Good afternoon, everyone. My name is Axel Dutte. I'm with the U.K. Healthcare team, Jefferies. Here today, we're joined by Sean Jefferies, CEO at Design Therapeutics. I'll let you carry on with your presentation, and we'll take five minutes at the end for Q&A. Thank you.
Thank you, and thank you to the Jefferies team for inviting us to the London conference. My name is Sean Jefferies, no relation to the bank, and I am Chief Operating Officer at Design Therapeutics. We're a clinical stage biotech company developing small molecule genomic medicines for serious degenerative genetic diseases. So during this presentation, I will make a variety of forward-looking statements related to our current expectations and plans. Actual results may differ materially due to various important factors, including those described in our risk factor section of the most recent Form 10-Q. These statements represent our views as of this presentation and should not be relied upon as representing our views as of any date in the future.
So what makes Design unique and compelling is that we are pioneering a novel class of small molecule genomic medicines that are designed to dial up or dial down the expression of an individual gene in the genome. And when you think about the role of individual genes and disease, there are many monogenic disorders where there's a single gene where the cause of that single gene mutation is well established. Our vision is to develop small molecules that can provide a restorative therapy and work with a patient's own natural genome to help the cells read the genes in a manner that restores cellular health despite the presence of these mutations. And we are working on multiple severe monogenic disorders. We are currently in the clinic for our Fuchs endothelial corneal dystrophy program.
We plan to be in the clinic for our Friedreich ataxia program in the first half of 2025. And all the programs that we're pursuing have the potential to be first or best-in-class medicines. Our genomic medicine platform has shown the promise to surpass competing genomic medicine modalities like gene editing and gene therapy for the treatment of these diseases. And in addition, we have an operating runway into 2029 with our planned operating expenses, which enables us to generate clinical proof of concept on up to all four of these programs pending R&D results. Success in any one of these programs has the potential to generate enormous value for both patients and shareholders. Our initial pipeline is focused on four serious monogenic diseases: Friedreich ataxia, Fuchs endothelial corneal dystrophy, Huntington's disease, and myotonic dystrophy type 1.
Each of these programs has a highly differentiated first or best-in-class profile and serves a significant market. Friedreich ataxia, or FA, is a debilitating neuromuscular disorder where hypertrophic cardiomyopathy is the primary cause of death. It's caused by a GAA repeat expansion in the frataxin gene, which is broadly expressed in the body, and our goal is to restore the expression of endogenous natural frataxin in patients, and despite limitations, we were able to demonstrate increasing frataxin expressions in the clinic in FA patients with our prior drug product, and now we're moving a new drug product, DT216P2, into the clinic with potentially improved injection site safety profile and exposure. We're planning an initial healthy volunteer study in the first half of 2025, and from there, we'll move into patients later in 2025.
In FECD, we have a phase one in healthy volunteers ongoing with data expected in the first half. And we're also pursuing an observational study in patients in order to determine the structure and endpoints of an interventional study. In Huntington's, the field has long sought after an allele-selective small molecule or non-oligo that has the potential to treat this disease. And that's been a profile that's elusive. And we have an inhibitor of mutant Huntington that meets this elusive profile. And similarly, in myotonic dystrophy, we have allele-selective compounds that we believe have best-in-class both foci reduction and splicing improvements. And for both HD and DM1, the next step will be declaration of a development candidate. So GeneTAC molecules have multiple advantages over other approaches in genomic medicine.
So first, GeneTACs, when systemically administered, can distribute to a broad set of tissues and cells to address the root cause of genetic disease without altering the genome. The advantage of GeneTAC molecules becomes more apparent when you consider how small these molecules are compared to other genomic medicine modalities, which further explains the broad distribution to both tissues and cells. Also, by restoring endogenous expression like in FA, the gene products are entirely normal and under normal physiological control. The structure of these GeneTAC molecules enables them to bind and act specifically at the site of the disease-causing mutation. They target the mutant gene and modulate the cell's native transcriptional machinery, selectively dialing up as on the top, as in the case in FA, or dialing down on the bottom to reduce the expression of pathogenic mRNA or protein production and restoring normal cellular function.
The versatility of the GeneTAC platform has allowed us to design molecules towards specific nucleotide repeat expansion diseases on a specific mutant gene, regardless of the number of repeats, and tailor it to express the underlying disease-causing mutation. So let's go into FA. So the root cause of FA lies in a single mutation in the frataxin gene. This mutation causes reduced frataxin expression, which is necessary for mitochondrial function and cellular function. The reduction in frataxin expression causes a constellation of debilitating symptoms, including dysarthria, issues with movements and walking, and unfortunately, hypertrophic cardiomyopathy, which is the primary cause of death in this patient population, and current treatment options are limited, and there's no disease-modifying therapies.
