NASDAQ:DSGN Design Therapeutics Q4 2023 Earnings Report $3.88 -0.36 (-8.49%) Closing price 04/25/2025 04:00 PM EasternExtended Trading$3.88 0.00 (0.00%) As of 04/25/2025 04:05 PM Eastern Extended trading is trading that happens on electronic markets outside of regular trading hours. This is a fair market value extended hours price provided by Polygon.io. Learn more. Earnings HistoryForecast Design Therapeutics EPS ResultsActual EPS-$0.21Consensus EPS -$0.32Beat/MissBeat by +$0.11One Year Ago EPSN/ADesign Therapeutics Revenue ResultsActual RevenueN/AExpected RevenueN/ABeat/MissN/AYoY Revenue GrowthN/ADesign Therapeutics Announcement DetailsQuarterQ4 2023Date3/19/2024TimeN/AConference Call DateTuesday, March 19, 2024Conference Call Time4:30PM ETUpcoming EarningsDesign Therapeutics' Q1 2025 earnings is scheduled for Tuesday, May 6, 2025, with a conference call scheduled on Thursday, May 8, 2025 at 4:00 PM ET. Check back for transcripts, audio, and key financial metrics as they become available.Conference Call ResourcesConference Call AudioConference Call TranscriptPress Release (8-K)Annual Report (10-K)Earnings HistoryCompany ProfilePowered by Design Therapeutics Q4 2023 Earnings Call TranscriptProvided by QuartrMarch 19, 2024 ShareLink copied to clipboard.There are 7 speakers on the call. Operator00:00:00Good afternoon, and welcome to DESIGN's Conference Call. At this time, all participants are in a listen only mode. There will be a question and answer session after the prepared remarks. Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Doctor. Operator00:00:17Shawn Jeffries, Chief Operating Officer of Design Therapeutics. You may begin. Speaker 100:00:26Welcome and thank you for joining us today. Earlier, we issued a press release outlining our Q4 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 Investors section of our website at designtx.com. I'm Shawn Jeffries, Chief Operating Officer of DESIGN, and I'm joined today on the call by our Chairman and CEO, Doctor. Pratik Shah. Speaker 100:00:58During this call, we will use forward looking statements related to our current expectations and plans, including our program development plans, which are subject to risks 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 ks. 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 Doctor. Speaker 100:01:30Shah. Speaker 200:01:32Thank you, Doctor. 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. Speaker 200:02:08Our 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 4 major such disorders: Friedreich's 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 1st in class or best in class. I'm Pratik Shah and I serve as the CEO. I was previously Chairman of Synthorix, which is now part of Sanofi as a result of a 2 point $5,000,000,000 acquisition and prior to that I was CEO of Auspex Pharmaceuticals, which was acquired for $3,500,000,000 There we had discovered and developed AUSTEDO, which is now doing over $1,000,000,000 in annual revenue. Speaker 200:03:08And I'm joined by an accomplished and capable leadership team at design, including Doctor. Sean Jeffries, our Chief Operating Officer and Doctor. Jay 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 5 year operating runway, which enables us to generate clinical proof of concept on up to 4 programs. Speaker 200:03:39Success in any one of these programs has the potential to generate enormous value for patients and shareholders. Each of our programs is pursuing the treatment of monogenic diseases where the single gene root cause is known. And our therapeutic strategy is to restore the normal gene expression state of this known single gene driver. Each of our programs has a 1st or best in class profile, which has highly differentiating features and each of these are substantial market opportunities. Friedreich's ataxia or FA is a debilitating neuromuscular disorder with hypertrophic cardiomyopathy as the primary cause of death. Speaker 200:04:23It's caused by a GAA repeat mutation in the Fertaxin gene, which is broadly expressed in the body. The goal of our genomic medicine is to increase levels of endogenous Fertaxin and address the monogenic cause of FA. We will address the background in greater detail later in the presentation. We had taken our lead molecule DT-two sixteen for Friedreich's ataxia into clinical trials in 2022 and 2023 and confirmed that DT-two sixteen can increase the level of for taxon RNA expression in patients with FA. We also learned about limitations to the prior formulation in human studies. Speaker 200:05:10Today, we would like to announce a new drug product using the same DT-two sixteen drug substance as before. We refer to this new drug product as DT-two 16 P2, which we believe has properties that resolve these prior barriers to progressing DT-two sixteen further into development. The market opportunity for a systemic therapy that can restore endogenous frataxin levels remains large and unaffected by progress by others in the field. The prior DT-two sixteen drug product had a rapid elimination from plasma during a period called the alpha phase and its exposure profile and therefore drug levels in the plasma were low after only a few hours. The orange curve shows the pharmacokinetics of the prior DT 216 drug product in non human primates. Speaker 200:06:09In green is the PK of DT 216P2, which has a shorter alpha phase and a more rapid transition to the beta phase and therefore a substantial increase in drug levels over a much longer period of time. Due to this increase in exposure, lower levels of administered drug are needed to achieve these desired profiles. In addition, a favorable injection site reaction profile has been seen with the new drug product in non clinical studies. With this new advance, we are back on a path to continue further development of DT-two sixteen for patients with FA. In the time since our last update, we have also advanced the GeneTAC platform and have refined our strategy and priorities for the programs. Speaker 200:07:04Our FECD program data have now been reviewed by the FDA, resulting in an IND cleared to proceed. As a result, we plan to initiate Phase 1 development for DT-one hundred and sixty eight this year. We have also decided to conduct an observational study in patients with FECD prior to conducting an investigational drug treatment trial in patients. We are also announcing for the first time our Huntington's disease program, where we have identified small molecule candidates that exhibit allele selective reduction of mutant Huntington expression, considered an ideal, although elusive profile for molecules that could be reasonably advanced as systemically administered and widely distributing compounds. Similarly, we have identified compounds exhibiting allele selective inhibition of mutant DMPK, which is the root cause of myotonic dystrophy with what we believe are best in class foci reduction and splicing restoration data. Speaker 200:08:17We aim to advance both HD and DM1 programs to declare development candidates. Gene editing and gene therapy have understandably captured the imagination of humankind. Ever since we learned that mutations in single genes cause disease, there has been a desire to edit the genome in some fashion to restore normal cellular health. Other approaches have also emerged that try to get at the root cause of monogenic diseases. However, if GeneTek molecules work in patients, there would be little doubt that they represent the best option in genomic medicine. Speaker 200:08:56Since GeneTek molecules when systemically administered can distribute widely to a broad set of tissues in the target cells broadly to affect the desired outcome without altering a patient's natural genome. Furthermore, investments into new platform companies often suffer from frequent rounds of dilution due to the necessary high R and D burn rates that often require investors to time their investment decisions with great care. Design's approach is more cost effective, making an investment decision for a longer horizon potentially quite attractive. The advantage of GeneTek molecules become more apparent when you consider how much smaller these molecules are than those of competing modalities, which further explains the broad distribution properties. Also by restoring endogenous gene expression like in FA, the gene products are entirely normal and under normal physiologic control. Speaker 200:10:00The