Top 10 Friedreich’s ataxia stories of 2023

Friedreich’s Ataxia News consistently covered the latest in scientific research, treatment development, and clinical studies for Friedreich’s ataxia (FA) throughout 2023. Here are the top 10 most widely read stories of last year:

No. 10 – Dosing starts in 2nd patient group in trial of gene therapy candidate

Dosing with LX2006, a gene therapy candidate for heart disease in people with FA, was started in a second group of patients by midyear in a Phase 1/2 clinical trial, following treatment of the study’s initial group of participants. Thus far, the investigational therapy has been well tolerated, and not linked to unexpected safety issues or toxicity in the one-year, dose-ascending, and open-label trial, according to its developer Lexeo Therapeutics. Given that, the Data Safety Monitoring Board that reviewed the SUNRISE-FA clinical trial (NCT05445323) supports using a likely higher, one-time dose in a new group of FA patients who have cardiomyopathy.

FA is caused by mutations in the FXN gene that interfere with the production of frataxin, a protein essential to the normal function of mitochondria, where cellular energy is produced. LX2006 is crafted to deliver, via a benign adeno-associated virus, a working FXN gene to heart muscle cells, with a goal of increasing frataxin levels and restoring mitochondrial function and energy production.

No. 9 – Adenosine in FA cell study mitigates mitochondria dysfunction

Researchers found that mitochondrial function in connective tissue cells called fibroblasts from an FA patient was improved by adenosine, a naturally occurring molecule. Mitochondrial dysfunction is an Friedreich’s ataxia hallmark.

These findings suggest that adenosine could serve a promising role in breakthrough FA therapies — it’s been shown to shield against cerebellar ataxia, a certain type of ataxia, or poor muscle control resulting in clumsy voluntary movements. Such ataxia results from damage to a brain area called the cerebellum. In this study, the scientists hypothesized that adenosine, which is widely distributed in the central nervous system, comprised of the brain and spinal cord, where it serves a number of functions, can help lessen the dysfunction of mitochondria in FA.

No. 8 – The antioxidant vitamin supplement CoQ10 could help in FA

The naturally occurring coenzyme Q10 (CoQ10) may potentially treat FA and other neurological disorders, according to a review article published in 2023. Found in some foods, the vitamin-like substance helps the body perform well and remain healthy. It also helps mitochondria with energy production and offsets oxidation by searching for harmful molecules, skirting damage.

In one study of 50 FA patients, many of them were found to have low blood levels of CoQ10. In nearly half, CoQ10 supplements, combined with vitamin E, eased their symptoms. The combination also improved energy production in the muscles of a number of patients who participated in a small, six-month study. Further study is needed, however, the review researchers noted.

No. 7 – MOXle trial shows no new cardiac or liver findings with Skyclarys

Analyses of study data indicated that Skyclarys (omaveloxolone) — the first treatment approved for FA, in a U.S. regulatory decision in February 2023 — showed a positive heart and liver safety profile in a Phase 2 clinical trial. That two-part clinical study, dubbed MOXle (NCT02255435), was conducted at sites in the U.S. and Australia, and in Europe. The oral medication by Reata Pharmaceuticals works to improve the health of mitochondria by activating a protein called Nrf2.

While Skyclarys was generally found to be safe and well tolerated — changes in heart or liver function generally did not occur with changes in disease symptoms — trial data prompted certain alterations in markers of heart and liver function to be noted on the treatment’s prescribing label. The findings were presented at the Muscular Dystrophy Association (MDA) Clinical & Scientific Conference in March.

No. 6 – Gene-editing platform could potentially fix FA deficits

A gene-editing technology, called Prime Editing, was found to have fixed the genetic deficits linked to FA and restored nerve cell projections in preclinical research using patient cells. According to its developer Prime Medicine, the technology has the potential to deliver one-time, curative genetic treatments in FA and other disorders, including cystic fibrosis.

A GAA trinucleotide repeat expansion is the most common type of FA-causing mutation. Nucleotides are the building blocks of DNA. In FA, there have been reports of hypermethylation in the FXN gene, which refers to a type of chemical modification (methylation) that works to regulate gene activity. Prime‘s technology extracts the deleterious GAA repeats in the FXN gene, with the goal of impeding excess methylation and restoring more normal frataxin levels.

