DT-216P2 shows promise in treating patients with Friedreich ataxia based on positive phase 1 trial results that indicated a significant increase in frataxin mRNA levels.
Pratik Shah, PhD
(Credit: Design Therapeutics)
According to a recent company update, Design Therapeutics is on track to complete good-laboratory-practice studies for DT-216P2, an investigational agent for Friedreich ataxia (FA), by year-end 2024 to start patient trials the following year in 2025.1 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.
“In the second quarter, the company continued to make steady progress advancing our portfolio of novel, small molecule GeneTAC candidates for the treatment of major genetic disorders,” Pratik Shah, PhD, chairperson and chief executive officer at Design Therapeutics, said in a statement.1 “Leading our portfolio of potential first- or best-in-class therapies is DT-216P2 for FA, a serious neuro-degenerative disease with a significant need for new therapies, and we remain on track to start patient trials in 2025. Our strategy is to address the disease’s root cause by increasing endogenous frataxin (FXN) levels.”
In August 2023, data announced from a phase 1, multiple-ascending dose study (NCT05285540) showed that treatment with DT-216 was generally well tolerated, with statistically significant and dose-related increases in FXN levels in skeletal muscle biopsies among patients with FA. 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 cutoff of August 7, 2023, findings showed no serious treatment-related adverse events (TEAEs) and no treatment-related discontinuations. 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. Any AEs found in the study were mild or moderate, with no new clinically significant safety observations. Five patients in 3 different dose groups reported injection site thrombophlebitis, 4 of which were considered mild and 1 considered moderate in severity.
"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," Susan Perlman, MD, clinical professor of neurology and director of Neurogenetics Clinical Trials at the University of California Los Angeles, said in a statement.2 "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."
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. Although projected to be lower than in animal studies, DT-216 muscle exposure in treated patients was sufficient to result in significant pharmacodynamic response in skeletal muscle.
In an exploratory, 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. Of note, the company did stated that the treatment effects seen were inconclusive because of high intra-individual 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 intra-individual coefficient of variation of 69%.
Because of the potential concern for worsening of injection site thrombophlebitis at higher doses, the company has shifted focus to develop a 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 FA patients —restoring endogenous transcription of FXN into therapeutically relevant levels," Joao Siffert, MD, president and chief executive officer, Design Therapeutics, said in a statement.2 "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."
