A Broad View of the Future of Friedreich's Ataxia Therapy

The approval of Skyclarys underscored the importance of sensitive outcome measures, say authors.

Louise Corben, Ph.D.

Cutting-edge developments in gene therapy and neuroprotective strategies are driving the future of Friedreich’s ataxia (FRDA) therapy. In a recent review of the therapeutic landscape for FA, Louise Corben, Ph.D., from the Bruce LeFroy Centre for Genetic Health Research in Australia, and colleagues provided a comprehensive review of current and emerging therapeutic strategies for FA, highlighting the urgent need for effective treatments to counteract the life-shortening effects of this condition.

The review, published in CNS Drugs, focused on drug and gene therapies that have progressed to phase 1 clinical trials and beyond, noting significant advancements and the challenges that remain, particularly in recruiting participants for clinical studies.

FRDA is a progressive neurodegenerative condition that affects balance, coordination, and, ultimately, the patient's quality of life. With an estimated 1 in 40,000 individuals affected by this debilitating disorder, the authors note the urgency for innovative treatments is more crucial than ever.

In recent years, there has been a surge in research dedicated to understanding the underlying mechanisms of FRDA, paving the way for groundbreaking therapies that were once considered out of reach.

Symptoms range from neurological issues, including ataxia and loss of reflexes, to non-neurological complications, such as diabetes and cardiomyopathy. The relentless progression of FRDA typically leads to significant disability and, on average, death by 40 years of age.

Key advances include the approval of Skyclarys (omaveloxolone) as the first treatment for FRDA patients aged 16 and older. According to the Corben and her co-authors, the FDA approval of Skyclarys in February 2023 underscored the importance of sensitive outcome measures and natural history data in trial evaluations, meaning that patients treated with the new drug demonstrated significant improvement over three years compared with the natural history of FRDA.

Some challenges in measuring therapeutic outcomes are due to the complexity and variability of FRDA symptoms among patients. Corben and her colleagues discuss various clinical scales, like Friedreich's Ataxia Rating Scale (FARS) and modified FARS, emphasizing their role in assessing neurological function but also noting their limitations in reflecting broader disease progression. They underscore the need for innovative and sensitive measures to capture treatment effects, especially in different stages of the disease.

New and emerging drug therapies for FA are categorized into those that reduce oxidative stress and improve mitochondrial function and those that modulate frataxin-controlled metabolic pathways. Promising compounds mentioned include MIB-626, elamipretide and nomlabofusp (formerly known as CTI-1601). Pending results of an open-label extension study, nomlabofusp will be up for an advanced approval target date of late 2025.

Current investigational gene therapies encompass novel approaches such as gene replacement and editing techniques. Gene therapy-specific trials, including phase 1/2 studies targeting cardiomyopathy associated with FRDA, indicate a proactive direction in therapeutic development.

The approval of Skyclarys marked a milestone for FRDA treatment. Still, it is just the beginning of what is needed to address the multifaceted nature of FRDA and improve patient outcomes. Future therapeutic strategies will likely focus on personalized medicine approaches, incorporating ongoing discoveries in genetics and treatment modalities.