. A great conference. And today, I will be using forward-looking statements with regard to the business, the R&D activities, financial condition, which, as you all know, is subject to known and unknown risks and uncertainties, and actual results may differ materially. And you can look up the factors in our risk section of our most recent 10-Q filed with the SEC.
So Design is doing or using a technology that's pretty unique. I mean, you're calling it GeneTACs . And I think just as a brief overview, can you tell us about how GeneTACs differ from ASO and small molecules, and how they're almost able to combine some of the properties of both?
Sure. GeneTACs stands for Gene Targeted Chimeras, and these are really unique hetero-bifunctional small molecules that have the ability to dial up or dial down the expression of an individual gene in the genome. And if you think about the role of individual genes in disease, there are many, many monogenic disorders where we know exactly what the root cause is of the disease condition. And what one would wish for is for a therapy to be able to restore the natural cellular state working with the patient's natural genome.
So if you could do this with no gene editing and no gene therapy, with a small molecule that can distribute widely to the organs, distribute widely into the cells, work with the natural genome to restore the healthy cellular state, despite the presence of the mutation, that would be remarkable, and that's what gene-targeted chimeras are intended to do. And so we're working on at least four major monogenic disorders, working in Friedreich's ataxia, where the goal is to restore natural levels of frataxin, working in Fuchs' corneal dystrophy, which is an eye disease where, again, there's a monogenic driver of the pathology, where you need to dial down the expression of the disease causing TCF4 mutation, working in Huntington's disease, where we know that mutant huntingtin is what drives Huntington's disease.
We've developed gene-targeted chimeras that can selectively down-regulate mutant huntingtin and leave wild-type huntingtin alone, which has been a very elusive profile that the whole field has been wanting to achieve. In myotonic dystrophy, where we have a selective inhibitor of mutant DMPK, which drives myotonic dystrophy. These are examples where we've actually been able to show data of the power and potential of gene-targeted chimeras.
Got it. And, you know, you mentioned four programs. Maybe we'll start with Friedreich's ataxia. Had a GeneTAC DT-216 that showed, I'd say, some proof of concept that the technology can work. But, you know, you guys decided to bring it back, optimize it a little further. So I guess, can you talk about sort of how you're viewing the initial DT-216 data, and then what drove the decision to optimize the formulation, maybe what changes you've made for the next-gen DT-216P2?
Yeah. What's very exciting about DT-216 is that we've shown in Friedreich's ataxia patients in trials that were conducted and completed last year, that DT-216 does increase endogenous normal frataxin expression in patients living with FA. And that's a remarkable feat. The issue we ran into is that the duration of exposure of the drug was shorter than we would have liked. And so, but for the duration that the drug is present, we see this really nice increase in endogenous frataxin RNA expression. And so we've measured this in, you know, various ways, including in tissue by muscle biopsy.
So our goal with DT-216 is now to extend the duration of exposure of 216, so that the effect that we saw that lasted at least for about two days, can be extended to about a week for what is intended to be a weekly dosing. And that sustained RNA expression would be the type of treatment effect that patients with FA have always hoped for. We've been able to achieve this sustained exposure with a new formulation, which is a remarkable increase in both levels of exposure as well as duration of exposure. And the other issue that we saw in the clinic was a sporadic and infrequent injection site reaction, that limited our ability to increase dosing or dosing frequency.
The new 216 formulation that we're calling DT-216P2 has solved all of these issues in non-clinical studies and puts us back on track to get into patients next year to fulfill the promise of what's already been shown to work in the clinic.
Got it. And can you maybe remind us, it sounds like you didn't make any changes to the backbone itself. I mean, does that suggest you're confident in the profile of DT-216 on a molecular structure? And then ultimately, what are you thinking for the target profile for DT-216P2? Are you thinking it's going to remain an IV? Can you formulate it into a sub-Q? And then as you contemplate the higher exposures, is that going to lead to higher dosing to try to drive more efficacy, or do you think you can use that buffer somewhere else?
We are highly confident in DT-216P2 based on the data that we've seen and shared. That confidence stems from the fact that we, as I mentioned, have seen DT-216 work in patients with FA. And now we have the profile that we're looking for in terms of both extended levels and duration. So, it's, I think, a better situation than programs that rely only on non-clinical or preclinical data, because we've now shown the proof of mechanism and efficacy in humans with the disease. In terms of the properties, actually, this is a well-behaved formulation, so, weekly IV is a well-accepted route and regimen in, you know, in these types of neuromuscular conditions, so certainly, that is an option.
Interestingly, DT-216P2 actually shows very good availability with a sub-Q route of administration as well. And so now we have that added option. And what that also allows is for potentially altering the dosing frequency. So in non-human primates, we have tested sort of the bookends at both weekly sub-Q injection as well as daily sub-Q injection by dividing the doses. And that gives us the option in the clinic to alter the dosing frequency based on whatever pharmacokinetic profile is observed. And so I think the first step in clinical development would be to confirm this PK in phase I with healthy volunteers, and then we would plan to go into patients next year to look for pharmacodynamic effect.