So if you consider the different average frataxin levels in healthy carriers and FA patients, you can see that carriers who do not have FA and have no disease burden in the middle have about half the level of normal frataxin as healthy individuals. FA patients have about a quarter to a fifth the level of normal on average. And of course, around every average, there is a distribution. And individuals who are above or below the mean may need different levels of restoration to get back into the normal zone, which is somewhere near carriers. But in general, the thought is a doubling of frataxin could be the therapeutic goal. So while most of the general population has less than 34 GAA repeats on their frataxin gene, FA patients have hundreds and sometimes over a thousand.
These repeats act like a series of speed bumps that slow the transcription of the frataxin gene. You can actually measure that with a simple blood test. If you take blood cells from an FA patient and you do a PCR to look at the expression of frataxin, you can see the gray bar on the right. FA patients have low levels of frataxin compared to a healthy sibling with two normal functional copies of their frataxin gene. What was truly exciting is that when you incubate these cells from an FA patient with our FA GeneTAC molecules, you see a dose-dependent restoration of frataxin expression back to normal levels. When you incubate cells from a healthy individual, you see no change in the frataxin expression. This is exactly what you would wish for as a treatment for this disease.
We learned from human studies that with our first drug product, the duration of adequate levels of exposure was much shorter than we had expected. While we knew the drug was short-lived in plasma, human studies showed that in muscle biopsies, it was also short-lived in tissue, and that what you got in plasma was very predictive of what was observed in tissue. The tissue levels from human muscle biopsies were approximately eight to 10 nanomolar two days after the injection, and the drug was mostly gone by seven days after the injection. Remarkably, despite this low level of drug and tissues, we saw robust and dose-dependent PD. There was a clear increase in frataxin expression in a dose-dependent fashion at day two, with even one patient starting to approach the carrier levels of frataxin expression.
But the increase in frataxin was largely gone by day seven because the drug was gone. So we were unable to increase dose level or dose frequency because of some observed injection site reactions in these patients with this drug product. So non-clinical studies showed that these injection site reactions were attributable to the formulation excipients in the drug product. So we sought to develop a new drug product that addressed these injection site reactions and sustained the drug exposure. So we believe that we've achieved that with our new drug product, DT216P2. This drug product uses the same API, DT216, and a proprietary and novel excipient, which we believe has a substantial improvement over our prior drug product. First, we've now conducted extensive non-clinical studies with DT216P2, which lead us to believe that the injection site issues have now been resolved.
And second, this has a much more sustained exposure profile, as seen in the single-dose IV PK curve in non-human primates. You can see that the levels are more than tenfold higher than our prior drug product, and with even a quarter or a tenth of the reference dose in orange. So the dark green is one quarter of the orange dose, and the light green is one tenth of the reference dose. Because we're using the same API, DT216, the elimination half-life between the prior drug product and the new drug product is very similar. But the extended exposure is really because of a shorter alpha phase that transitions to the elimination phase at a much higher exposure level. Additionally, DT216P2 has a sustained exposure profile when administered SubQ, as shown on the right-hand side. And the prior drug product was not available by SubQ.
This profile administered SubQ as a blunted Cmax and a sustained exposure with lower peak-to-trough fluctuations. We have flexibility both in the route of administration but also in the frequency. You can see here, this was dosed either daily or weekly for a month. You can see that you can reach steady state and sustain exposure well above the levels that showed PD in patients in our prior formulation. Given the very different PK profile seen in preclinical studies, our plan is to now conduct a phase 1 single-dose clinical trial in healthy volunteers via both IV and SubQ administration, beginning in the first half of 2025, to assess both PK and injection site tolerability. Then we anticipate progressing into patients later in 2025. Let's move on to our other clinical stage program, Fuchs endothelial corneal dystrophy.
So FECD is a degenerative disease of the corneal endothelium that was characterized by Dr. Fuchs over a century ago. The literature widely asserts that the disease affects about 4% of all adults over the age of 40. But only in the last decade or so was it identified that about 70% of these cases are driven by a single gene mutation, a CTG repeat in the TCF4 gene. There are no approved disease-modifying therapies, and treatment is really restricted to things like hypertonic saline that is used to try to dehydrate the cornea. And eventually, a small fraction of patients, you can see that up in red, receive a corneal transplant surgery, of which there are about 18,000-30,000 surgeries done in the U.S. annually. But most patients, unfortunately, quietly suffer from declining visual quality.