mechanism of action of these gene type molecules, which drive these remarkable observations are shown in this animation that I'll walk you through. First, we start with FA. FA is caused by low levels of expressed in the body. So if you look inside the cell and inside the nucleus, the frataxin gene has a GAA repeat expansion shown in red, which causes the RNA polymerase to slow down through this region and produce low levels of for tax and pre mRNA and therefore low levels of express translated protein and that's what drives the dysfunction. GeneTek candidates are hetero bifunctional small molecules where one it it distributes widely, gets into the cell, gets into the nucleus and then recognizes the GAA repeat expansions by binding to the minor groove of intact double stranded DNA in the frataxin gene and the other end of the molecule recruits a transcriptional elongation complex. Speaker 200:11:13The presence of these transcriptional elongation complexes enables the RNA polymerase to now rapidly read through the repeat region and therefore produce normal levels of the Fertaxin pre mRNA. Because the repeat expansion is in an intron, that portion of the RNA is just spliced out normally to produce normal levels of intact full length endogenous mRNA, which produces normal endogenous frataxin protein with all of its natural isoforms under the native regulatory control. This restores frataxin levels and therefore cellular health. Now, for the other side of the platform, long repeat expansions in non coding regions of genes are shown in red in the upper half. This is the case in diseases like fuchsendothelial corneal dystrophy and myotonic dystrophy. Speaker 200:12:13Repeat expansions in coding regions of genes are shown in the lower half in red as is the case in Huntington's disease. And it only takes one allele to cause the disease. So patient has 1 wild type allele shown in the strand without the red and a mutant allele shown in the strand with the red expanded regions. Now, in the upper half, this mutant allele is transcribed by RNA polymerase to create RNA, which then folds over on itself causes tangles and sequesters MBNL proteins. This causes nuclear foci and sliceopathy and other cellular dysfunction. Speaker 200:12:57Now in the lower half, the RNA is transcribed and then translated by ribosomes to make toxic mutant proteins. These proteins cause toxic aggregates as is the case in mutant Huntington protein causing Huntington's disease. GeneTAC molecules selectively target these abnormal alleles at the repeat expansions shown in red and they dial down transcription of toxic mutant gene products and thereby restore cellular health. The wild type alleles continue to function normally. This slide summarizes the mechanism of action that we've just reviewed in the animation. Speaker 200:13:39And now for a deeper dive into our FA program. The root cause of FA lies in the single gene for taxon and it's the reduction in for taxon expression that causes the dysfunction, whether it's in the CNS, musculoskeletal tissues, cardiac hypertrophy or metabolic problems that patients face. When we look at frataxin levels in healthy individuals, carriers and patients. We see that carriers have approximately half the level of their Fotaxin as indicated by the black line representing the group average. Carriers do not have FA and have no disease burden. Speaker 200:14:58FA patients have a quarter to a 5th of normal Of course, around every mean is a distribution and there may be individuals who are above or below the mean And different individuals might require different levels of restoration to get back into the normal zone, which is somewhere near carrier levels. And that is the therapeutic goal, which is thought to be about a doubling. Now most of the general population has less than 34 GAA repeats in their for tax and gene, but someone with FAA has 400 or over 1,000 and these repeats reduce the level of normal FRA toxin. And it turns out you can measure this reduction with a blood test. What's shown on the top right is a result of a PCR test conducted on blood cells from patients. Speaker 200:15:48You can see in the gray bar on the graph that RNA levels are low in patient cells when compared with Fertaxin from an unaffected sibling who has 2 normal copies of the Fertaxin gene. You can imagine our excitement when we were able to observe that when cells from patients are incubated with GeneTek molecules, there's a restoration of protaxin to normal levels in a dose dependent fashion. And when cells from unaffected siblings are incubated with the compounds, the FRAITAXA levels remain unaltered. This is exactly what one would wish for an FA, a medicine that restores natural levels of the single gene product that causes all of these problems. And that's what's so exciting about design is we have an opportunity to provide a restorative therapy of natural protaxent from the patient's own genes and to do it with a small molecule. Speaker 200:16:39Now we've seen that this effect is observed in a wide variety of cell types tested. Shown here is the result of treating terminally differentiated neurons taken from patient derived iPS cells. On the left is an increase in for tax in RNA and on the right is an increase in for tax in protein, which follows a few days later and has a long half life of several days. DT-two sixteen was taken into clinical trials in patients with FA in 2022 2023 with a prior formulation and the trial design is shown here. We learned from the human studies that the duration of adequate levels of exposure of DT-two sixteen was much shorter than expected. Speaker 200:17:26While we knew that the drug was short lived in plasma, human studies showed by muscle biopsy that it was also short lived in tissue and that what you observe in plasma is predictive of what is observed in tissue. The tissue levels from human muscle biopsies were approximately only 8 to 10 nanomolar at day 2 and the drug was almost gone with levels at 1 nanomolar by day 7. Well, despite that, there was a clear increase in for tax and expression observed in treated patients in a dose dependent fashion with one patient's frataxin level going to clinically normal carrier levels as shown in the right. However, the effect was transient because the drug exposure was transient. So, we needed to develop a new drug product that could sustain this drug exposure. Speaker 200:18:23While the drug was generally well tolerated, there were injection site thrombophlebitis events observed, which limited the frequency and levels of dosing with the prior product candidate. Non clinical studies show that these reactions were attributable to the formulation excipients in the drug product. We have now conducted new non GLP animal studies with DT 216P2, which lead us to believe that these issues have now been solved and we can progress to confirmatory GLP studies to get back into the clinic. Furthermore, this new drug product appears suitable for IV administration, compatible with injections or infusions, peripheral or central and also appears suitable for a subcutaneous route of administration. As we showed in the beginning, the new drug product DT 216P2 has a much more sustained exposure profile as seen in the single dose IVPK curve from non human primates. Speaker 200:19:36You can see between day 1 day 7, the levels are 10 to perhaps a 100 fold higher than the prior drug product, even with a quarter to approximately a 10th of the reference dose. This is because of a shorter alpha phase and the elimination half life between the prior and new drug products are very similar. This profile has been achieved by using a proprietary and novel excipient in the formulation. DT216P2 also has a sustained exposure profile when administered by subcutaneous route of administration as shown on the right slide. This profile has a blunted Cmax and a sustained exposure with low peak to trough level fluctuations. Speaker 200:20:30We have flexibility in both route of administration as well as frequency of dosing as seen here with both a daily or weekly subcutaneous injection in non human primates. In the clinical trial, we observed that the tissue level as measured by muscle biopsy was in line with the plasma exposure and this is typical of a small molecule drug. The new drug product also shows that the tissue levels as measured by muscle biopsy in non human primates is in line with