DT-216 Resulted in a Significant Increase in FXN mRNA Levels in Skeletal Muscle of FA Patients
Treatment Generally Well-Tolerated; Injection Site Reactions Attributable to Current Formulation Composition
Design Plans to Proceed with an Improved DT-216 Formulation and Initiate a Multiple Dose Phase 1 Clinical Study in the Second Half of 2024
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CARLSBAD, Calif., Aug. 14, 2023 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc. (Nasdaq: DSGN), a clinical-stage biotechnology company developing treatments for serious degenerative genetic diseases, today reported initial results from the company’s Phase 1 multiple-ascending dose (MAD) clinical trial of DT-216 in patients with Friedrich ataxia (FA). As of a data cutoff date of August 7, 2023, results showed that DT-216 was generally well-tolerated and achieved a statistically significant and dose-related increase in frataxin (FXN) mRNA levels in skeletal muscle biopsies.
FA is a multisystem degenerative disease caused by a GAA nucleotide repeat expansion in the FXN gene that impairs transcription and reduces FXN mRNA. Low FXN expression 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.
“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,” said Susan Perlman, M.D., Clinical Professor of Neurology and Director of Neurogenetics Clinical Trials at UCLA. “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.”
Observational Biomarker Study in Friedreich AtaxiaIn parallel to the Phase 1 MAD study, Design conducted an observational study to evaluate FA biomarker assays in blood and skeletal muscle from individuals with FA, FA carriers and normal healthy volunteer controls for use in DT-216 interventional studies. The company developed procedures and methods to measure both FXN mRNA and FXN protein in muscle. Initial data from the observational study is based upon a data cutoff of August 7, 2023. The observational study enrolled a total of 56 participants. Skeletal muscle biopsies were obtained from study participants at two visits several days apart to measure FXN mRNA and protein levels and characterize inter-and intra-individual variability.
Study results showed that levels of endogenous FXN mRNA across individuals with FA, FA carriers and healthy individuals differed significantly. Additionally, levels in the interquartile range for FA patients did not overlap with FA carriers, which shows FXN mRNA levels between these two populations are distinct. Design believes these data support use of the muscle FXN mRNA assay as a sensitive indicator of clinical activity in FA, with the ability to discriminate clinically meaningful changes in endogenous FXN mRNA.
FXN protein measurements in skeletal muscle had substantial overlap between FA patients and carriers and showed high intra-individual variability. More than half of FA patients had 25% or more variation in FXN protein levels between visits, with intra-individual coefficient of variation of 69%. The variability of results observed with this current method substantially limited the utility of FXN protein measurements to assess DT-216 pharmacology.
DT-216 Phase 1 MAD Trial DesignThe Phase 1 MAD clinical trial is a randomized, double-blind, placebo-controlled study designed to evaluate multiple ascending 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 three weekly doses of DT-216 in FA patients. As an exploratory objective, the company also evaluated FXN expression including levels of FXN mRNA and protein in skeletal muscle biopsies obtained at pre-dose baseline and two and seven days after the third weekly dose.
Initial data from the Phase 1 MAD trial is based upon a data cutoff of August 7, 2023. The study is fully enrolled but currently ongoing, with blinded PK and pharmacodynamic (PD) data available in the full 100 and 200mg dose cohorts and 11 of 14 participants in the 300mg dose cohort. Safety data remain blinded.
The study enrolled 29 adult participants with genetically confirmed FA. Symptomatic FA patients were adequately distributed across dose cohorts. Study participants received three weekly intravenous injections across the 100mg, 200mg, and 300mg cohorts (N=4, 11, and 14, respectively) and were randomized to receive either DT-216 or matching placebo.
Blinded Safety DT-216 was generally well-tolerated after three intravenous doses of DT-216 or placebo:
- There were no treatment-related serious adverse events (SAEs) and no treatment-related discontinuations.
- All adverse events (AEs) were mild or moderate.
- There were five cases of injection site thrombophlebitis observed across all three cohorts; four were considered mild and one was considered moderate.
- There were no new clinically significant safety observations.
Pharmacokinetics Plasma PK data were available in participants at 100mg, 200mg, and 300mg DT-216 doses. Plasma levels of DT-216 were approximately dose proportional. The average DT-216 concentration in muscle was approximately 8-10nM two days after the third weekly dose and approximately 1nM seven days after the third weekly dose in both the 200mg and 300mg cohorts. DT-216 muscle exposure in FA patients was lower than projected from animal studies but was sufficient to result in significant PD response in skeletal muscle.
DT-216 PharmacodynamicsTo better understand the pharmacodynamics of DT-216 directly in tissues relevant for FA disease symptoms, the company developed procedures and methods to measure FXN expression in skeletal muscle. As of the data cutoff date, exploratory analyses of muscle FXN mRNA levels from the Phase 1 MAD study showed that:
- FA patients in the 300mg cohort had a 30% mean increase from baseline in FXN mRNA two days after the third weekly dose, which was significant compared to placebo (p