DT-216P2 shows early signs of benefit in Friedreich’s ataxia clinical trial
Four patients on highest dose had functional score improvements
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Four weeks of treatment with the highest tested dose of the experimental therapy DT-216P2 was associated with improvements in functional scores for four people with Friedreich’s ataxia (FA) in an early clinical trial.
Data also indicate that DT-216P2 was generally well tolerated and showed biomarker activity consistent with increasing production of the frataxin protein, according to data reported by the therapy’s developer, Design Therapeutics.
“These data represent an advancement for Friedreich ataxia treatment, demonstrating that DT-216P2 increased endogenous [naturally produced by the body] frataxin and translated biomarker observations into clinical improvements after only four weeks of treatment,” Pratik Shah, Design’s CEO, said in a company press release.
With these data in hand, Design said it plans to pursue a registrational development path for DT-216P2. The company said it will provide an update on these plans later this year.
DT-216P2 aims to boost frataxin
FA is caused by mutations in the FXN gene, which provides instructions to make the frataxin protein. Without enough of this protein, mitochondria — the cell’s energy-producing structures — do not work properly, ultimately leading to FA symptoms.
Almost everyone with FA carries a specific type of mutation called a GAA trinucleotide repeat expansion, where three nucleotides, or building blocks of the genetic code, are repeated too many times. This repeat reduces the activity of the FXN gene, leading to lower frataxin protein production. DT-216P2 is designed to target the GAA repeat expansion and increase FXN gene activity, with the goal of boosting frataxin production.
Design had previously tested an earlier formulation designed to work in a similar way, but that therapy was associated with injection reactions in early clinical testing. The company then reworked the therapy to create DT-216P2, with the aim of retaining the same biological activity while avoiding those problematic reactions.
Design sponsored a Phase 1/2 clinical trial called RESTORE-FA (NCT06874010) to test DT-216P2’s safety, how it moves through the body, its biological effects, and exploratory clinical measures in people with FA. A total of 16 participants were given weekly infusions of the therapy at various doses (0.1, 0.3, 0.6, or 1 mg/kg) for four weeks.
Safety data showed the experimental treatment was generally well tolerated, with no serious side effects reported. In three patients, there were temporary elevations of alanine transaminase (ALT), a liver enzyme that can rise when the liver is stressed or injured. None of these ALT elevations led to symptoms of liver issues, and Design said temporary ALT elevation is anticipated with enhanced mitochondrial activity.
Highest dose raised frataxin markers
Biomarker data showed that, in the four patients given the highest tested dose of DT-216P2, levels of frataxin in blood increased from the study’s start to two weeks after the last dose, by an average of 22%-27%, depending on the specific form of the protein assessed. Levels of FXN messenger RNA — an intermediary molecule produced when the gene is read to make frataxin protein — also increased, by 65% in blood and by 42% in muscle tissue after four weeks of treatment.
The four patients given the highest tested dose of DT-216P2 also showed improvements in the modified Friedreich’s Ataxia Rating Scale (mFARS), a standard measure of FA severity. After four weeks on DT-216P2, mFARS scores decreased, indicating improvement, by 6.4 points on average.
Shah noted that the new result for DT-216P2 “is the first time increases in endogenous [frataxin] have been observed alongside clinical improvements of this magnitude in patients with FA.”
Along with the improvements in mFARS, the four patients given the highest tested dose of DT-216P2 also had an average 2.7-point improvement in the Upright Stability Score, a measure of balance, and an improvement of more than five points in a measure of fatigue called the PROMIS Fatigue Scale. An improvement of three points in the PROMIS Fatigue Scale is generally considered a minimal important change in fatigue.
“We observed both dose-dependent increases in [frataxin] levels and dose-dependent improvements across multiple clinical measures, including mFARS, upright stability score and patient-reported fatigue,” Shah said. “Based on these findings, we believe DT-216P2 has the potential to be a best-in-disease treatment for patients with FA and look forward to advancing the program toward registrational development.”
