Design Therapeutics NASDAQ: DSGN outlined its strategy and trial design for DT-216 in Friedreich’s ataxia (FA), emphasizing that its ongoing RESTORE-FA multiple ascending dose study is intended to determine whether the therapy can meaningfully increase endogenous frataxin levels and help define a potential regulatory path.
Chief Executive Officer Pratik Shah said the company is using the quarterly update to provide additional context on “the key objectives of the RESTORE-FA study, and the multiple biomarker endpoints being evaluated.” He added that the trial “is proceeding well,” and repeatedly pointed to the company’s expectation for a data readout in the second half of 2026.
DT-216’s approach and rationale in FA
Shah described FA as a debilitating disease caused by a mutation in the frataxin gene that leads to low frataxin production and downstream dysfunction across multiple organs. He noted that there is an approved therapy, omaveloxolone, but said it targets Nrf2 rather than frataxin itself.
DT-216, by contrast, is designed to address the underlying genetic mechanism. Shah said FA is driven by a GAA repeat expansion in the first intron of the frataxin gene, which lowers normal mRNA and therefore protein. DT-216 is a “heterobifunctional gene-targeted chimera or GeneTAC molecule” intended to recognize these long GAA repeats and “dial up normal frataxin RNA transcription.”
Shah pointed to cellular data supporting the idea that relatively low concentrations may be sufficient if drug exposure is sustained. He said cell work suggests “10 nanomolar levels may be sufficient to increase frataxin as long as there is sufficient duration of exposure,” and described comparative cell experiments where higher concentrations appeared to show stronger early activity but where prolonged exposure at 10 nanomolar appeared capable of achieving “full pharmacology in cells.”
Pharmacokinetics and the move into RESTORE-FA
Discussing prior clinical work, Shah referenced 2023 studies in which plasma exposures at day two were “approximately 40 nanomolar-75 nanomolar,” corresponding to “approximately 8 nanomolar-10 nanomolar” in muscle. He said the day two data showed an “unmistakable increase in frataxin RNA expression,” followed by a drop-off after day two “because the drug is gone.”
He then described a single-dose pharmacokinetic profile for the company’s current drug product, DT-216P2, stating that about 40 milligrams produced sustained plasma levels of “40 nanomolar-75 nanomolar all the way till the end of one week,” which he said supports a weekly dosing strategy and could “build to a higher steady-state level” with multiple doses.
Based on those exposures, the company initiated RESTORE-FA, a multiple ascending dose study in FA patients.
RESTORE-FA design: dose escalation, duration, and endpoints
Shah detailed how the escalation strategy was shaped by non-clinical toxicology coverage and a desire to reach target exposures efficiently. When the study began, he said the company had “four weeks of non-clinical tox coverage.” In that four-week context, the study escalates from 0.1 mg/kg to 0.3 mg/kg to 0.6 mg/kg. Shah noted that the ~40 mg single-dose exposure observed in healthy volunteers corresponds to the 0.6 mg/kg level.
To increase exposure, Design Therapeutics has also started a 1 mg/kg group over four weeks. In addition, to enable a 12-week assessment, the protocol includes 12-week treatment cohorts, including at 1 mg/kg. Shah said the company expects additional 12-week cohorts because pharmacokinetic projections “do support additional dose levels within the non-clinical safety exposures.”
On route of administration, Shah said subcutaneous infusion details “are still being determined.” Because IV dosing is “fully bioavailable,” he said the company preferred starting with IV to determine dose levels before moving to subcutaneous cohorts.
The study includes multiple biomarker measures of endogenous frataxin across tissues and analytes, along with exploratory clinical endpoints. Shah said Design is evaluating endogenous frataxin in both blood and muscle, measuring both mRNA and protein. Exploratory clinical measures include:
- mFARS (Modified Friedreich’s Ataxia Rating Scale), a commonly used clinician-administered assessment in FA and used in omaveloxolone studies
- Upright Stability Score (USS), described as a component of mFARS and “the most objective, least variable component of mFARS,” and used as a primary endpoint in the approved drug’s BRAVE study
- PROMIS Fatigue Scale, a validated patient-reported outcome measure; Shah cited a publication describing a “3-point improvement” as a minimal important change
Biomarker strategy and regulatory considerations
Shah described RESTORE-FA’s objectives as “threefold”: (1) provide a go/no-go decision for the FA program, (2) “hopefully establish a clinical proof of concept,” and (3) inform the regulatory path and probability of a future approval.
He contrasted two general regulatory frameworks, including an accelerated pathway in which a frataxin biomarker could serve as a primary endpoint, subject to regulatory alignment. He said the company’s goal is to use RESTORE-FA data from “four measures across blood and muscle and mRNA and protein” to “zero in on a single biomarker” that could be considered “reasonably likely to predict clinical benefit.”
Shah also explained why the company chose both whole blood and muscle. He said whole blood protein was selected because it is central to natural history datasets used in the literature to support frataxin as a reasonably likely surrogate and therefore may be the “most robust biomarker” from a regulatory alignment standpoint. Muscle measures were included in part because the company already had an assay from prior studies and because muscle is an affected tissue.
On assay performance, Shah said the company has been conducting background studies in untreated patients and healthy individuals to assess assay performance and intra-patient variability. He said the assays perform “acceptably,” while noting that blood assays are “tighter than the muscle biopsy-based assays.”
He added that due to the lack of normalized standards in the FA field and the influence of assay variability, the company plans to report results based on change from baseline rather than absolute thresholds. He also said the blood mRNA assay has shown the least overlap between patient and carrier levels, making it, in the company’s view, best suited to evaluate whether drug effect enters a carrier range.
What Design hopes RESTORE-FA will answer
Shah said there is not yet a definitive answer for “how much frataxin” is enough because “no one has increased endogenous frataxin production,” and he framed the ultimate determination as dependent on correlating frataxin changes with clinical outcomes. He cited natural history studies suggesting frataxin differences correlate with major clinical outcomes such as age of onset, loss of ambulation, disease severity, and progression.
For RESTORE-FA’s biomarker readouts, Shah said the key questions are:
- Does DT-216 increase frataxin mRNA in either tissue?
- Does DT-216 increase frataxin protein in blood or muscle?
- Does DT-216 show activity in both blood and muscle using either mRNA or protein?
He said the readout will indicate whether DT-216 meets none, one, two, or all three criteria. Shah cautioned that the study is not expected at this stage to show clinical benefit, though he said any observed clinical trends could be helpful for designing future studies.
In reviewing historical clinical observations, Shah noted that in omaveloxolone’s MOXIe study, an “approximately 2.4 point group difference” on mFARS at 48 weeks was observed. He also referenced public commentary from other sponsors, stating that Lexeo has reported a “2-point improvement change from baseline” at six months with N=16, and Larimar has reported a “2.25 point improvement over baseline” at one year with N=8.
Shah concluded by reiterating that the company looks forward to RESTORE-FA results in the second half of 2026.
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.
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