On the right is a Photoshop image composed by a patient to show the impact on visual quality. People often liken this to a foggy and rainy windshield. This results in loss of low contrast visual acuity, glare, contrast sensitivity. And we have heard from several clinicians who see these patients regularly that an eye drop that slows progression would be widely used. So FECD is actually caused by dysfunction of the corneal endothelium. You can see this is the basement layer of the cornea. It's a single cell layer that separates the cornea from the aqueous humor. In normal function, these corneal endothelial cells will pump water out of the stroma and into the aqueous humor. And in FECD, these cells don't function properly. And so you get corneal edema or corneal swelling.
And in about 70% of cases, this is caused by a CTG repeat expansion in the TCF4 gene, very akin to myotonic dystrophy. This repeat, this toxic RNA gets expressed, and the C's and G's fold over onto each other, and they create these toxic hairballs, these foci that trap MBNL1 splicing factors and cause missplicing across the cell. And so we've developed DT168 to target these repeats and, in an allele-specific fashion, block the expression of the TCF4 toxic RNA. And you can actually see these foci. You can see them. You can stain for them. And you can see them here. These are cells taken from a surgically removed cornea from a patient who's getting a corneal transplant. And you can stain these cells, and you can see these toxic RNA foci in the top middle panel.
When you take these primary corneal endothelial cells taken directly from a diseased patient and you treat them with DT168, you see these foci disappear, and you can see on the right-hand side that these are very potent, nanomolar potent. DT168 is very potent in the nanomolar potency range, and then, importantly, we were able to develop DT168 into an eye drop, and we're currently progressing with phase one ongoing right now, and we'll have data from that phase one healthy volunteer study in the first half of next year. Additionally, we are determining the potential impact of this type of treatment on the progression of the disease. For that purpose, we're working to gain experience with possible endpoints and patient characteristics and visual quality, but also anterior eye tomography.
This allows us to look in a detailed fashion at corneal swelling, as well as you can actually look at this monolayer of cells directly with corneal endothelial microscopy. We'll be evaluating this across this full patient population for progression. Once we've gathered sufficient data to understand the disease progression and the performance of these endpoints, we'll then follow up with an interventional study. In summary, our GeneTAC platform is designed to address blockbuster markets and is meaningfully differentiated from other genomic medicine modalities. We'll be in the clinic next year with two of our four pipeline programs. We ended the third quarter with approximately $254 million. That gives us a cash runway into 2029 with our current operating plan and would support generating clinical proof of concept on up to four of these programs pending R&D results.
We believe each of these programs has the potential to meaningfully transform the treatment of these debilitating conditions. And success in any one of these programs would create significant value for investors. So thank you for your time and attention. And I have a couple of minutes for questions. And for the FA program, do you look at heterogeneous expression across the patients? So do you have to give different doses depending on their baseline expression?
So we've looked across dozens and dozens of patients with different genotypes. And we see similar potency across all the different patients, really regardless of the repeat length. That makes sense. First of all, these patients typically have hundreds of repeats. And then, additionally, the repeats act like a self-titrating mechanism. So the more repeats that you have, the more transcriptional repression that you see. But additionally, now you have more binding sites, which brings in more drug and a higher concentration of drug at the local site. And so we see a really consistent potency across all patients with all genotypes.
I've got another one, if that's OK.
Yeah.
Just on the excipient, did you say that you developed that in-house?
It's a proprietary and novel excipient. Yeah.
OK.
Yeah.
Are you going to any detail?
I mean, we first looked at your typical excipients. I mean, it makes sense in an effort to try to get the product into the clinic as quickly as possible. And we were able to find a set of excipients that certainly worked, but were obviously suboptimal. So when we discovered that, we pushed outside into proprietary and novel excipient space. And we've seen, I think, really good early data.
Brilliant. Thanks very much.
Given the underlying chronic nature of these diseases and so the need for frequent injections, would a sustained release formulation so that maybe can deliver your GeneTAC platform for three months, six months, whatever, would that be of interest?
I mean, these are patients that are suffering right now with a massive amount of unmet need. Our focus is on demonstrating efficacy and getting something to these patients who have this degenerative condition as quickly as possible. In terms of evaluating things that could improve patient convenience, that's something we can do with subsequent products. But our focus, really guided by the patient community, is to get something for a degenerative condition as quickly as possible to the patient community. Great. Well, thank you all for your time.