No. 5 – Skyclarys slows disease progression in long-term study

Months after Skyclarys made news by becoming the first therapy approved by the U.S. Food and Drug Association (FDA) for Friedreich’s ataxia, it also was found to slow the disease’s progression. Indeed, disease progression among patients treated in the MOXie study and its extension for three years was found to be more than 50% slower compared with that of participants in a natural history study, an analysis showed.

With this study, researchers sought to frame Skyclarys’ long-term effects against what would likely occur without treatment. In all, the researchers said the collective results showed that treatment with Skyclarys resulted in clinically meaningful slowing of FA progression relative to participants in the Friedreich Ataxia Clinical Outcome Measures Study (NCT0309789). That study, opened in the early 2000s, gathered data on FA progression in some 1,000 patients who received no disease-specific treatment.

No. 4 – Vatiquinone seen to slow FA progression by 75% in MOVE-FA

In the MOVE-FA trial, nearly 1.5 years of treatment with vatiquinone (PTC-743) was found to slow disease advancement by 75% in pediatric and adult FA patients. The Phase 2/3 trial (NCT04577352) opened in 2020 with 146 children and adults with FA who could walk at least 10 feet in one minute and swallow capsules.

Top-line data showed that, while the PTC Therapeutics oral therapy failed to meet its primary endpoint of an overall statistically significant change in FA progression, it did show significant benefits among patients in easing fatigue and face and neck symptoms, and improving upright ability.

No. 3 – Dimethyl fumarate gets tested in Phase 2 trial as potential FA treatment

With dimethyl fumarate (DMF) already approved to treat multiple sclerosis and psoriasis, researchers launched a clinical trial last year to assess the therapy for its safety and efficacy in FA. The Phase 2 clinical study EudraCT (2021-006274-23), underway in Italy, also is testing DMF’s molecular impact. The oral inflammatory and antioxidant molecule showed the ability in preclinical studies to dose-dependently raise frataxin levels in FA patient cells and mouse models, as well as to improve the synthesis of mitochondria and their function.

DMF also has been found to activate the protein Nrf2. which is involved in mitochondrial function. Scientists previously found that three months of DMF treatment was linked to an 85.1% rise in FXN activity, in addition to increases in markers of mitochondrial function among those with multiple sclerosis using the treatment.

No. 2 – Reata’s omaveloxolone becomes 1st FDA-approved treatment for FA

Making history, the FDA approved the once-daily oral treatment Skyclarys for adults and adolescents ages 16 and older with FA. The approval carried a rare pediatric disorder priority review voucher for the therapy’s developer Reata, which may be used for a quicker review of a subsequent application for a different treatment or be sold to another company.

Reata early in 2022 started a rolling application for Skyclarys with the FDA, finishing it two months later. The regulatory agency had placed the application under priority review. The regulatory submission was supported by data from the two-part MOXie clinical trial. The therapy earned orphan drug status in the U.S. and Europe, in addition to fast track designation in the U.S.

No. 1 – MRI study backs FA as ‘whole brain’ disorder

Scientists used the findings of an MRI study to support the widely-held view that Friedreich’s ataxia is a whole-brain condition — and to back associations between imaging markers of total-brain abnormalities. The results showed that altered connections between the cerebellum and the cerebral cortex — two key brain regions — are linked to greater FA severity. Further, unusual connectivity changes correlate with damages to the brain’s white matter, mainly composed of nerve fibers.

However, the scientists also noted that more research is needed to study cerebellum-cerebral connectivity alternations over time, how they relate to symptom progression, and their promise as biomarkers to track disease. The cerebellum is a brain region that is key to coordinating voluntary movements, while the cerebral cortex is involved in higher-level processes.

We at Friedreich’s Ataxia News hope these articles and our reporting throughout 2023 have been informative and have helped to improve the lives of those affected by FA. In wishing our readers a very happy new year, we look forward to continuing to being of service to the community in 2024.