Clinical evidence of interventions assessed in Friedreich ataxia: a systematic review

Abstract

Objectives:

The rare inherited autosomal recessive disease Friedreich ataxia (FA) causes progressive neurodegenerative changes and disability in patients. A systematic literature review (SLR) was carried out to understand and summarize the published efficacy and safety of therapeutic interventions in this disease.

Methods:

Database searches were carried out in MEDLINE, Embase, and Cochrane by two independent reviewers. In addition, trial registries and conference proceedings were hand-searched.

Results:

Thirty-two publications were deemed eligible according to PICOS criteria. Twenty-four publications detail randomized controlled trials. The most frequently identified therapeutic intervention was idebenone ( n = 11), followed by recombinant erythropoietin ( n = 6), omaveloxolone ( n = 3), and amantadine hydrochloride ( n = 2). Other therapeutic interventions were investigated in one publication: A0001, CoQ10, creatine, deferiprone, interferon-γ-1b, the L-carnitine levorotatory form of 5-hydroxytryptophan, luvadaxistat, resveratrol, RT001, and vatiquinone (EPI-743). These studies included patients from 8 to 73 years old, and disease duration varied from 4.7 to 19 years. Disease severity as per the mean GAA1 and GAA2 allele repeat length ranged from 350 to 930 and 620 to 987 nucleotides, respectively. Most frequently reported efficacy outcomes were the International Cooperative Ataxia Rating Scale (ICARS, n = 10), the Friedreich Ataxia Rating Scale (modified FARS and FARS-neuro, n = 12), the Scale for Assessment and Rating of Ataxia (SARA, n = 7), and the Activities of Daily Living scale (ADL, n = 8). Each of these assesses the severity of disability in FA patients. In many studies, patients with FA deteriorated according to these severity scales regardless of treatment, or inconclusive results were found. Generally, these therapeutic interventions were well-tolerated and safe. Serious adverse events were atrial fibrillation ( n = 1), craniocerebral injury ( n = 1), and ventricular tachycardia ( n = 1).

Conclusion:

Identified literature showed a considerable unmet need for therapeutic interventions that halt or slow the deteriorating nature of FA. Novel efficacious drugs should be investigated that aim to improve symptoms or slow disease progression.

Plain Language Summary

A systematic review investigating the effectiveness and safety of treatments for Friedreich ataxia

What is Friedreich ataxia?

Friedreich ataxia (FA) is a rare genetic condition that causes nervous system damage and movement problems, including muscle weakness and impaired coordination (ataxia). Heart problems, vision problems, spine problems, and diabetes can occur, too. Within 10 to 20 years of the first symptoms, an individual with FA generally requires a wheelchair.

Why was this study done?

Currently there are no approved treatments for FA. Current treatments focus on relieving symptoms. This study was carried out to obtain a landscape view of all the published evidence about FA treatments.

What did the researchers find?

• Two scales were most frequently used to assess disease severity: the International Cooperative Ataxia Rating Scale (ICARS) and the FA Rating Scale (modified FARS and FARS-neuro).

• Patients on idebenone at 1350 to 2550 mg per day showed improvement in ICARS and FARS scores over 6 months, but scores deteriorated after 12 months in ambulatory patients with FA.

• Omaveloxolone at doses of 2.5 to 300 mg per day showed significant improvement in mFARS scores and FA Activity of Daily Living scores at 48 weeks compared with placebo.

• Patients treated with vatiquinone showed significant improvements in FARS-neuro scores at 24 months versus natural disease progression.

• Other treatments did not show evidence of significant improvement.

What does this mean?

FA leads to nervous system damage slowly, over an extended period. It is important to keep in mind that many of the studies reviewed here were of fairly short duration, meaning that the effects of a treatment may not have been detectable.

Why is this important?

This study was undertaken in the hopes that a comprehensive picture of the current treatment landscape for FA will help promote research that will eventually lead to effective treatments to slow down or reverse the damage caused by disease, which are vitally needed.