DT-216P2

DT-216P2 is an investigational small-molecule drug candidate developed by Design Therapeutics for the treatment of Friedreich's ataxia (FA). It is a "GeneTAC" (gene-targeted chimera) compound designed to increase expression of frataxin by targeting the expanded GAA trinucleotide repeat in the FXN gene, the genetic cause of the disease.[1][2] As of 2026 it is in Phase 1/2 clinical testing and has not been approved for medical use in any country.[3]

DT-216P2 is a reformulation of the first-generation candidate DT-216, developed after injection-site reactions limited the earlier compound. It can be administered by intravenous infusion or by subcutaneous injection or infusion.[1][4]

Mechanism of action

DT-216P2 is based on Design Therapeutics' GeneTAC platform of gene-targeted chimera small molecules. The molecule combines a programmable DNA-binding moiety that targets the expanded GAA repeat within the FXN gene with a tethered ligand that recruits the cell's own transcriptional machinery, helping to overcome the transcriptional block caused by the repeat expansion and thereby restoring production of endogenous frataxin messenger RNA and protein.[2][1] The compound is intended to address the underlying cause of FA by raising frataxin levels rather than treating symptoms.[1]

Development

The first-generation candidate, DT-216, was evaluated in Phase 1 single-ascending-dose and multiple-ascending-dose trials in adults with FA.[5][6] In March 2022, the FDA granted DT-216 Fast Track designation for the treatment of FA.[1] While DT-216 produced statistically significant, dose-related increases in frataxin mRNA in skeletal muscle, several patients experienced injection-site thrombophlebitis attributed to formulation excipients, leading Design Therapeutics to reformulate the drug.[2][3]

In March 2024 the company announced the new formulation, DT-216P2 (distinguished from the original formulation, retrospectively termed DT-216P1), reporting greater than tenfold and more sustained drug exposure together with an improved injection-site safety profile in nonclinical studies.[4][1] Good Laboratory Practice studies were completed in 2024, and a Phase 1 single-ascending-dose study in healthy volunteers began in Australia in early 2025.[1]

Design Therapeutics submitted an Investigational New Drug (IND) application for DT-216P2 to the U.S. Food and Drug Administration (FDA); the FDA placed the application on clinical hold, citing nonclinical deficiencies.[7]

RESTORE-FA trial

RESTORE-FA (Reactivating Expression Suppressed Through Overcoming Repeat Expansion for FA) is an ongoing Phase 1/2 multiple-ascending-dose trial evaluating the safety, pharmacokinetics, pharmacodynamics and exploratory clinical effects of DT-216P2 in patients with FA. Patient dosing began outside the United States, in Australia, in 2025.[7]

In May 2026, Design Therapeutics reported data on 16 patients who had completed four weeks of weekly intravenous dosing across four dose cohorts (0.1, 0.3, 0.6 and 1 mg/kg). According to the company, patients in the highest-dose cohort showed mean improvements from baseline of 6.4 points on the modified Friedreich's Ataxia Rating Scale (mFARS) and increases in endogenous frataxin, including a 65% rise in whole-blood frataxin mRNA and a 42% rise in muscle frataxin mRNA. The drug was described as generally well tolerated, with no serious adverse events; transient, asymptomatic elevations of alanine transaminase were observed in three patients. The company stated that it intended to pursue a registrational development path and to provide further plans in the fourth quarter of 2026.[8]

References

  1. 1 2 3 4 5 6 7 "DT-216P2". Friedreich's Ataxia Research Alliance. Retrieved 23 June 2026.
  2. 1 2 3 Scott, Varlli; Delatycki, Martin B.; Tai, Genevieve; Corben, Louise A. (2024). "New and Emerging Drug and Gene Therapies for Friedreich Ataxia". CNS Drugs. 38 (10): 791–805. doi:10.1007/s40263-024-01113-z. PMC 11377510. PMID 39115603.
  3. 1 2 Stansfield, Noah (21 May 2026). "DT-216P2 Shows Dose-Dependent Frataxin Increases and Clinical Improvements After 4 Weeks of IV Dosing in Friedreich Ataxia". NeurologyLive. Retrieved 23 June 2026.
  4. 1 2 Cutting, Emily (17 August 2023). "Design Therapeutics announce results from Phase 1 FA trial". Ataxia UK. Retrieved 23 June 2026.
  5. ↑ Clinical trial number NCT05285540 for "A Study of DT-216 in Patients With Friedreich Ataxia" at ClinicalTrials.gov
  6. ↑ Clinical trial number NCT05573698 for "A Phase 1b Multiple Ascending Dose Study of DT-216 in Adult Patients With Friedreich Ataxia" at ClinicalTrials.gov
  7. 1 2 "Design Therapeutics Announces Start of Friedreich Ataxia Patient Dosing Ex-U.S. in its RESTORE-FA Phase 1/2 Multiple-Ascending Dose Trial of DT-216P2" (Press release). Design Therapeutics. June 2025. Retrieved 23 June 2026.
  8. ↑ "Design Therapeutics Announces Four-Week IV Data from the RESTORE-FA Trial of DT-216P2 Demonstrating Clinical Improvements and Comprehensive Biomarker Activity in Friedreich Ataxia" (Press release). Design Therapeutics. 18 May 2026. Retrieved 23 June 2026.


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