Design Therapeutics, Inc. reported progress across its portfolio of novel GeneTAC small molecules. Today's updates include initial results on DT-216 from the company's single-ascending dose (SAD) Phase 1 clinical trial in patients with Friedreich ataxia (FA). The results show that DT-216 was generally well-tolerated and able to overcome the frataxin (FXN) transcription impairment that causes FA, with a greater than two-fold increase in FXN mRNA in the cohort with the highest response.

These data support the continued advancement of DT-216 in the ongoing multiple-ascending dose (MAD) Phase 1 trial and the anticipated Phase 2 clinical trial in FA patients, which is on track to begin in 2023. FA is a multisystem degenerative disease caused by a GAA nucleotide repeat expansion in the FXN gene that impairs transcription and reduces FXN mRNA. Reduced FXN transcription results in mitochondrial and cellular dysfunction and leads to all FA disease manifestations.

DT-216 is a GeneTAC™ small molecule designed to specifically target the GAA repeat expansion mutation, unblock the transcriptional machinery, and restore the production of functional, natural FXN mRNA. DT-216 Phase 1 SAD Trial Design: The Phase 1 SAD clinical trial is a randomized, double-blind, placebo-controlled study designed to evaluate single doses of DT-216 administered intravenously in adult patients with FA. The primary and secondary study objectives were to evaluate safety and tolerability, and pharmacokinetics (PK) of DT-216 in FA patients.

Change in FXN mRNA and protein expression relative to baseline, measured in a circulating subset of white blood cells, known as peripheral blood mononuclear cells (PBMCs), were included as exploratory pharmacodynamic (PD) assessments. Thirty-nine FA patients (mean age 32 years, 49% female) were dosed across six dose cohorts (5-10 patients per cohort) ranging from 25 mg to 600 mg and were randomized to receive either DT-216 (N=26) or placebo (N=13). All patients were homozygous for a GAA repeat expansion (mean=580, SD=203).

The study protocol was prospectively designed for DT-216 to be administered either as a single dose bolus or as a single dose split-administration on the same day. Patients in Cohorts 1-4 were dosed with a single bolus dose of DT-216 at increasing levels from 25 mg to 200 mg. Patients in Cohort 5 (400 mg) received either a single dose bolus or single dose split administration of DT-216, and all patients in Cohort 6 (600 mg) received a single dose split administration of DT-216.

Safety assessments were conducted for 30 days post dosing. Pharmacokinetic and Pharmacodynamic Results: PK data were available for 32 patients (Cohorts 1-3, 5 and 6). PD data were available for 33 patients; data from Cohort 4 (200 mg) were excluded from this analysis due to third-party issues with sample handling.

Plasma levels of DT-216 increased in an approximately dose-proportional manner, with peak concentrations within minutes, followed by a decrease in plasma levels within several hours. Treatment with a single dose of DT-216 resulted in a 2.24-fold increase in FXN mRNA, at 24 hours post-dose compared with pre-treatment baseline, in the cohort with the highest response (p < 0.01 DT-216 [N=3] vs. pooled placebo [N=11]).

Treatment with a single dose of DT-216 in all cohorts 100 mg and above resulted in a statistically significant increase in FXN mRNA at 24 hours post dose. Individual patient responses to single doses of DT-216 ranging from 100-600 mg resulted in an increase in FXN mRNA at 24 hours ranging from 1.24 to 2.62-fold. A relationship between plasma exposure and treatment effect was observed in PBMCs.

As expected with short-term plasma exposure, there was no observed increase in FXN protein from baseline in PBMCs from patients treated with a single dose of DT-216 or placebo. Ex vivo DT-216 treatment for 60 hours of PBMCs isolated pre-treatment from patients enrolled in this trial elicited a doubling of FXN protein levels, confirming that, with sufficient duration of exposure to DT-216, an increase in FXN mRNA naturally translated to an increase in FXN protein. Design is evaluating DT-216 in an ongoing MAD Phase 1 clinical trial designed to evaluate the safety, tolerability, PK, and PD effects of three weekly doses of DT-216 in adult patients with FA.

The first MAD cohort of 100 mg has begun dosing. Design plans to dose at least three cohorts and report data from the MAD trial in mid-2023.