Clinical trials in Friedreich’s ataxia

Last updated April 25, 2024, by Lindsey Shapiro, PhD
Medically reviewed by David Lynch, MD, PhD

Friedreich’s ataxia (FA) is caused by mutations in the FXN gene, leading to a lack of the frataxin protein that is critical for mitochondrial function. Experimental approaches for treating FA involve strategies to increase FXN activity, offer functional frataxin protein, or modulate the downstream processes of frataxin that become dysregulated in FA, such as mitochondrial function.

Frataxin replacement

Nomlabofusp (previously known as CTI-1601), from Larimar Therapeutics, is a recombinant fusion protein designed to deliver human frataxin to the mitochondria via subcutaneous injection. It is currently being evaluated in a Phase 2 trial (NCT05579691) involving adults with FA.

Top-line data indicated that nomlabofusp was well tolerated and associated with dose-dependent frataxin increases in skin and buccal cells. An open-label extension trial was launched in January 2024. Clinical development of nomlabofusp remains under a partial clinical hold in the U.S. due to safety concerns raised in nonhuman primate tests.

FXN-targeted therapies

Gene replacement and editing

LX2006 is an FXN gene replacement therapy candidate designed by Lexeo Therapeutics for the treatment of FA cardiomyopathy. It is currently being evaluated in an open-label, ascending dose Phase 1/2 clinical trial called SUNRISE-FA (NCT05445323). Recruitment of adult FA patients, ages 18-50, with cardiomyopathy is ongoing at sites in the U.S. and Canada.

Another gene therapy in clinical development is AAVrh.10hFXN. This is a gene replacement therapy for FA-associated cardiomyopathy being developed at Cornell University. A Phase 1a clinical trial (NCT05302271) is evaluating its safety and preliminary efficacy in adult FA patients with cardiomyopathy.

Increasing FXN expression

Design Therapeutics’ DT-216 is designed to recruit an endogenous transcriptional elongation complex to the expanded GAA sequence in the FXN gene of FA patients, unblocking the transcriptional machinery and restoring frataxin production.

It was recently evaluated in a Phase 1 multiple ascending dose trial (NCT05573698). Interim results indicated that DT-216 led to dose-dependent increases in frataxin mRNA levels in skeletal muscle tissue of FA patients. However, it was associated with phlebitis (blood clots) and the study did not reach its maximum dose. This adverse event will require modification of the drug or its administration before returning to clinical trials.

Mitochondrial function and oxidative stress

A number of experimental therapies for FA aim to ameliorate the cellular consequences of frataxin loss by boosting mitochondrial function or combating oxidative stress.

The most advanced in clinical development is PTC Therapeutics’ vatiquinone, an oral small molecule targeting 15-lipoxygenase, a regulator of energetic and oxidative stress pathways. Vatiquinone was evaluated in the global MOVE-FA Phase 2/3 trial (NCT04577352), involving FA patients ages 7 and older.

The trial failed to meet its primary endpoint of demonstrating statistically significant changes in disease progression, relative to placebo, after 72 weeks of thrice daily treatment. Vatiquinone was, however, associated with significant treatment benefits in mFARs subscales of upright stability and bulbar symptoms, and significantly eased fatigue. The study revealed few adverse events.

Other modulators of mitochondrial function being evaluated for FA include:

• Elamipretide: A synthetic peptide from Stealth Biotherapeutics that targets cardiolipin on the inner mitochondrial membrane. A pilot Phase 1/2 trial (NCT05168774) is evaluating the effects of daily subcutaneous elamipretide on high contrast visual acuity in 18 FA patients, ages 16 and older.
• Dimethyl fumarate: An oral anti-inflammatory and antioxidant molecule used to treat multiple sclerosis and found to increase frataxin production. It’s being tested in a Phase 2 trial (EudraCT 2021-006274-23) in Europe, involving FA patients, ages 12 and older.

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