plasma exposures, providing comfort that the extended profile seen in plasma will provide the desired extended profile in tissues. Repeat dose studies done in non GLP assessments have also been encouraging and the program will be proceeding to GLP studies, which are planned to be completed by the end of this year to support patient dosing in 2025. Given the very different PK profile seen in the preclinical studies, our plan is now to conduct a Phase 1 clinical trial in healthy volunteers so as to confirm the pharmacokinetics and also to confirm injection site tolerability. Speaker 200:21:54This will also help us in choosing a dosing route and dosing frequency for longer term studies. Subsequent trials will be in FA patients, which we plan to conduct to determine safety, tolerability and the effect of treatment on endogenous for taxin levels. Skyleris is now approved for the treatment of FA and its update confirms that this is a large market opportunity. Since Skyclaris does not affect for taxin levels, we believe this approval has no appreciable impact on the potential opportunity for DT-two sixteen. As we've discussed before, gene tag small molecules have several potential advantages over any other genomic medicine modalities. Speaker 200:22:47Now in case you see any literature reports of possible effects of other molecules on frataxin expression, we show here that GeneTek molecules restore frataxin in a more substantial way than anything literature, which is not surprising given its direct and elegant mechanism of action. Duke's endothelial corneal dystrophy or FECD is a degenerative disease of the cornea that's been known for over 100 years. The literature widely sites that this disease affects 4% of all adult Americans over the age of 40. Only in the last decade though, has it been shown that approximately 70% to 80% of these adults get the condition due to inheriting a monogenic repeat CTG expansion in the TCF4 gene. Based on the current census, this works out to approximately 4,600,000 to 5,300,000 US FECD patients. Speaker 200:23:51There are no approved disease modifying prescription drugs for FECD and treatment is restricted to things like hypertonic saline drops to try and dehydrate the cornea. Eventually, a small fraction of patients get a corneal transplant surgery, which there are about 18000 to 30000 corneal transplant surgeries done in the United States annually. And that's a very small fraction and represented by the red figure. Most patients unfortunately quietly suffer from declining visual quality. On the right is a photoshop image composed by a patient to communicate her loss of visual quality in late stage fuchs. Speaker 200:24:33The analogy is sometimes that of a foggy and rainy shield resulting in loss of low contrast visual acuity, glare and contrast sensitivity. And we have heard from a number of clinicians who see these patients that if there was anything that slowed progression and was well tolerated, they would treat everyone, even patients who were pre symptomatic. FECD is caused by dysfunction in the cells of the endothelial monolayer of the cornea. And these cells have a role in maintaining a dehydrated stroma and keep the cornea free of extracellular matrix deposits. These cells are slowly lost over time due to the disease. Speaker 200:25:20And they're sick because of the TCF4 mutation, which is the CTG repeat expansion in the non coding region of the gene. This inherited mutation can be detected by means of a blood test. So how can one develop a therapy for this? By helping restore cellular health to the endothelial layer. And this cell dysfunction arises from this single inherited mutant allele. Speaker 200:25:48The polymerase reads the mutant allele and makes an RNA containing these repeats. The RNA folds over on itself, creates tangles and you can see them, you can stain for them. These tangles sequester MBN Splice proteins and cause misplicing of a number of downstream genes, which then drives cellular dysfunction. We have designed GeneTx to bind and recognize these long CTG repeat regions in the mutant allele and shut off production of the toxic TCF4 mutant RNA. This slide shows the effectiveness of the GeneTek molecule. Speaker 200:26:28Recall, I said that you could stain for these mutant foci. They're shown in the above panel in the middle section as dots that light up with a fluorescently labeled probe inside the nucleus of endothelial cells taken directly from discarded cornea of patients who've undergone surgery. On the lower panel, we observed that these foci largely go away when these patient corneal cells are treated with DT168. The compound has low nanomolar potency as shown in the dose response curve on the right. This slide shows the results of assaying for wild type TCF4 transcripts from patient cells as shown here. Speaker 200:27:13Drug treatment has no effect on the wild type TCF4 expression. This is an allele selective inhibition, which is highly desirable. This slide looks at misplicing that occurs in a variety of downstream genes at baseline in light green and with drug treatment as mutant TCFR expression is dialed down and sequestered splicing proteins are released, downstream normal splicing is restored leading to a treatment of the cellular dysfunction. Not only do we see an allele selective effect, which is the desired product profile, we have also been able to formulate this to be suitably delivered as an eye drop. All the required non clinical safety studies have been conducted and reviewed by the FDA, resulting in an IND that's been cleared. Speaker 200:28:07We plan to initiate Phase 1 development for DT168 in 2024. We now need to determine the impact of this type of treatment on the progression of this degenerative corneal disease. And for that purpose, we need to gain experience with various possible endpoints and patient characteristics. Therefore, prior to jumping into an interventional trial in patients, we believe the correct strategy for clinical development is to first run an observational study with patients diagnosed with Fuchs who have a genetically confirmed TCF4 expansion mutation. We have begun enrollment in such a trial and plan to recruit 200 patients during the year and plan to follow them for 2 years. Speaker 200:28:57This will enable us to understand the patient characteristics and endpoints that allow us to measure and progression in these patients. Once we have gathered sufficient data to measure disease progression and the performance of various endpoints, we will then focus on an interventional treatment trial. These endpoints include measures of visual quality, anterior eye tomography and also microscopic visualization of the corneal endothelium. We are revealing for the first time our program for Huntington's disease. As you know, HD is a devastating neurodegenerative disease caused by an axionic repeat expansion in the Huntington gene. Speaker 200:29:45A long standing objective in the field has been for there to be a selective inhibition of the mutant Huntington allele with a molecule that can distribute widely to the affected cells. And this has been a very elusive profile to achieve. Here is data looking at the effect of 1 of our 2 candidate molecules on wild type and mutant Huntington RNA from treated patient fibroblast cells. The left panel shows data from a normal onset HD genotype and the right panel, the effect on an early onset HD genotype, which contains a longer repeat expansion. We observe an allele selective inhibition of mutant Huntington RNA. Speaker 200:30:31The effect is even more pronounced in the early onset genotype. This is particularly encouraging because regardless of the genotype, it is known that the repeats undergo somatic expansion of various lengths in different neurons over time. And this data suggests that the compound would have an even more profound impact on those cells, which have undergone a longer somatic expansion of their CAG repeats. This slide shows that the RNA effect shown earlier translated to the expected effect on mutant Huntington protein. The above panel shows that a mutant huntingtin selective antibody is able to detect mutant protein disappearing with increasing concentrations of drug. Speaker 200:31:22The middle panel uses an antibody that detects both wild type and mutant huntingtin. And you can see an expected reduction due to the mutant protein being reduced. Now the size of