Got it. And I guess as you've sat with the data and just, you know, in general, what's your latest thinking on what the efficacy bar is as you try to improve patients? I mean, do you think something like the 25%-50% increase from baseline is what you've been talking about before? Is that still fair? I guess, do you have any latest views on what the bar would be?
Yeah. So, carriers have about 1/2 the level of frataxin as normal individuals, and they are completely clinically normal, completely asymptomatic. So we know that getting to carrier levels would be a situation where there's, you know, no one would doubt that those levels of frataxin ought to have restoration effect on cellular health. Patients on average, tend to have about 1/2 the level of carriers. But having said that, I do think that any measurable, meaningful increase in frataxin expression that is endogenous frataxin could have a clinically beneficial effect.
Makes sense. Can you just remind us where you are now in the development of P2, what the timelines are for when we might see an entry into the clinic phase I?
Yeah. We are conducting GLP studies in order to confirm the data that we've shared from our non-GLP studies. Those GLP studies are intended to support getting back into the clinic. Our first objective would be to conduct phase I studies in healthy volunteers, and subsequent to that, we would go into patients with FA to look for pharmacodynamic effect. Our plan is to get into these patient studies next year.
Got it. And then, as we sort of look at the commercial landscape in FA, I guess we're seeing SKYCLARYS launch, are there any learnings you're taking away from how, you know, other products are launching, what that tells you about the size of the FA opportunity, you know, potential excitement for other modalities, other mechanisms?
Well, the SKYCLARYS approval and launch has, I think, underscored that there is a big opportunity for anything that, you know, is approved for patients living with FA. And of course, you know, Reata was acquired for, I think it was, you know, north of $7 billion. So any investors who were sort of not sure how big a commercial opportunity the FA unmet need provides, I think that question's been squarely answered. But SKYCLARYS really has no mechanistic impact or is not intended to have any impact on the root cause of the disease, which is driven by frataxin.
So we think that really it supports the opportunity, and there's nothing about SKYCLARYS that negatively impacts the potential for a GeneTAC that would increase endogenous frataxin levels, which really gets at the root cause of the condition. So we feel very well positioned to, you know, add to the complement of treatment options for patients in a way that really no other therapy is positioned to do.
Makes sense. You know, just thinking far ahead, obviously, you mentioned that the goal is to modulate the actual gene expression. So, you know, as you think about potential regulatory paths down the line, is accelerated approval something you can look at? Do you think there's sufficient evidence, or would you have to generate evidence for the FDA that frataxin levels can be a valid surrogate biomarker? I mean, have you thought about this? Have you had any preliminary conversations with the agency?
Yeah, in general, I think it's, you know, I'm in general reticent to try and set any expectations about what the FDA will or won't do with regard to a surrogate, you know, marker-based approval. Having said that, you know, Subpart H was written for these types of situations where you have a well-accepted, known driver. While this can be thought of as a biomarker, it's actually the root cause of the condition. And so, you know, we will certainly keep an eye on whether such an opportunity, you know, presents itself, but it's all based on the evidence generation and the case that's made subsequent to showing frataxin restoration that's sustained with a GeneTAC treatment.
Makes sense. As you mentioned at the start, you have three other programs. So, you know, wanted to shift gears to the Fuchs' corneal dystrophy program. I guess, what makes this indication amenable to a GeneTAC approach? And I guess, can you talk about maybe some of the preclinical data you have that suggests that, you know, GeneTACs can actually modify the disease?
Yeah. You know, Fuchs' dystrophy is a surprisingly common condition. It was described, gosh, over 100 years ago by Dr. Fuchs as having these characteristic clouding of the cornea. But it wasn't until just a few years ago that it was published that this is actually largely driven by a single gene mutation that acts in a dominant negative fashion, and this was a surprise to the field. And you could determine this inheritance just with a blood test. And the mutation occurs in a gene called TCF4, where a single inherited allele of TCF4 that carries this CTG DNA repeat expansion causes a TCF4 RNA to be made that has this long CTG stretch, and the RNA folds over into itself, and it sort of looks like an RNA hairball, which you can see.
You can actually visualize it when you look at the affected cells, which are the endothelial layer of the cornea. So we asked surgeons who conduct these corneal transplants if we could have some of these discarded cornea. And when you look at the cells from patients who've undergone a [keratoplasty] corneal transplant, you can actually see these RNA hairballs as intranuclear dots or foci. They light up when you look at them under the microscope. And the question was, you know, could there be a treatment that could shut off the production of this mutant TCF4 while not touching the wild type?
And that's a very challenging profile for any genomic medicine modality to be able to achieve, and yet we designed TCF4 specific GeneTACs that show that when you take these cells from patients and you incubate them with DT-168, in about a week or two, these foci vanish, and so that's a remarkable observation, and when you look for the wild-type TCF4 RNA, it remains untouched. And so that was in itself a remarkable finding because now you have a way to get these endothelial cells to stay healthy despite the presence of this disease-causing mutation, and that in itself was a remarkable advance. Furthermore, we were able to formulate this so that it can be delivered as an eye drop.
