Design Therapeutics (NASDAQ:DSGN) outlined progress across three clinical-stage programs and discussed upcoming catalysts during an Oppenheimer healthcare conference presentation led by CEO Pratik Shah. The company is developing what it describes as “small molecule genetic medicines” designed to modulate expression of individual genes—either increasing or decreasing expression—to address the root cause of certain single-gene disorders.
Platform focus: small molecules to modulate gene expression
Shah said Design’s approach aims to overcome limitations of larger genomic medicines that can face challenges with cellular uptake and broad tissue distribution. He argued that small molecules have inherent advantages in entering cells and reaching tissues more broadly, enabling “pan-cellular” distribution. The company’s programs use its GeneTAC approach to target repeat expansions in DNA that drive disease biology, with the goal of dialing gene expression up or down without gene editing or exogenous gene delivery.
- Friedreich’s ataxia (FA): RESTORE-FA multiple ascending-dose trial in patients; data anticipated in the second half of this year.
- Fuchs’ endothelial corneal dystrophy (FECD): exploratory biomarker study using DT-168 eye drops to assess splicing impact in patients scheduled for corneal transplant.
- Myotonic dystrophy type 1 (DM1): a phase I multiple ascending-dose study with DT-818; the company plans to begin dosing patients in the first half of this year, with data expected next year.
Shah also noted the company is working on a preclinical program in Huntington’s disease.
Friedreich’s ataxia: DT-216 and RESTORE-FA design
In FA, Shah said patients produce normal frataxin, but at low levels due to abnormally long GAA repeats in the frataxin gene that reduce expression. Design’s candidate, DT-216, is designed to recognize those repeats and “smooth the path” for the transcription machinery, increasing endogenous frataxin expression.
Shah highlighted preclinical work showing that 10 nanomolar levels were sufficient to generate “full pharmacology” in patient-derived cells. He also reviewed prior clinical experience from a 2023 trial in FA patients, where Design measured 8–10 nanomolar exposures in muscle for two days after dosing and observed what he described as an “unmistakable” increase in frataxin expression. He said this helped validate in vitro pharmacology in human studies, though exposure duration was limited in that earlier work.
Since then, the company has developed a new formulation with the same active pharmaceutical ingredient, DT-216P2, which Shah said produced more sustained exposure in updated pharmacokinetic data. Whether sustained exposure translates to sustained pharmacology is now being tested in the ongoing multiple ascending-dose RESTORE-FA trial.
On success criteria, Shah said the company views any increase in endogenous frataxin in patients as meaningful, noting that “no one has ever been able to create an increase” in normal endogenous frataxin expression in FA patients. Design is measuring frataxin in whole blood—described as a well-studied marker in natural history studies—and in muscle, an affected tissue.
FECD: DT-168 eye drops and a new splicing biomarker approach
Shah described FECD as a condition with progressive vision loss caused by loss of corneal endothelial cells and said there are about 2 million diagnosed cases in the U.S. He explained that an abnormal CTG expansion in the TCF4 gene leads to production of a toxic RNA that forms nuclear foci, traps splice proteins, and triggers widespread missplicing that contributes to cell dysfunction and death.
Design’s DT-168 is intended to recognize the abnormally long repeats in DNA and reduce production of the toxic RNA. Shah presented preclinical observations showing a significant reduction in toxic RNA foci, low nanomolar potency, selectivity for the mutant allele, and improvement in missplicing across multiple genes.
He also said Design completed a multiple-dose healthy volunteer study of DT-168 eye drops, reporting no clinically significant adverse events. To support clinical evaluation, Shah described development of a potential biomarker for missplicing using RNA extracted from discarded FECD corneal endothelium removed during transplant surgeries. The exploratory patient study will dose individuals for several weeks prior to their scheduled transplant and then evaluate splicing changes in the removed tissue.
Shah emphasized limitations of this approach, including enrollment of late-stage patients and the inability to measure splicing pre-treatment, which he said introduces the possibility of a false negative. However, he added that a positive result would provide strong evidence the molecule is acting as designed in corneal endothelial cells.
DM1: DT-818 preclinical profile and upcoming phase I study
For DM1, Shah described the disease mechanism as a CTG repeat expansion in the DMPK gene that produces toxic RNA, forms nuclear foci, and traps splice proteins, resulting in splice defects. He said Design’s GeneTACs are designed to stop production of mutant DMPK toxic RNA while leaving the wild-type allele unaffected.
Shah discussed learnings from other DM1 programs, including that targeting mutant DMPK can yield clinically measurable benefits in as little as 12 weeks. He also pointed to the importance of model selection, noting that patient-derived myotube models with the mutation in the DMPK gene may be more predictive of human splice effects than some other commonly used models.
He highlighted a phenomenon in which repeat length in affected tissue such as muscle can be much longer than repeat length measured from blood, potentially by about 10x, and suggested this could matter for approaches that have difficulty targeting increasingly long repeats.
Shah said Design set out to develop a potentially differentiated program aiming for broad tissue distribution, activity across shorter and longer repeat expansions while maintaining mutant selectivity, and greater pharmacologic impact on mutant DMPK RNA and splicing. He presented data for DT-818 showing low nanomolar potency and comparable activity in myotube systems with shorter (330 repeats) and longer (2,600 repeats) expansions, along with corresponding splice improvements. In the same type of assay system used widely in the field, he said DT-818 showed more than a 90% reduction in toxic DMPK RNA and foci, while published sponsor data showed approximately 30%–55% reductions in comparable assays.
Shah added that DT-818 showed no observed effect on wild-type DMPK kinase in the presented data, contrasting that with a control antisense oligonucleotide expected to reduce wild-type DMPK RNA. He also described in vivo work in an actin repeat mouse model showing improved myotonia on a pinch test and reduced toxic foci in muscle, as well as non-human primate plasma exposure data at two illustrative doses. The company plans to dose DM1 patients once weekly initially and will also evaluate subcutaneous administration, which Shah said could be a differentiator if successful.
Cash position and upcoming catalysts
Shah said Design ended the third quarter with $206 million in cash, which he characterized as providing runway to conduct the company’s programs and work toward clinical proof of concept.
In Q&A, Shah told Oppenheimer’s Kostas Biliouris that whole-blood frataxin measurements in untreated FA individuals do not meaningfully move with placebo and that RESTORE-FA comparisons will be made against an individual patient’s pre-treatment baseline. He also said the company is assessing frataxin levels in an untreated FA population to contextualize responses.
On DM1 translation, Shah said definitive links between foci reduction and clinical outcomes are not yet established, but argued it is mechanistically plausible that greater impact on the toxic RNA tangles could drive greater splicing improvement and potentially stronger clinical benefit. He added that broader tissue distribution beyond muscle could also contribute to improved outcomes, and said the company expects its upcoming multiple ascending-dose study to help clarify these questions.
About Design Therapeutics (NASDAQ:DSGN)
Design Therapeutics, Inc 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.