these proteins are hard to resolve in the normal onset genotype in the left panel gels. But in the early onset genotypes, the mutant and wild type proteins are different enough in size to actually show up as 2 bands on the middle panel on the right side. This is the RNA inhibition data from candidate 2 showing a similar allele selective inhibition. Speaker 200:31:57And this is the protein inhibition data from candidate 2 also showing an effect as expected from the RNA inhibition. We expect to choose one of these compounds to move forward with as a development candidate once further testing is conducted. Having seen these exciting profiles, we are encouraged at the preliminary non GLP tolerability of these molecules in both rodents and non human primates. We've conducted pharmacology assessments of these molecules and have selected a widely used Q175 DN pharmacodynamic mouse model to assess PD. We observe in this study that with systemic administration, there is an over 50% reduction of mutant huntingtinRNA and protein in the striatum of mice, which supports the idea that this compound is able to get into the brain and get into the cells and have the intended effect with systemic administration. Speaker 200:33:06We are very encouraged to see this in vivo confirmation of the activity seen in cells derived from patients. If this pans out, HD GeneTek molecules hold the potential of selectively reducing mutant Huntington with a widespread distribution profile and systemic administration regardless of the patient's HD genotype. This would be a best in class profile. Our next milestone for the program is to choose a development candidate. We are also working on a program in myotonic dystrophy. Speaker 200:33:44DM1 is caused by a CTG repeat in the DMPK gene in the 3 prime untranslated region. Much like the FVCD story, mutant DMPK RNA form toxic foci and downstream splicing dysfunction. It would be highly desirable and a best in class profile to have a selective inhibitor of mutant DMPK for the treatment of myotonic dystrophy that would distribute broadly in all affected tissues and cell types. This data shows that we have a gene tag molecule that reduce these toxic DMPK Foci with low nanomolar potency. This is a splicing index from panel of misplice genes with 7 days of treatment from patient derived myotubes showing that the DM1 Fosai Reduction does have beneficial downstream effect on cellular health. Speaker 200:34:43The next milestone for this program is DC declaration. In summary, we have a promising new platform for genomic medicine that is meaningfully differentiated from other genomic medicine modalities. We have 4 drug programs, each in significant markets and with highly differentiated profiles. The first two of which are expected to be clinical stage next year. We ended 2023 with approximately $281,000,000 and this gives us a cash runway for the next 5 years. Speaker 200:35:26Pending future R and D results and ongoing strategic review, this cash runway would support generating clinical proof of concept data in up to 4 programs. We believe each of these programs has the potential to transform the treatment of these debilitating conditions and success in any one of these would create significant value for investors. We are dedicated to moving these molecules forward and welcome you to participate in this journey and help us get to success. This concludes our prepared remarks and we'll now move to Q and A. Operator? Speaker 300:36:47And that will come from the line of Joseph Schwartz with Leerink Partners. Please go ahead. Speaker 400:36:53Hi, thanks very much for the update. 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-two sixteen as well as the new one? Thank you. Speaker 200:37:27Thank 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 AC90. So that 8 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. Speaker 200:38:15And 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 that 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 a subsequent slide here that there's adequate levels of drug seen in a broad set of tissues against that target level of 8 to 10 nanomoles that we require to see a biological effect. Speaker 200:39:33And so once you exceed the threshold required for biological effect, there is 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 4 weeks, which gives us further confidence that the injection site tolerability issues appear resolved. Speaker 400:40:44Great. Thank you. Speaker 300:40:47Thank you. One moment for our next question. And that will come from the line of Leonid Timoshenko with RBC Capital Markets. Your line is open. Speaker 500:41:03Hi, everyone. This is Nevan on for Leo. Thank you for taking our questions. So just a couple from us. How are you thinking about designing your Phase 1 for DT 216 P2? Speaker 500:41:16And 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 biology and the FDA's views on that? And then should we also expect similar patient numbers to the original sat in that study? Thank you. Speaker 200:41:40Okay. Thank you for the question. 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-two 16P2. Speaker 200:42:15Once 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. Okay. Speaker 200:43:10Thank you. Speaker 300:43:12Thank you. One moment for our next question. And that will come from the line of Laura Chico with Wedbush. Your line is open. Laura, your line is open. Speaker 600:43:36Sorry about that. Thank you very much for taking the question. I believe you were also working in parallel on some new method development with respect to for tax 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. Speaker 200:44:01Thank you, Laura. We are dedicated to continuing to work on whatever improvements we can make in measurement of for taxon levels. We have robust assays that we've already used in prior clinical studies for measurement of Fertaxin RNA. And we continue to make improvements on our ability to reliably measure for tax and protein and possible changes in for tax and protein and we'll provide updates on that progress as we progress to the clinic. Speaker 600:44:43Okay. Thank you very much. And then just quickly with respect to Fuchs, I know this may have 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. Speaker 200:45:20Thank 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 3 different broad buckets. 1 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. 2nd 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. Speaker 200:46:24And there are ways in the clinic to measure this subclinical edema using anterior eye tomography, for example. So we including those measures in the observational study. And 3rd, as you've there are analogous or corresponding ways to directly 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. Speaker 600:47:08Thanks very much. Speaker 300:47:11Thank 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. Speaker 200:47:20Well, 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.Read morePowered by Conference Call Audio Live Call not available Earnings Conference CallDesign Therapeutics Q4 202300:00 / 00:00Speed:1x1.25x1.5x2x Earnings DocumentsPress Release(8-K)Annual report(10-K) Design Therapeutics Earnings HeadlinesDesign Therapeutics Announces Update on DT-168 Program for Fuchs Endothelial Corneal Dystrophy at Eyecelerator 2025April 22, 2025 | nasdaq.comDesign Therapeutics to Present Phase 1 Data for Fuchs Endothelial Corneal Dystrophy Program at Eyecelerator @ Park City 2025April 21, 2025 | globenewswire.comHere’s How to Claim Your Stake in Elon’s Private Company, xAIEven though xAI is a private company, tech legend and angel investor Jeff Brown found a way for everyday folks like you… To partner with Elon on what he believes will be the biggest AI project of the century… Starting with as little as $500.April 27, 2025 | Brownstone Research (Ad)Design Therapeutics appoints Chris Storgard as CMOApril 19, 2025 | markets.businessinsider.comDesign Therapeutics Appoints Veteran Industry Executive Chris Storgard, M.D., as Chief Medical OfficerApril 17, 2025 | globenewswire.comBright Peak Therapeutics Appoints John Schmid to its Board of DirectorsApril 17, 2025 | markets.businessinsider.comSee More Design Therapeutics Headlines Get Earnings Announcements in your inboxWant to stay updated on the latest earnings announcements and upcoming reports for companies like Design Therapeutics? Sign