DT-216 was Generally Well-Tolerated and Resulted in a More than Doubling of Frataxin mRNA in Patients with Friedreich Ataxia

Second GeneTACTM Development Candidate, DT-168, Selected for the Treatment of Fuchs Endothelial Corneal Dystrophy Administered as an Eye Drop; IND Expected in 2023

Advancing Myotonic Dystrophy Type-1 GeneTACTM Lead Molecules; IND Expected in 2024

CARLSBAD, CA, USA I December 07, 2022 I Design Therapeutics, Inc. (Nasdaq: DSGN), a clinical-stage biotechnology company developing treatments for serious degenerative genetic diseases, today 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.

“It is very encouraging to see single doses of DT-216 overcome the RNA transcription block of the FXN gene that causes FA,” said Susan Perlman, M.D., Professor of Neurology and Head of Division of Neurogenetics at UCLA. “These Phase 1 data underscore the potential for modifying the course of FA and improving the quality and length of life for those diagnosed with the condition. DT-216 is one of the most promising candidates for future treatment options for FA patients and I look forward to its continued development.”

“We started Design to address the known monogenic causes of a range of inherited degenerative diseases and in just a few short years, are able to report clinical data that support our founding hypothesis,” said Pratik Shah, Ph.D., executive chair of Design Therapeutics. “GeneTAC™ molecules are thoughtfully designed to dial up or down the expression of specific genes, addressing the root cause of disease without the need for irreversible genetic modification. In FA, where deficiency of FXN causes its clinical manifestations, we believe that FXN restoration by DT-216 can have a meaningful clinical impact. The data from our SAD trial demonstrate proof-of-concept with DT-216 and highlight its safety profile and ability to increase FXN mRNA – the first step to increasing FXN protein and restoring mitochondrial function.”

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.

Safety Results

Safety data are available by treatment assignment for Cohorts 1-5 (N=33). Cohort 6 (600 mg; N=6) treatment assignment remains blinded pending completion of the 30-day safety assessment, per study protocol.

DT-216 was generally well-tolerated throughout the Phase 1 SAD trial. Findings from Cohorts 1-5 were:  

  • No treatment-related serious adverse events (SAEs) reported
  • 16 (73%) patients on DT-216 and eight (73%) patients on placebo reported at least one treatment-emergent adverse event
  • Most adverse events (AEs) were mild and transient; there were no severe AEs
  • No clinically significant changes in vital signs, physical exams, electrocardiogram, and clinical safety laboratories (including liver function tests and serum creatinine)
  • Three patients had a localized superficial vein thrombosis at the injection site; of which two were mild and one was moderate; and all three were self-limited

The blinded safety profile of Cohort 6 is consistent with the prior cohorts.

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.

Pipeline Updates

Fuchs endothelial corneal dystrophy (FECD)

Design nominated its second GeneTAC™ development candidate, DT-168, an eye drop for the treatment of FECD, a genetic eye disease caused by a CTG repeat expansion. FECD is characterized by progressive degeneration of the corneal endothelium and subsequent loss of vision that affects millions of people. The company plans to submit an Investigational New Drug application (IND) for DT-168 in the second half of 2023.

Myotonic dystrophy type-1 (DM1)

Design has continued to advance its preclinical characterization of several lead DM1 GeneTAC™ molecules and now expects to submit an IND in 2024. Design’s DM1 GeneTAC™ molecules are designed to prevent the formation of the CUG hairpin structures that trap splicing proteins and produce pathogenic nuclear foci. There is currently no cure for this debilitating and deadly neuromuscular disease.

“The clinical proof-of-concept of DT-216 in FA underscores the enormous opportunity of our small molecule GeneTAC™ platform to expand the therapeutic landscape for people suffering with serious monogenic diseases,” said João Siffert, M.D., president and chief executive officer of Design Therapeutics. “Not only do these data support the continued advancement of our FA program, but they demonstrate our expertise in designing novel GeneTACTM molecules and provide strong support for our entire portfolio of potential first-in-class GeneTAC™ programs, including in FECD and DM1. With one program in the clinic, an anticipated second clinical-stage program in 2023, and plans for a steady cadence of new GeneTAC™ candidates and clinical trials, we are well-positioned to deliver on our goals. I am proud of the Design team for its incredible efforts and extend our sincerest gratitude to the patients and caregivers participating in our clinical trials. We are also thankful to the Friedreich Ataxia Research Alliance for their steadfast support on behalf of the FA community.”

Webcast and Conference Call Information
Design will host a live webcast and conference call today at 4:30 p.m. EST to discuss these updates. The event is accessible through the “Events” section of the Investors page of www.designtx.com. A replay of the webcast will be archived on the Design website for 30 days.

Dial-in information for conference participants may be obtained by registering for the event here.

About Design Therapeutics
Design Therapeutics is a clinical-stage biotechnology company developing a new class of therapies based on its platform of GeneTAC™ gene targeted chimera small molecules. The company’s GeneTAC™ molecules are designed to either dial up or dial down the expression of a specific disease-causing gene to address the underlying cause of disease. Design’s lead program is focused on the treatment of Friedreich ataxia, followed by programs in Fuchs endothelial corneal dystrophy and myotonic dystrophy type-1 and discovery efforts for multiple other serious degenerative disorders caused by nucleotide repeat expansions. For more information, please visit designtx.com.

SOURCE: Design Therapeutics