Design Gets FDA OK to Start Phase 1 Trial of DT-216 for FA

The U.S. Food and Drug Administration (FDA) has cleared Design Therapeutics to begin a Phase 1 clinical trial investigating its GeneTAC small molecule DT-216 for the treatment of Friedreich’s ataxia (FA).

This clearance comes after the submission of an investigational new drug (IND) application based on promising data in preclinical studies. Enrollment for the trial is expected to start in the coming weeks, and topline data from the trial is expected in the second half of 2022, Design announced.

“The IND clearance for DT-216 is an important milestone for the company, further validating the therapeutic potential of our GeneTAC platform, a new class of medicines being developed for serious degenerative diseases caused by a single gene defect,” João Siffert, MD, president and CEO of Design, said in a press release.

FA is caused by mutations in the FXN gene that result in a deficiency of the frataxin protein, which is required for energy production. The most common disease-causing mutation consists of excessive repeats of a series of three nucleotides — DNA building blocks; one guanine (G) and two adenines (A) — in a region of the gene.

While that sequence is repeated multiple times in healthy people, around five to 33 times, FA patients often have hundreds of repeats, which disrupts the production of frataxin.

GeneTACs are small molecules that can target nucleotide repeat expansions and either promote or prevent proteins from being built. DT-216 was designed to specifically target the mutated region in the FXN gene and restore its function, enabling the production of a working frataxin protein.

“GeneTAC molecules, designed based on decades of pioneering research into the mechanisms of gene transcription, are capable of dialing up or dialing down the expression of disease-causing genes and therefore have the potential to address the root cause of genetic diseases,” Siffert said.

The upcoming Phase 1 trial is designed to evaluate DT-216’s safety, tolerability, and pharmacokinetics — the movement of the drug into, through, and out of the body — in FA patients. The treatment’s ability to increase frataxin levels will also be monitored.

The trial builds on previous preclinical studies, in which low doses of DT-216 restored frataxin levels in lab-grown, patient-derived nerve and heart muscle cells — to levels comparable to those seen in cells from healthy people. Of note, nerve and heart muscle cells are most affected by a frataxin deficiency.

Furthermore, repeated administration of DT-216 was well-tolerated in rodents and non-human primates at doses higher than those needed to restore frataxin production.

The data altogether suggested that DT-216 could safely and successfully restore frataxin levels, and may be able to slow FA disease progression.

Design is also developing a second GeneTAC program for myotonic dystrophy type-1, another inherited nucleotide repeat expansion disease for which no approved therapies exist.

“DT-216 is the first in a pipeline of GeneTAC molecules, which can be designed and selected for desirable pharmaceutical properties such as tolerability, broad tissue distribution, including the CNS [central nervous system], efficient manufacturing, and convenient administration. We are eager to begin clinical development of DT-216 for people with FA, for whom there are no disease-modifying treatments available today,” Siffert said.