First Clinical Trial of GeneTAC Therapy for FA Expected in 2022

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Design Therapeutics announced that it remains on track to launch the first clinical trial of its lead experimental candidate — gene-targeted chimera (GeneTAC) — for the treatment of Friedreich’s ataxia (FA) for the first half of 2022.

The planned Phase 1 trial will test the therapy in patients, and top-line results are anticipated in the second half of next year.

Such development plans are supported by favorable feedback from both the U.S. Food and Drug Administration and the European Medicines Agency, and are also supported by the company’s ability to manufacture the therapy at a scale sufficient for clinical use.

“We’ve made substantial progress as a company, highlighted by the compelling new data from ongoing IND [investigational new drug]-enabling studies with our lead GeneTAC program for Friedreich ataxia,” João Siffert, MD, Design’s president and CEO, said in a press release.

IND-enabling studies comprise preclinical research to secure clearance for clinical trials.

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“Importantly, we’ve observed well-tolerated GeneTAC doses in rodents and non-human primates that produced ample biodistribution into key tissues affected by the disease, including the brain, increasing our confidence in the potential of this program as a disease-modifying treatment for patients,” Siffert added.

Friedreich’s ataxia, a rare progressive disease that mainly affects nerve cells and muscles, is caused by excessive repeats of three nucleotides, the building blocks of DNA — one guanine (G) and two adenines (A) — in the first intron of the FXN gene.

An intron is a genetic area that does not provide instructions to make a protein and that is later removed from the intermediate messenger RNA (mRNA) molecules that guide protein production.

These excessive GAA repeats prevent the FXN gene from making full-length mRNA molecules that serve as templates for the production of frataxin, a protein with a key role in iron metabolism and required for energy production in mitochondria (the cells’ powerhouses).

GeneTACs are a new class of small molecules designed to target the underlying cause of inherited nucleotide repeat expansion diseases by either promoting or preventing the generation of full-length mRNA molecules. They are meant to be administered directly into the bloodstream once a week.

The FA-targeting GeneTAC molecule contains a portion that binds specifically to the GAA repeats in the FXN gene and another that recruits protein complexes that allow the production of a full-length mRNA.

Given that excessive GAA repeats are located in an FXN’s noncoding region, they are naturally excluded from the protein production process, allowing the generation of a working frataxin protein.

Data from preclinical studies in FA patient-derived nerve and heart muscle cells grown in the lab showed that low doses of FA GeneTAC were sufficient for robust and sustained increases in FXN’s mRNA and for frataxin levels that reached those seen in cells from healthy people.

In addition, repeated therapy dosing in healthy rodents and nonhuman primates was generally well tolerated and achieved higher concentrations in the brain, spinal cord, heart, and skeletal muscle than those needed to restore frataxin production.

These preclinical findings indicate that FA GeneTAC led to sustained increases in frataxin at levels approaching those of healthy people, suggesting it may halt disease progression in people living with FA.

Design is also working on a second GeneTAC program focused on myotonic dystrophy type-1, an inherited nucleotide repeat expansion disease that causes progressive muscle weakness and for which no approved therapies exist.

“Design is well positioned to advance our research and development activities targeting a number of nucleotide repeat expansion diseases,” said Pratik Shah, PhD, Design’s co-founder and executive chair.

“We are now preparing for the important transition to a clinical-stage organization, bringing us another step closer to delivering a new class of genomic medicines for a range of serious disorders currently without approved treatments,” Shah added.