Design Therapeutics (DSGN) Status update summary

Clinical and biomarker results

• Four-week RESTORE-FA data showed DT-216/DT-216P2 was well-tolerated with only mild to moderate adverse events and no discontinuations.

• Significant, dose-dependent increases in endogenous frataxin mRNA and protein were observed in both blood and muscle, with a 65% increase in whole blood mRNA and 42% increase in muscle mRNA at the highest dose.

• Clinical endpoints showed improvements in mFARS, upright stability, and fatigue, with the highest dose (1 mg/kg) yielding a 6.4-point mFARS improvement and over six-point PROMIS fatigue improvement.

• All patients in the 1 mg/kg cohort showed improvement in mFARS and PROMIS, with USS improvements accounting for less than half of the total mFARS benefit.

• 10 of 16 patients were on stable omaveloxolone therapy for over 5 years, providing a relevant background for comparison.

Mechanistic insights and comparative context

• DT-216 is a GeneTAC small molecule designed to upregulate endogenous frataxin by targeting GAA repeat expansions, leading to increased mRNA and protein without exceeding normal levels.

• The observed biomarker and clinical effects are consistent with preclinical findings and support a mechanistic link between frataxin restoration and clinical benefit.

• Effects were observed in patients already on standard of care, suggesting additive benefit.

• Blood frataxin protein levels, especially the M isoform, best correlated with clinical improvements, particularly in upright stability score.

• The magnitude of clinical improvement at four weeks surpasses that seen in previous studies with approved and investigational therapies.

Safety and tolerability

• No serious adverse events or discontinuations were reported; all adverse events were mild or moderate.

• Mild, transient ALT elevations were observed in three patients, all on background omaveloxolone, with no associated bilirubin increases.

• ALT/AST elevations may reflect on-target metabolic effects rather than liver toxicity, consistent with observations from other frataxin-restoring agents.