Good afternoon, and welcome to Design’s Conference Call. [Operator Instructions]. Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Dr. Sean Jeffries, Chief Operating Officer of Design Therapeutics. You may begin.

Welcome and thank you for joining us today. Earlier, we issued a press release outlining our fourth quarter and full year 2023 financial results and updates across our portfolio of GeneTAC small molecule genomic medicines. The slides that we'll be using today during today's call will be available along with the recording of this call in the investor section of our website at designtx.com. I'm Sean Jeffries, Chief Operating Officer of Design, and I'm joined today on the call by our Chairman and CEO, Dr. Pratik Shah. During this call, we will use forward-looking statements to related to our current expectations and plans, including our program development plans, which are subject to risk and uncertainties. Actual results may differ materially due to various important factors, including those described in the risk factors section of our most recently filed Form 10-K. These statements represent our views as of this call and should not be relied upon as representing our views as of any date in the future. We take no obligation to publicly update any forward-looking statements. With that, I'd like to turn the call over to Dr. Shah.

Thank you, Dr. Jeffries, and good afternoon, everyone. I'm excited to present Design Therapeutics’ First Significant Update for 2024. What makes this company unique and compelling is that we have discovered a new class of small molecules that are designed to dial up or dial down the expression of an individual gene in the genome. When you think about the role of individual genes and disease, there are many monogenic disorders where the single gene that causes the disease is well established. Our vision is to develop small molecules that can provide a restorative therapy and work with the patient's natural genome to help cells read the genes in a manner that restores cellular health despite the presence of the mutations. We are working on at least four major such disorders, Friedreich Ataxia, Fuchs Endothelial Corneal Dystrophy, Huntington’s Disease, and Myotonic Dystrophy. Each of the programs we are pursuing in these areas have the potential to be first in class or best in class. I'm Pratik Shah, I serve as the CEO. I was previously Chairman of Synthorx, which is now part of Sanofi as a result of $2.5 billion acquisition, and prior to that I was CEO of Auspex Pharmaceuticals, which was acquired for $3.5 billion. There we had discovered and developed AUSTEDO, which is now doing over $1 billion in annual revenue, and I'm joined by an accomplished and capable leadership team at Design, including Dr. Sean Jeffries, our Chief Operating Officer; and Dr. Jae Kim. Our Chief Medical Officer. Design's genomic medicine platform has the potential to surpass competing modalities like gene editing and gene therapy for the treatment of these diseases. In addition, we have a five-year operating runway, which enables us to generate clinical proof of concept on up to four programs. Success in any…

[Operator Instructions] That will come from the line of Joseph Schwartz with Leerink Partners.

I was wondering if you could tell us more about the tissue distribution relative to the plasma distribution for DT-216P2 in all of the relevant tissue types for patients affected by FA? And then have you gone back and back tested the ISR profile for the original formulation of DT-216, as well as the new one.

Thank you, Joe, for that question. On the exposure profile. As a reminder, one of the major learnings from our prior clinical trial was that the levels of drug required in tissue are similar to the in vitro EC90. So that eight to 10 animal exposure that we saw in muscle in patients from the trial is something that sets a target. The prior drug product had this disconnect between the duration of plasma and tissue levels in animals. We did not observe any such disconnect in humans and the new drug product DT-216P2 is well behaved in that even in animals there's no longer a disconnect between plasma and tissue levels. And this is what you would expect with a small molecule drug. So if you reference slide 22, muscle biopsies showed the tissue levels were predicted by plasma levels. And that turns out to then also be true with our DT-216P2, where on the right you see that in non-human primate studies, the plasma levels are much higher and so are the tissue levels as shown by muscle biopsy from these NHPs. In addition, we have some additional confirmatory data in a rat distribution study, which we can show you in the subsequent slide here, that there's adequate levels of drugs seen in a broad set of tissues against that target level of eight to 10 animals that we require to see a biological effect. And so, once you exceed the threshold required for biological effect, there's no excessive pharmacology. So we feel that the exciting results we've seen with the plasma PK do also set us up well for good tissue distribution. On your other question about injection site reactions, non-clinical studies show that the injection site reactions were attributable to the excipients in the prior clinical formulation. And now the new non-GLP studies that we've conducted with DT-216P2 support the conclusion that this formulation has resolved the injection site issues and is suitable to progress into confirmatory GLP studies. And in fact, in one arm of the study, we've included daily injections over four weeks, which gives us further confidence that the injection site tolerability issues appear resolved.

Will come from the line of Leonid Timashev with RBC Capital Markets.

This is Nevin on for Leo. Just a couple from us. How are you thinking about designing your Phase 1 for DT-216P3. And then if you show for tax and expression increases in patients, do you think that that might potentially open a path forward for accelerated approval given some of the latest understanding of the biology and the FDA's views on that? And then should we also expect similar patient numbers to the original SAT in that study?

With regard to the Phase 1 studies, because we see this remarkably different PK profile that hits all of the criteria that we were looking for. Our approach here is to first conduct a Phase 1 PK study in healthy volunteers. And this is to confirm the encouraging PK profile of DT-216P2. Once we get data from that study, we then plan to conduct patient studies beginning in 2025. With regard to your next question on FDA and endpoints, I would say that the unmet need here is high. We don't have anything to add in terms of what the FDA may or may not require in the future. We've had productive engagement with the FDA previously and we'll continue to engage with the agency upon resumption of clinical studies.

[Operator Instructions] And that will come from the line of Laura Chico with Wedbush.

Thank you very much for taking the question. I believe you were also working in parallel on some new method development with respect to frataxin and detection on a protein level. I'm wondering if you can share any details kind of on where that methodology stands at present and maybe kind of timing to advance those efforts. And then I have one quick follow up.

We are dedicated to continuing to work on whatever improvements we can make in measurement of frataxin levels. We have robust assays that we've already used in prior clinical studies for measurement of frataxin RNA, and we continue to make improvements on our ability to reliably measure frataxin protein and possible changes and frataxin protein. And we will provide updates on that progress as we progress to the clinic.

And then just quickly with respect to Fuchs, and this may come out in your observational study, but I'm kind of curious with AMD visual acuity measurements are pretty straightforward, but contrast that with something else like geographic atrophy and it's a little bit more challenging to characterize progression or loss of vision. So I'm curious, where does Fuchs kind of shake out in that spectrum and any ideas in terms of kind of measurements that you think might be most promising?

Thank you for the question. We're conducting an observational study in patients with Fuchs, with a confirmed TCF4 mutation to better understand both patient characteristics as well as the characteristics of the endpoints and disease progression. And those come in three different broad buckets. One is a variety of measures of visual quality, and there are numerous reports in the literature of ways to measure the loss of visual quality in patients with Fuchs. And we'll be getting direct experience with those types of measures. Second is measures of edema or fluid buildup in the cornea, because the endothelial cell layers, function is to dehydrate the stroma and keep the cornea clear. And there are ways in the clinic to measure this subclinical edema using anterior eye tomography, for example. We including those measures in the observational study. And third, as you've seen in the back of the eye in geographic atrophy, there are analogous or corresponding ways to directly visualize the corneal endothelium in patients using specialized microscopy. And so, we'll be including those measures as well. And that will give us a variety of tools to examine the characteristics of the patients and the disease progression.

Thank you. I'm showing no further questions in the queue at this time. I would now like to turn the call back over to Mr. Pratik Shah for any closing remarks.

Thank you everyone for joining us on today's call. We look forward to updating you as we continue to make exciting progress at Design.

Thank you all for participating. This concludes today's program. You may now disconnect.