Now we have an IND cleared by the FDA, so we're planning to commence phase I development with DT-168. So having a drug that can restore the natural state despite the presence of this disease-causing mutation is what gives us a path to try and positively impact these patients. Because once they have this cellular health problem in the endothelium of the cornea, over time, those corneal endothelial cells just get worse and worse. They eventually die off, and at the very end stages of the disease, patients are left with really very, very poor visual quality, and a few of them are able to get a keratoplasty. And that's really the only sort of treatment option available at the very, very end.
And so if there was an eye drop that could slow the progression by keeping the cells healthy, that would be a transformative opportunity for these patients to preserve their endothelial function and therefore their visual quality.
Got it. So as you mentioned, the program has the IND cleared, rapidly moving towards the clinic. So can you talk about the clinical program? I guess, you're gonna start phase one. What are your expectations there? And you're also going to run a natural history study. So can you maybe talk about what you hope to learn from there, and maybe how both of these studies can come together to inform, you know, how you're thinking about going forward to phase II?
Yeah. We're starting phase I in order to evaluate the safety and tolerability of DT-168. The, in parallel, we're running an observational study in order to set the metrics to understand both patient characteristics, as well as understand the endpoints and the performance, so that we're not only relying on the literature reports. By getting experience in our own hands with recruiting patients who have genetically confirmed TCF4 mutations, we're going to look at the characteristics as well as three domains of endpoints, where we're looking at a variety of measures of visual quality. But in addition, we can look at other features of the disease pathology, such as corneal swelling or corneal edema, which is measured by anterior eye tomography.
We can also directly visualize the corneal endothelium now with microscopes that are available that can visualize these cells directly in patients. And so by understanding these patient characteristics and metrics, that will inform the right design for a Phase II trial so that we can understand what is the clinical impact of DT-168 in slowing progression of patients with Fuchs.
Got it. And just maybe a question on the disease itself. I guess, at times, early in the early stage of the disease course, it can be asymptomatic. So how do you imagine doctors and physicians using this drug, assuming it makes it to the market? I guess, is there going to be work that needs to be done on patient finding, or would this be more positioned for patients that are more clearly headed towards a corneal transplant in the later stages?
Fuchs' is actually diagnosed routinely by slit lamp examination by either an optometrist or an ophthalmologist. This is already being routinely picked up in annual eye exams. You know, you'll have people by slit lamp examination see that they have an abnormal cornea. And in some cases, surprisingly, patients aren't even actually told that they have this pathology observed in a slit lamp because there's really no treatment option. But often you hear that when people are told, "Oh, yeah, you have an abnormal cornea," all of a sudden, they report all of these visual issues they've been having that they thought was just a function of them getting older. And so the diagnosis is not really the issue.
In fact, there's, if you look at the CDC, vision and eyesight, you know, health, database, it appears that there's, you know, quite a large number of already diagnosed individuals. I think it's, you know, by the IRIS Registry, it's certainly north of a million. It might even be, you know, north of two million diagnosed FECD patients. And then there's widely publicized, epidemiology data that says it's about 4% of adults over the age of 40, which works out to 6.5 million, people with this condition. And if you take the 70%-80% that have this specific mutation, which is called the CTG18.1 mutation, that works out to about 5.5 million people with Fuchs.
And we have heard very consistently that if there was an eye drop that could slow the progression, clinicians would use it in everyone because they would want people to be able to preserve whatever endothelial function they have and whatever vision they have. And so there's already a desire and demand for something that could go after the root cause, particularly if it was administrable as an eye drop.
Got it. I want to pivot to another program, Huntington's disease. That's an area that's been getting a lot of focus now. We have ASOs, we have small molecules. I guess, can you talk about how you can leverage GeneTAC advantages to potentially treat Huntington's in, in the most specific way?
Yeah. In Huntington's, the advantage of GeneTACs relative to other modalities is even more evident because small molecules distribute widely when they're administered. They get into cells, they get into the nucleus. They don't require the fancy delivery modalities that typically are associated with the limitations of genomic medicines, right? Whether it's gene editing, gene therapy, oligonucleotides. So in Huntington's, not only do we have that fundamental advantage, where with a systemic administration, we've seen in preclinical studies in a mouse model, that the GeneTAC gets into the brain, gets into the striatum, and selectively lowers mutant Huntington in the striatum of these mice brains, both with RNA and protein, while keeping wild type spare. Right? And that's a remarkable profile.
This is what the whole field of Huntington's has been hoping for and trying to achieve, which has just been a really difficult profile to achieve. And so in that sense, having the selectivity, having the distribution properties, and being suitable to work essentially across all genotypes, are all unique advantages that the Huntington's gene tech molecules have for patients. So if this works in patients, there's little doubt that this would be, you know, the best in-class profile for patients living with the disease. And, you know, Huntington's is a field that I've worked in.
As you know, I was involved in Auspex, where we developed Austedo for treating chorea of Huntington's, and that's a product that, you know, has had a positive impact, but again, isn't mechanistically anything to do with going after the root cause of the disease. So really excited to bring this forward and try and make a difference in the field.
Got it. Unfortunately, we're out of time, but there's always so much more to ask. But thank you for being here.
Thank you.
And for the informative discussion.
Thank you for your attention and your questions.