All signs indicate 2023 will prove a pivotal year in Friedreich’s ataxia drug development. Reata’s omaveloxolone, which met its primary endpoint in a Phase II trial, is up for FDA approval on February 28. Meanwhile, a Phase II/III trial of PTC’s vatiquinone, a Phase I/II trial of Stealth Bio’s elamipretide, and a Phase II study of Larimar’s CI-1601 all have key results expected in 2023.

Friedreich’s ataxia, which affects approximately one in 50,000 people, usually begins in childhood and causes progressive nervous system damage and impaired muscle coordination known as ataxia. With no approved treatments, the need for new therapies to treat the debilitating disease looms large.

Drug development challenges

There have been nearly 20 clinical trials for Friedreich’s ataxia that failed to meet their primary endpoints, despite strong preclinical data and trial designs, explains Dr. Susan Perlman, a neurologist at the University of California Los Angeles. “This speaks to the complexity of the disease,” she says.

Friedreich’s ataxia causes a deficiency in the protein frataxin, which is important for preserving mitochondrial function. Because the disease is a single gene disorder, early researchers thought it would be fairly straightforward to treat, Perlman says. However, a series of early trial failures prompted further research into mitochondrial function, leading to a new wave of drug development approaches eyeing better outcomes, she adds.

Meanwhile, clinical trial design in Friedreich’s ataxia presents its own challenges, adds Dr. Marcondes Cavalcante França Jr., neurologist at Universidade Estadual de Campinas, Brazil. Inconsistent disease progression and a small and heterogeneous patient population make it tough to measure clinically meaningful benefits in the clinical trial setting, he notes.

According to GlobalData’s clinical trials database, there has been a slight uptick in drug trials in Friedreich’s ataxia since 2010. In 2022, Friedreich’s ataxia trials accounted for 0.19% of drug trials for central nervous system conditions, up from 0.04% of such trials in 2010. GlobalData is the parent company of Clinical Trials Arena.

“We're far ahead of where we were in 1997 when the Friedreich’s ataxia gene was first discovered,” Perlman says. “But we still do not have an approved drug.”

Reata’s omaveloxolone up for approval

Reata’s small molecule omaveloxolone is up for approval on February 28, based on the Phase II MOXIe trial (NCT02255435) and a subsequent open-label extension. Given the high unmet need and successful study, Perlman says omaveloxolone will likely get approved.

The MOXIe trial met its primary endpoint of change in the modified Friedreich's ataxia rating scale (mFARS) after 48 weeks, which França says is the most accepted clinical trial endpoint for the disease. The mFARS is a 93-point scale measuring Friedreich’s ataxia disease progression, including neurological decline. Meanwhile, subsequent open-label extension data suggests omaveloxolone’s treatment effect persists after several years.

PTC Therapeutics’ vatiquinone late stage readout

PTC’s small molecule vatiquinone has results from the Phase II/III MOVE-FA trial (NCT04577352) expected in Q2 2023. Like omaveloxolone’s MOXIe, MOVE-FA uses mFARS as a primary endpoint, but with a longer double-blind period of 72 weeks. However, while MOXIe recruited patients ages 16–40, MOVE-FA recruited patients as young as 7 years old.

Overall, Perlman says the two small molecules from Reata and PTC “may have longer-term, disease-slowing impact.” With key results for vatiquinone expected shortly after the omaveloxolone approval decision, all eyes will be PTC’s Friedreich’s ataxia program.

Stealth Bio’s elamipretide tests tetra peptide approach

Meanwhile, Stealth Bio’s elamipretide has interim results from the investigator-sponsored Phase I/II ELViS-FA trial (NCT05168774) expected in H1 2023. The study will test whether the tetra peptide elamipretide can treat vision loss in children with Friedreich’s ataxia.

The 18-patient study, which is sponsored by the Children's Hospital of Philadelphia, has a primary endpoint of change in high contrast visual acuity after 52 weeks. Elamipretide is under development for multiple mitochondrial diseases, including Friedreich’s ataxia, mitochondrial myopathy, and Barth Syndrome.

Larimar’s CI-1601 assesses fusion protein strategy

Finally, Larimar Therapeutics’s CTI-1601 has a topline Phase II (NCT05579691) data expected in the second half of 2023. The primary endpoint is adverse events, with secondary endpoints focused on the fusion protein’s pharmacokinetics and pharmacodynamic (PK/PD) effects.

CTI-1601 is designed to deliver frataxin protein directly into patients with Friedreich’s ataxia, which is characterized by a frataxin deficiency. “Just like a diabetic gets insulin, somebody with Friedreich’s ataxia should get frataxin protein,” Perlman says. “Larimar’s agent is designed to cross cell membranes and enter the mitochondria to perform its normal job of protecting protein.”