up for Earnings360's daily newsletter to receive timely earnings updates on Design Therapeutics and other key companies, straight to your email. Email Address About Design TherapeuticsDesign Therapeutics (NASDAQ:DSGN) a biopharmaceutical company, researches, designs, develops, and commercializes small molecule therapeutic drugs for the treatment of genetic diseases in the United States. The company utilizes its GeneTAC platform to design and develop therapeutic candidates for inherited diseases caused by nucleotide repeat expansion. Its lead product candidates for potentially disease-modifying treatment comprises Friedreich Ataxia, a monogenic, autosomal recessive, progressive multi-system disease that affects organ systems dependent on mitochondrial function that brings to neurological, cardiac, and metabolic dysfunction; Myotonic Dystrophy Type-1, a dominantly-inherited, monogenic progressive neuromuscular disease affecting skeletal muscle, heart, brain, and other organs; Fuchs Endothelial Corneal Dystrophy, a genetic eye disease characterized by bilateral degeneration of corneal endothelial cells and progressive loss of vision; and Huntington's Disease, a dominantly inherited, monogenic neurodegenerative disease characterized by movement, cognitive, and psychiatric disorders. Design Therapeutics, Inc. was incorporated in 2017 and is headquartered in Carlsbad, California.View Design Therapeutics ProfileRead more More Earnings Resources from MarketBeat Earnings Tools Today's Earnings Tomorrow's Earnings Next Week's Earnings Upcoming Earnings Calls Earnings Newsletter Earnings Call Transcripts Earnings Beats & Misses Corporate Guidance Earnings Screener Earnings By Country U.S. Earnings Reports Canadian Earnings Reports U.K. Earnings Reports Latest Articles Markets Think Robinhood Earnings Could Send the Stock UpIs the Floor in for Lam Research After Bullish Earnings?Market Anticipation Builds: Joby Stock Climbs Ahead of EarningsIs Intuitive Surgical a Buy After Volatile Reaction to Earnings?Seismic Shift at Intel: Massive Layoffs Precede Crucial EarningsRocket Lab Lands New Contract, Builds Momentum Ahead of EarningsAmazon's Earnings Could Fuel a Rapid Breakout Upcoming Earnings Cadence Design Systems (4/28/2025)Welltower (4/28/2025)Waste Management (4/28/2025)AstraZeneca (4/29/2025)Mondelez International (4/29/2025)PayPal (4/29/2025)Starbucks (4/29/2025)DoorDash (4/29/2025)Honeywell International (4/29/2025)Regeneron Pharmaceuticals (4/29/2025) Get 30 Days of MarketBeat All Access for Free Sign up for MarketBeat All Access to gain access to MarketBeat's full suite of research tools. 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There are 7 speakers on the call. Operator00:00:00Good afternoon, and welcome to DESIGN's Conference Call. At this time, all participants are in a listen only mode. There will be a question and answer session after the prepared remarks. Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Doctor. Operator00:00:17Shawn Jeffries, Chief Operating Officer of Design Therapeutics. You may begin. Speaker 100:00:26Welcome and thank you for joining us today. Earlier, we issued a press release outlining our Q4 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 Investors section of our website at designtx.com. I'm Shawn Jeffries, Chief Operating Officer of DESIGN, and I'm joined today on the call by our Chairman and CEO, Doctor. Pratik Shah. Speaker 100:00:58During this call, we will use forward looking statements related to our current expectations and plans, including our program development plans, which are subject to risks 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 ks. 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 Doctor. Speaker 100:01:30Shah. Speaker 200:01:32Thank you, Doctor. 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. Speaker 200:02:08Our 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 4 major such disorders: Friedreich's 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 1st in class or best in class. I'm Pratik Shah and I serve as the CEO. I was previously Chairman of Synthorix, which is now part of Sanofi as a result of a 2 point $5,000,000,000 acquisition and prior to that I was CEO of Auspex Pharmaceuticals, which was acquired for $3,500,000,000 There we had discovered and developed AUSTEDO, which is now doing over $1,000,000,000 in annual revenue. Speaker 200:03:08And I'm joined by an accomplished and capable leadership team at design, including Doctor. Sean Jeffries, our Chief Operating Officer and Doctor. Jay 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 5 year operating runway, which enables us to generate clinical proof of concept on up to 4 programs. Speaker 200:03:39Success in any one of these programs has the potential to generate enormous value for patients and shareholders. Each of our programs is pursuing the treatment of monogenic diseases where the single gene root cause is known. And our therapeutic strategy is to restore the normal gene expression state of this known single gene driver. Each of our programs has a 1st or best in class profile, which has highly differentiating features and each of these are substantial market opportunities. Friedreich's ataxia or FA is a debilitating neuromuscular disorder with hypertrophic cardiomyopathy as the primary cause of death. Speaker 200:04:23It's caused by a GAA repeat mutation in the Fertaxin gene, which is broadly expressed in the body. The goal of our genomic medicine is to increase levels of endogenous Fertaxin and address the monogenic cause of FA. We will address the background in greater detail later in the presentation. We had taken our lead molecule DT-two sixteen for Friedreich's ataxia into clinical trials in 2022 and 2023 and confirmed that DT-two sixteen can increase the level of for taxon RNA expression in patients with FA. We also learned about limitations to the prior formulation in human studies. Speaker 200:05:10Today, we would like to announce a new drug product using the same DT-two sixteen drug substance as before. We refer to this new drug product as DT-two 16 P2, which we believe has properties that resolve these prior barriers to progressing DT-two sixteen further into development. The market opportunity for a systemic therapy that can restore endogenous frataxin levels remains large and unaffected by progress by others in the field. The prior DT-two sixteen drug product had a rapid elimination from plasma during a period called the alpha phase and its exposure profile and therefore drug levels in the plasma were low after only a few hours. The orange curve shows the pharmacokinetics of the prior DT 216 drug product in non human primates. Speaker 200:06:09In green is the PK of DT 216P2, which has a shorter alpha phase and a more rapid transition to the beta phase and therefore a substantial increase in drug levels over a much longer period of time. Due to this increase in exposure, lower levels of administered drug are needed to achieve these desired profiles. In addition, a favorable injection site reaction profile has been seen with the new drug product in non clinical studies. With this new advance, we are back on a path to continue further development of DT-two sixteen for patients with FA. In the time since our last update, we have also advanced the GeneTAC platform and have refined our strategy and priorities for the programs. Speaker 200:07:04Our FECD program data have now been reviewed by the FDA, resulting in an IND cleared to proceed. As a result, we plan to initiate Phase 1 development for DT-one hundred and sixty eight this year. We have also decided to conduct an observational study in patients with FECD prior to conducting an investigational drug treatment trial in patients. We are also announcing for the first time our Huntington's disease program, where we have identified small molecule candidates that exhibit allele selective reduction of mutant Huntington expression, considered an ideal, although elusive profile for molecules that could be reasonably advanced as systemically administered and widely distributing compounds. Similarly, we have identified compounds exhibiting allele selective inhibition of mutant DMPK, which is the root cause of myotonic dystrophy with what we believe are best in class foci reduction and splicing restoration data. Speaker 200:08:17We aim to advance both HD and DM1 programs to declare development