Design Therapeutics' DT-216 Displays Positive Phase 1 Results in Friedreich Ataxia


Data from a multiple-ascending dose study suggest the investigational agent developed by Design Therapeutics was generally well tolerated with dose-related increases in frataxin levels.

A version of this article originally appeared on our sister site, NeurologyLive.

Susan Perlman, MD, clinical professor of neurology and director of Neurogenetics Clinical Trials at the University of California Los Angeles

Susan Perlman, MD

Data from a phase 1, multiple-ascending dose (MAD) study (NCT05285540) suggest DT-216, an investigational agent developed by Design Therapeutics, was generally well tolerated among patients with Friedreich ataxia (FA), with statistically significant and dose-related increases in frataxin (FXN) levels in skeletal muscle biopsies.

Design also noted that it plans to initiate another multiple-dose phase 1 trial assessing an improved DT-216 formulation in the second half of 2024, with initial clinical data expected in the first half of 2025. DT-216 is a gene-targeted chimera (referred to as 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.

"I’m encouraged by the data from the phase 1 MAD trial of DT-216, which is the first to show a drug candidate increasing transcription of endogenous FXN mRNA in an affected tissue in FA. Given the lack of treatment options to address the root cause of this debilitating disease, DT-216 is a highly promising candidate, and I am eager to see its continued development," Susan Perlman, MD, clinical professor of neurology and director of Neurogenetics Clinical Trials at the University of California, Los Angeles, said in a statement.1

The double-blind, placebo-controlled trial included 29 adults with genetically confirmed FA who received 3 weekly injections of either DT-216 or placebo at doses of 100 mg (n = 4), 200 mg (n = 11), and 300 mg (n = 14). Using a data cutoff of August 7, 2023, findings showed no serious treatment-related adverse events (TEAEs) nor any treatment-related discontinuations. The AEs observed were mild or moderate, with no new clinically significant safety observations; 5 patients in 3 different dose groups reported injection site thrombophlebitis, 4 of which were considered mild and 1 considered moderate in severity.

Notably, investigators observed a 30% mean increase in FXN mRNA levels 2 days after the third weekly dose, which was significant compared with placebo (P <.05). A trend in increased FXN mRNA was also observed 7 days post dose.

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Among treated individuals, plasma levels of DT-216 were approximately dose proportional. The average DT-216 concentration in muscle was approximately 8-10 nM 2 days after the third weekly dose and approximately 1 nM 7 days after the third weekly dose in both the 200-mg and 300-mg cohorts. Additionally, DT-216 muscle exposure in treated patients was sufficient to result in significant pharmacodynamic response in skeletal muscle, despite projections that it would be lower than in animal studies.

As for exploratory outcomes, findings indicated that the mean increase in FXN mRNA in the 300-mg cohort was above the 75th percentile of patients with FA observed in an observational biomarker study conducted in parallel with the phase 1 MAD study. Additionally, investigators observed a significant DT-216 dose-dependent trend with responses (P <.05) and tissue exposure-response relationship (P <.05) with muscle FXN mRNA expression. Design Therapeutics did notably state that the treatment effects were inconclusive because of high intraindividual variability, although they were consistent with the observational study.

The observational study, designed to evaluate FA biomarker assays in individuals with FA, FA carriers, and normal health volunteer controls, showed significant differences in endogenous FXN mRNA across groups. Comprised of 56 participants, skeletal muscle biopsies showed substantial overlap in FXN protein between patients with FA and carriers, as well as high intra-individual variability. More than half of patients with FA had 25% or more variation in FXN protein levels between visits, with intraindividual coefficient of variation of 69%.

Because of the potential concern for worsening of injection site thrombophlebitis at higher doses, the company has shifted its focus to develop the aforementioned new formulation of DT-216 in another multiple-dose phase 1 trial expected to begin in the second half of 2024. According to Design, this new formulation is expected to enable higher exposures and chronic intravenous administration, and has shown more favorable injection site tolerability following multiple intravenous administrations.

"Data from the phase 1 program showed that the therapeutic hypothesis of DT-216 is playing out in [patients with FA]—restoring endogenous transcription of FXN into therapeutically relevant levels," Joao Siffert, MD, president and chief executive officer, Design Therapeutics, said in a statement.1 "The totality of the data from our phase 1 program supports the continued development of DT-216 for FA, and we believe leveraging an improved formulation will enable us to explore the full DT-216 therapeutic potential for treatment of people with FA, which is our ultimate goal."

1. Design Therapeutics reports initial results from phase 1 multiple-ascending dose study of DT-216 for the treatment of Friedreich ataxia. News release. Design Therapeutics. August 14, 2023. Accessed August 22, 2023.
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