Design Therapeutics (NASDAQ:DSGN) said results from a four-week dosing portion of its RESTORE-FA study showed increases in frataxin biomarkers and improvements on clinical measures in patients with Friedreich ataxia, leading the company to begin planning a potential registration path for its investigational therapy DT-216P2.
Chief Executive Officer Pratik Shah said the company is reporting the readout earlier than anticipated from a multiple ascending dose study in 16 patients across four dose levels. Patients received once-weekly intravenous dosing for four weeks. Shah said DT-216P2, also known as DT-216 for injection, was generally well tolerated, with no serious adverse events and no study discontinuations.
Company Reports Clinical Improvements at 1 mg/kg Dose
Design said the most notable clinical results were observed at the 1 mg/kg IV weekly dose. Shah reported a 6.4-point improvement on the modified Friedreich Ataxia Rating Scale, or mFARS, and a 2.7-point improvement on the upright stability score, a component of mFARS that evaluates balance, stance and gait.
Shah said all patients in the 1 mg/kg cohort showed improvement on mFARS. In response to an analyst question, he said the 2.7-point upright stability score improvement accounted for slightly less than half of the overall 6.4-point mFARS improvement, with additional improvements seen in other components.
The company also reported a greater than six-point improvement at the 1 mg/kg dose on the PROMIS fatigue scale, which Shah described as a disease-agnostic measure used in other drug studies. He said three of four patients in the 1 mg/kg cohort had more than a five-point improvement on that measure, above the three-point threshold he described as a minimal important change.
Shah emphasized that the study was not a head-to-head comparison with other therapies. He said Design conducted exploratory, ad hoc cross-study comparisons against placebo data from prior Friedreich ataxia studies, including the MOXIe study of omaveloxolone, marketed as SKYCLARYS.
Biomarker Data Show Frataxin Increases in Blood and Muscle
Design said DT-216P2 met three biomarker criteria the company had outlined: increasing frataxin mRNA, showing that mRNA increases translated into protein increases and demonstrating activity in both blood and muscle.
After four weeks of treatment at 1 mg/kg, Shah said whole blood frataxin mRNA rose 65% from baseline. Whole blood frataxin-M and frataxin-E protein levels increased 22% to 27% from baseline two weeks after the last dose, and muscle frataxin mRNA rose 42% from baseline.
During the question-and-answer session, Shah said the changes were measured against each patient’s own baseline before dosing. He said comparisons with untreated individuals were used to understand typical longitudinal variability in Friedreich ataxia.
Shah said individual clinical responses, particularly on upright stability score, were best correlated with blood frataxin protein levels. He said the company viewed that as consistent with natural history studies suggesting endogenous blood frataxin protein may be a surrogate marker for clinical benefit.
Safety Findings Include Mild to Moderate ALT Elevations
Design reported that all adverse events in the study were mild or moderate. Adverse events considered possibly or probably related to DT-216P2 and occurring in more than one patient were transient ALT elevations in three patients. Shah said all three were asymptomatic, had no associated bilirubin increases and were receiving background omaveloxolone therapy.
Ten of the 16 patients in the study were on background omaveloxolone therapy for an average of more than five years, according to Shah. He said the observed effects were “add-on benefits” in patients already receiving standard of care.
Registration Planning Expected to Be Updated in Fourth Quarter
Based on the data, Shah said Design believes it has identified a suitable dose and route of administration — 1 mg/kg IV weekly — to advance toward a registration path. He said the company expects to provide more clarity on registration plans in the fourth quarter of this year.
Analysts asked about potential FDA engagement, Breakthrough Therapy designation and whether longer-term data would be needed before a pivotal study. Shah said those considerations are now “on the table,” but the company needs time to evaluate the data and develop its plans.
Shah also said RESTORE-FA will remain ongoing to support more extended dosing. Future updates on additional data, including potential work on less frequent dosing intervals or subcutaneous administration, have not yet been scheduled. He described those topics as not being on the critical path to registration planning.
DT-216 is a heterobifunctional GeneTAC small molecule designed to address the underlying genetic mechanism of Friedreich ataxia by increasing endogenous frataxin expression. Shah said the clinical data strengthened the company’s conviction in its GeneTAC platform, while noting that each pipeline program has its own molecule and development considerations.
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.