candidates. Gene editing and gene therapy have understandably captured the imagination of humankind. Ever since we learned that mutations in single genes cause disease, there has been a desire to edit the genome in some fashion to restore normal cellular health. Other approaches have also emerged that try to get at the root cause of monogenic diseases. However, if GeneTek molecules work in patients, there would be little doubt that they represent the best option in genomic medicine. Speaker 200:08:56Since GeneTek molecules when systemically administered can distribute widely to a broad set of tissues in the target cells broadly to affect the desired outcome without altering a patient's natural genome. Furthermore, investments into new platform companies often suffer from frequent rounds of dilution due to the necessary high R and D burn rates that often require investors to time their investment decisions with great care. Design's approach is more cost effective, making an investment decision for a longer horizon potentially quite attractive. The advantage of GeneTek molecules become more apparent when you consider how much smaller these molecules are than those of competing modalities, which further explains the broad distribution properties. Also by restoring endogenous gene expression like in FA, the gene products are entirely normal and under normal physiologic control. Speaker 200:10:00The mechanism of action of these gene type molecules, which drive these remarkable observations are shown in this animation that I'll walk you through. First, we start with FA. FA is caused by low levels of expressed in the body. So if you look inside the cell and inside the nucleus, the frataxin gene has a GAA repeat expansion shown in red, which causes the RNA polymerase to slow down through this region and produce low levels of for tax and pre mRNA and therefore low levels of express translated protein and that's what drives the dysfunction. GeneTek candidates are hetero bifunctional small molecules where one it it distributes widely, gets into the cell, gets into the nucleus and then recognizes the GAA repeat expansions by binding to the minor groove of intact double stranded DNA in the frataxin gene and the other end of the molecule recruits a transcriptional elongation complex. Speaker 200:11:13The presence of these transcriptional elongation complexes enables the RNA polymerase to now rapidly read through the repeat region and therefore produce normal levels of the Fertaxin pre mRNA. Because the repeat expansion is in an intron, that portion of the RNA is just spliced out normally to produce normal levels of intact full length endogenous mRNA, which produces normal endogenous frataxin protein with all of its natural isoforms under the native regulatory control. This restores frataxin levels and therefore cellular health. Now, for the other side of the platform, long repeat expansions in non coding regions of genes are shown in red in the upper half. This is the case in diseases like fuchsendothelial corneal dystrophy and myotonic dystrophy. Speaker 200:12:13Repeat expansions in coding regions of genes are shown in the lower half in red as is the case in Huntington's disease. And it only takes one allele to cause the disease. So patient has 1 wild type allele shown in the strand without the red and a mutant allele shown in the strand with the red expanded regions. Now, in the upper half, this mutant allele is transcribed by RNA polymerase to create RNA, which then folds over on itself causes tangles and sequesters MBNL proteins. This causes nuclear foci and sliceopathy and other cellular dysfunction. Speaker 200:12:57Now in the lower half, the RNA is transcribed and then translated by ribosomes to make toxic mutant proteins. These proteins cause toxic aggregates as is the case in mutant Huntington protein causing Huntington's disease. GeneTAC molecules selectively target these abnormal alleles at the repeat expansions shown in red and they dial down transcription of toxic mutant gene products and thereby restore cellular health. The wild type alleles continue to function normally. This slide summarizes the mechanism of action that we've just reviewed in the animation. Speaker 200:13:39And now for a deeper dive into our FA program. The root cause of FA lies in the single gene for taxon and it's the reduction in for taxon expression that causes the dysfunction, whether it's in the CNS, musculoskeletal tissues, cardiac hypertrophy or metabolic problems that patients face. When we look at frataxin levels in healthy individuals, carriers and patients. We see that carriers have approximately half the level of their Fotaxin as indicated by the black line representing the group average. Carriers do not have FA and have no disease burden. Speaker 200:14:58FA patients have a quarter to a 5th of normal Of course, around every mean is a distribution and there may be individuals who are above or below the mean And different individuals might require different levels of restoration to get back into the normal zone, which is somewhere near carrier levels. And that is the therapeutic goal, which is thought to be about a doubling. Now most of the general population has less than 34 GAA repeats in their for tax and gene, but someone with FAA has 400 or over 1,000 and these repeats reduce the level of normal FRA toxin. And it turns out you can measure this reduction with a blood test. What's shown on the top right is a result of a PCR test conducted on blood cells from patients. Speaker 200:15:48You can see in the gray bar on the graph that RNA levels are low in patient cells when compared with Fertaxin from an unaffected sibling who has 2 normal copies of the Fertaxin gene. You can imagine our excitement when we were able to observe that when cells from patients are incubated with GeneTek molecules, there's a restoration of protaxin to normal levels in a dose dependent fashion. And when cells from unaffected siblings are incubated with the compounds, the FRAITAXA levels remain unaltered. This is exactly what one would wish for an FA, a medicine that restores natural levels of the single gene product that causes all of these problems. And that's what's so exciting about design is we have an opportunity to provide a restorative therapy of natural protaxent from the patient's own genes and to do it with a small molecule. Speaker 200:16:39Now we've seen that this effect is observed in a wide variety of cell types tested. Shown here is the result of treating terminally differentiated neurons taken from patient derived iPS cells. On the left is an increase in for tax in RNA and on the right is an increase in for tax in protein, which follows a few days later and has a long half life of several days. DT-two sixteen was taken into clinical trials in patients with FA in 2022 2023 with a prior formulation and the trial design is shown here. We learned from the human studies that the duration of adequate levels of exposure of DT-two sixteen was much shorter than expected. Speaker 200:17:26While we knew that the drug was short lived in plasma, human studies showed by muscle biopsy that it was also short lived in tissue and that what you observe in plasma is predictive of what is observed in tissue. The tissue levels from human muscle biopsies were approximately only 8 to 10 nanomolar at day 2 and the drug was almost gone with levels at 1 nanomolar by day 7. Well, despite that, there was a clear increase in for tax and expression observed in treated patients in a dose dependent fashion with one patient's frataxin level going to clinically normal carrier levels as shown in the right. However, the effect was transient because the drug exposure was transient. So, we needed to develop a new drug product that could sustain this drug exposure. Speaker 200:18:23While the drug was generally well tolerated, there were injection site thrombophlebitis events observed, which limited the frequency and levels of dosing with the prior product candidate. Non clinical studies show that these reactions were attributable to the formulation excipients in the drug product. We have now conducted new non GLP animal studies with DT 216P2, which lead us to believe that these issues have now been solved and we can progress to confirmatory GLP studies to get back into the clinic. Furthermore, this new drug product appears suitable for IV administration, compatible with