Phase 1 DT-216 Program for FA on Track; Initial Data Expected Soon

Program includes single-ascending dose, multiple-ascending dose studies of adults

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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The Phase 1 clinical program of DT-216, Design Therapeutics’ experimental therapy for Friedreich’s ataxia (FA), remains on track, with initial data expected by year’s end.

The program includes a single-ascending dose Phase 1a trial (NCT05285540) and a multiple-ascending dose Phase 1b study (NCT05573698), both testing the therapy in adults with FA, ages 18–55. Both studies are underway at Clinilabs in Eatontown, New Jersey. The Phase 1b trial is still recruiting.

“Our Phase 1 clinical program evaluating DT-216, our lead GeneTAC molecule, as a treatment for patients with Friedreich ataxia (FA) is progressing well,” João Siffert, MD, Design’s president and CEO, said in a company press release. “We have enrolled patients in the final [group] of the single-ascending dose trial, and plan to assess and report initial data next month. In addition, we recently initiated dosing in the multiple-ascending dose trial, keeping us on-track to complete Phase 1 mid next year.”

The single-ascending dose Phase 1a trial is testing how safe and well tolerated a single injection of increasing doses of DT-216 is versus a placebo in up to 25 adults with a genetically confirmed FA diagnosis. It’s also testing the therapy’s pharmacokinetics (movement into, through, and out of the body) and pharmacodynamics (effects in the body).

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The multiple-ascending dose Phase 1b trial is evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of three weekly injections of one of several doses of DT-216 against a placebo in up to 38 adult patients.

FA is caused by deficient levels of frataxin — a protein essential for the proper functioning of mitochondria, the cell’s power plants — due to mutations in the FXN gene. The most common disease-causing mutation consists of excessive repeats of a specific DNA sequence, GAA.

While that sequence is repeated up to 33 times in healthy people, FA patients often have hundreds to thousands of repeats, which disrupts frataxin production. The number of GAA repeats is linked to how severe FA symptoms are and how quickly they progress.

Administered directly into the bloodstream, DT-126 is one of Design’s proprietary GeneTACs molecules, which are made to target specific DNA repeat sequences and promote or suppress the resulting protein’s production.

DT-126 was created to bind to the GAA repeats in the FXN gene and restore frataxin production. One of the molecule’s ends binds to the GAA repeats, whereas the other end binds to a protein complex involved in translating information in DNA into messenger RNA (mRNA), the molecule derived from DNA that guides protein production.

Early this year, the company got the green light from the U.S. Food and Drug Administration to move DT-126 into clinical testing after it submitted an application based on positive preclinical data. These findings were recently presented at the International Congress for Ataxia Research, Nov. 1–4, in Dallas, Texas.

The presentation was titled “GeneTAC small molecules increase frataxin in a mouse model of Friedreich ataxia, restore FXN and improve mitochondrial function in patient-derived cells, and achieve sustained biodistribution in CNS and heart in rats and non-human primates.”

Data showed DT-126 increased FXN mRNA by about 10 times in white blood cells collected from 23 people with FA who carried hundreds to thousands of GAA repeats in their FXN gene. The therapy’s effects were dose-dependent, with higher doses leading to higher FXN mRNA levels.

Treating FA patient-derived nerve cells with DT-126 at a dose of 10 nanomoles per liter — associated with 90% maximal response — for 14 days increased frataxin protein production to levels similar to healthy nerve cells.

DT-216 also was seen to improve mitochondria’s energy production in FA immune cells and patient-derived heart cells.

The company is also testing GeneTACs candidates in other DNA repeat-associated diseases, such as myotonic dystrophy.

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