injections or infusions, peripheral or central and also appears suitable for a subcutaneous route of administration. As we showed in the beginning, the new drug product DT 216P2 has a much more sustained exposure profile as seen in the single dose IVPK curve from non human primates. Speaker 200:19:36You can see between day 1 day 7, the levels are 10 to perhaps a 100 fold higher than the prior drug product, even with a quarter to approximately a 10th of the reference dose. This is because of a shorter alpha phase and the elimination half life between the prior and new drug products are very similar. This profile has been achieved by using a proprietary and novel excipient in the formulation. DT216P2 also has a sustained exposure profile when administered by subcutaneous route of administration as shown on the right slide. This profile has a blunted Cmax and a sustained exposure with low peak to trough level fluctuations. Speaker 200:20:30We have flexibility in both route of administration as well as frequency of dosing as seen here with both a daily or weekly subcutaneous injection in non human primates. In the clinical trial, we observed that the tissue level as measured by muscle biopsy was in line with the plasma exposure and this is typical of a small molecule drug. The new drug product also shows that the tissue levels as measured by muscle biopsy in non human primates is in line with plasma exposures, providing comfort that the extended profile seen in plasma will provide the desired extended profile in tissues. Repeat dose studies done in non GLP assessments have also been encouraging and the program will be proceeding to GLP studies, which are planned to be completed by the end of this year to support patient dosing in 2025. Given the very different PK profile seen in the preclinical studies, our plan is now to conduct a Phase 1 clinical trial in healthy volunteers so as to confirm the pharmacokinetics and also to confirm injection site tolerability. Speaker 200:21:54This will also help us in choosing a dosing route and dosing frequency for longer term studies. Subsequent trials will be in FA patients, which we plan to conduct to determine safety, tolerability and the effect of treatment on endogenous for taxin levels. Skyleris is now approved for the treatment of FA and its update confirms that this is a large market opportunity. Since Skyclaris does not affect for taxin levels, we believe this approval has no appreciable impact on the potential opportunity for DT-two sixteen. As we've discussed before, gene tag small molecules have several potential advantages over any other genomic medicine modalities. Speaker 200:22:47Now in case you see any literature reports of possible effects of other molecules on frataxin expression, we show here that GeneTek molecules restore frataxin in a more substantial way than anything literature, which is not surprising given its direct and elegant mechanism of action. Duke's endothelial corneal dystrophy or FECD is a degenerative disease of the cornea that's been known for over 100 years. The literature widely sites that this disease affects 4% of all adult Americans over the age of 40. Only in the last decade though, has it been shown that approximately 70% to 80% of these adults get the condition due to inheriting a monogenic repeat CTG expansion in the TCF4 gene. Based on the current census, this works out to approximately 4,600,000 to 5,300,000 US FECD patients. Speaker 200:23:51There are no approved disease modifying prescription drugs for FECD and treatment is restricted to things like hypertonic saline drops to try and dehydrate the cornea. Eventually, a small fraction of patients get a corneal transplant surgery, which there are about 18000 to 30000 corneal transplant surgeries done in the United States annually. And that's a very small fraction and represented by the red figure. Most patients unfortunately quietly suffer from declining visual quality. On the right is a photoshop image composed by a patient to communicate her loss of visual quality in late stage fuchs. Speaker 200:24:33The analogy is sometimes that of a foggy and rainy shield resulting in loss of low contrast visual acuity, glare and contrast sensitivity. And we have heard from a number of clinicians who see these patients that if there was anything that slowed progression and was well tolerated, they would treat everyone, even patients who were pre symptomatic. FECD is caused by dysfunction in the cells of the endothelial monolayer of the cornea. And these cells have a role in maintaining a dehydrated stroma and keep the cornea free of extracellular matrix deposits. These cells are slowly lost over time due to the disease. Speaker 200:25:20And they're sick because of the TCF4 mutation, which is the CTG repeat expansion in the non coding region of the gene. This inherited mutation can be detected by means of a blood test. So how can one develop a therapy for this? By helping restore cellular health to the endothelial layer. And this cell dysfunction arises from this single inherited mutant allele. Speaker 200:25:48The polymerase reads the mutant allele and makes an RNA containing these repeats. The RNA folds over on itself, creates tangles and you can see them, you can stain for them. These tangles sequester MBN Splice proteins and cause misplicing of a number of downstream genes, which then drives cellular dysfunction. We have designed GeneTx to bind and recognize these long CTG repeat regions in the mutant allele and shut off production of the toxic TCF4 mutant RNA. This slide shows the effectiveness of the GeneTek molecule. Speaker 200:26:28Recall, I said that you could stain for these mutant foci. They're shown in the above panel in the middle section as dots that light up with a fluorescently labeled probe inside the nucleus of endothelial cells taken directly from discarded cornea of patients who've undergone surgery. On the lower panel, we observed that these foci largely go away when these patient corneal cells are treated with DT168. The compound has low nanomolar potency as shown in the dose response curve on the right. This slide shows the results of assaying for wild type TCF4 transcripts from patient cells as shown here. Speaker 200:27:13Drug treatment has no effect on the wild type TCF4 expression. This is an allele selective inhibition, which is highly desirable. This slide looks at misplicing that occurs in a variety of downstream genes at baseline in light green and with drug treatment as mutant TCFR expression is dialed down and sequestered splicing proteins are released, downstream normal splicing is restored leading to a treatment of the cellular dysfunction. Not only do we see an allele selective effect, which is the desired product profile, we have also been able to formulate this to be suitably delivered as an eye drop. All the required non clinical safety studies have been conducted and reviewed by the FDA, resulting in an IND that's been cleared. Speaker 200:28:07We plan to initiate Phase 1 development for DT168 in 2024. We now need to determine the impact of this type of treatment on the progression of this degenerative corneal disease. And for that purpose, we need to gain experience with various possible endpoints and patient characteristics. Therefore, prior to jumping into an interventional trial in patients, we believe the correct strategy for clinical development is to first run an observational study with patients diagnosed with Fuchs who have a genetically confirmed TCF4 expansion mutation. We have begun enrollment in such a trial and plan to recruit 200 patients during the year and plan to follow them for 2 years. Speaker 200:28:57This will enable us to understand the patient characteristics and endpoints that allow us to measure and progression in these patients. Once we have gathered sufficient data to measure disease progression and the performance of various endpoints, we will then focus on an interventional treatment trial. These endpoints include measures of visual quality, anterior eye tomography and also microscopic visualization of the corneal endothelium. We are revealing for the first time our program for Huntington's disease. As you know, HD is a devastating neurodegenerative disease caused by an axionic repeat expansion in the Huntington gene. Speaker 200:29:45A long standing objective in the field has been for there to be a selective inhibition of the mutant Huntington allele with a molecule that can distribute widely to the affected cells. And this has been a very elusive profile to achieve. Here is data looking at the effect of 1 of our 2 candidate molecules on wild type and mutant Huntington RNA from treated patient fibroblast cells. The left panel shows data from a normal onset HD genotype and the right panel, the effect on an early onset HD genotype, which contains a longer repeat expansion. We observe an allele selective inhibition of mutant Huntington RNA. Speaker 200:30:31The effect is even more pronounced in the early onset genotype. This is particularly encouraging because regardless of the genotype, it is known that the repeats undergo somatic expansion of various lengths in different neurons over time. And this data suggests that the compound would have an even more profound impact on those cells, which have undergone a longer somatic expansion of their CAG repeats. This slide shows that the RNA effect shown earlier translated to the expected effect on mutant Huntington protein. The above panel shows that a mutant huntingtin selective antibody is able to detect mutant protein disappearing with increasing concentrations of drug. Speaker 200:31:22The middle panel uses an antibody that detects both wild type and mutant huntingtin. And you can see an expected reduction due to the mutant protein being reduced. Now the size of these proteins are hard to resolve in the normal onset genotype in the left panel gels. But in the early onset genotypes, the mutant and wild type proteins are different enough in size to actually show up as 2 bands on the middle panel on the right side. This is the RNA inhibition data from candidate 2 showing a similar allele selective inhibition. Speaker 200:31:57And this is the protein inhibition data from candidate 2 also showing an effect as expected from the RNA inhibition. We expect to choose one of these compounds to move forward with as a development candidate once further testing is conducted. Having seen these exciting profiles, we are encouraged at the preliminary non GLP tolerability of these molecules in both rodents and non human primates. We've conducted pharmacology assessments of these molecules and have selected a widely used Q175 DN pharmacodynamic mouse model to assess PD. We observe in this study that with systemic administration, there is an over 50% reduction of mutant huntingtinRNA and protein in the striatum of mice, which supports the idea that this compound is able to get into the brain and get into the cells and have the intended effect with systemic administration. Speaker 200:33:06We are very encouraged to see this in vivo confirmation of the activity seen in cells derived from patients. If this pans out, HD GeneTek molecules hold the potential of selectively reducing mutant Huntington with a widespread distribution profile and systemic administration regardless of the patient's HD genotype. This would be a best in class profile. Our next milestone for the program is to choose a development candidate. We are also working on a program in myotonic dystrophy. Speaker 200:33:44DM1 is caused by a CTG repeat in the DMPK gene in the 3 prime untranslated region. Much like the FVCD story, mutant DMPK RNA form toxic foci and downstream splicing dysfunction. It would be highly desirable and a best in class profile to have a selective inhibitor of mutant DMPK for the treatment of myotonic dystrophy that would distribute broadly in all affected tissues and cell types. This data shows that we have a gene tag molecule that reduce these toxic DMPK Foci with low nanomolar potency. This is a splicing index from panel of misplice genes with 7 days of treatment from patient derived myotubes showing that the DM1 Fosai Reduction does have beneficial downstream effect on cellular health. Speaker 200:34:43The next milestone for this program is DC declaration. In summary, we have a promising new platform for genomic medicine that is meaningfully differentiated from other genomic medicine modalities. We have 4 drug programs, each in significant markets and with highly differentiated profiles. The first two of which are expected to be clinical stage next year. We ended 2023 with approximately $281,000,000 and this gives us a cash runway for the next 5 years. Speaker 200:35:26Pending future R and D results and ongoing strategic review, this cash runway would support generating clinical proof of concept data in up to 4 programs. We believe each of these programs has the potential to transform the treatment of these debilitating conditions and success in any one of these would create significant value for investors. We are dedicated to moving these molecules forward and welcome you to participate in this journey and help us get to success. This concludes our prepared remarks and we'll now move to Q and A. Operator? Speaker 300:36:47And that will come from the line of Joseph Schwartz with Leerink Partners. Please go ahead. Speaker 400:36:53Hi, thanks very much for the update. 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-two sixteen as well as the new one? Thank you. Speaker 200:37:27Thank 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 AC90. So that 8 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. Speaker 200:38:15And 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 that 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 a subsequent slide here that there's adequate levels of drug seen in a broad set of tissues against that target level of 8 to 10 nanomoles that we require to see a biological effect. Speaker 200:39:33And so once you exceed the threshold required for biological effect, there is 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 4 weeks, which gives us further confidence that the injection site tolerability issues appear resolved. Speaker 400:40:44Great. Thank you. Speaker 300:40:47Thank you. One moment for our next question. And that will come from the line of Leonid Timoshenko with RBC Capital Markets. Your line is open. Speaker 500:41:03Hi, everyone. This is Nevan on for Leo. Thank you for taking our questions. So just a couple from us. How are you thinking about designing your Phase 1 for DT 216 P2? Speaker 500:41:16And 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 biology and the FDA's views on that? And then should we also expect similar patient numbers to the original sat in that study? Thank you. Speaker 200:41:40Okay. Thank you for the question. 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-two 16P2. Speaker 200:42:15Once 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. Okay. Speaker 200:43:10Thank you. Speaker 300:43:12Thank you. One moment for our next question. And that will come from the line of Laura Chico with Wedbush. Your line is open. Laura, your line is open. Speaker 600:43:36Sorry about that. Thank you very much for taking the question. I believe you were also working in parallel on some new method development with respect to for tax 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. Speaker 200:44:01Thank you, Laura. We are dedicated to continuing to work on whatever improvements we can make in measurement of for taxon levels. We have robust assays that we've already used in prior clinical studies for measurement of Fertaxin RNA. And we continue to make improvements on our ability to reliably measure for tax and protein and possible changes in for tax and protein and we'll provide updates on that progress as we progress to the clinic. Speaker 600:44:43Okay. Thank you very much. And then just quickly with respect to Fuchs, I know this may have 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. Speaker 200:45:20Thank 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 3 different broad buckets. 1 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. 2nd 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. Speaker 200:46:24And there are ways in the clinic to measure this subclinical edema using anterior eye tomography, for example. So we including those measures in the observational study. And 3rd, as you've there are analogous or corresponding ways to directly 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. Speaker 600:47:08Thanks very much. Speaker 300:47:11Thank 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. Speaker 200:47:20Well, 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.Read morePowered by