Key Challenges in Treating Friedreich Ataxia

AJMC^®: What is your background in treating Friedreich ataxia (FA) in clinical practice and in clinical trials?

KUO: I am the director of Columbia University’s ataxia center and have extensive experience in caring for patients with FA. I provide clinical care, symptomatic therapy, and prescription management and dedicate significant time to this population. Our center has conducted substantial clinical research on ataxia, focusing on both motor and nonmotor symptoms. Our expertise extends to physiology-intensive clinical trials and participation in various ataxia studies.

AJMC^®: Why has developing therapies for FA proven difficult?

KUO: Challenges in developing therapies for FA are numerous. First, precise target identification and dosing pose difficulties due to the lack of reliable biomarkers. The disease progression, often gauged through neurologic deterioration, further complicates measurement. Establishing a natural history study to track progression was time-consuming but crucial for demonstrating the efficacy of interventions. The recent approval of omaveloxolone, the first FDA-approved therapy for FA, marked a significant breakthrough. The approval addresses previous regulatory uncertainties regarding end points and creates a possible pathway for the approval of future therapies.

AJMC^®: What are the key challenges facing individuals with FA?

KUO: Patients with FA face substantial challenges with motor function coordination and quality of life due to neurologic symptoms. These include imbalance, slurred speech, dexterity issues (upper extremity function), and double vision, which significantly impact daily life. For instance, motor symptom onset often leads to difficulty in activities like running, participating in physical education, navigating stairs, or even walking. Progression necessitates use of mobility aids like canes or walkers, and, eventually, many patients become bedridden or wheelchair-bound. Hand dexterity diminishes as well, severely affecting patients’ abilities. Speech difficulties add to patients’ challenges, hindering communication and potentially making maintaining regular employment a significant struggle.

AJMC^®: How does FA impact patients’ daily lives?

KUO: FA severely impacts daily life, particularly in terms of physical activities and independence. Progressive motor dysfunction leads to increased dependence on others and diminishes independence, especially when patients require a walker. Social interactions are heavily influenced by patients’ ability to communicate effectively, which is hindered as their speech becomes slurred and slower over time; this impedes meaningful engagement.

AJMC^®: How do secondary symptoms impact patient well-being?

KUO: Heart complications, notably severe in later disease stages, require use of diuretics and can lead to respiratory issues, significantly limiting activity. Fatigue is a prevalent nonmotor symptom that necessitates frequent rest breaks. Additionally, some patients develop diabetes, which imposes dietary restrictions and, sometimes, requires insulin management. Diabetes also brings potential complications like neuropathy and infections. Arrhythmia is a common cardiac issue, requiring interventions like pacemaker placement for stability.

AJMC^®: Before the approval of omaveloxolone, how were patients with FA managed?

KUO: Traditionally, managing intense neurologic symptoms in FA involved prescribing physical therapy or occupational therapy, focusing on exercise therapy. Off-label use of various medications (eg, riluzole) or supplements (eg, coenzyme Q10) were also attempted to alleviate ataxia symptoms, although efficacy was often limited and inconsistent across clinical trials.^1,2

AJMC^®: What are the most pressing research gaps for FA?

KUO: The most pressing gaps relate to effectively addressing the disease’s biology. Although omaveloxolone shows promise in slowing disease progression, it’s not curative. Research should focus on developing diverse and potent therapies targeting the disease’s biology to further slow progression. Additionally, understanding the potential for early intervention before symptom onset is crucial. Omaveloxolone targets symptomatic individuals, but investigating whether it can delay symptom onset is vital. Lastly, there’s a need for effective symptomatic therapies to provide immediate relief and potentially restore abnormal brain circuits to complement omaveloxolone therapy in managing FA.

AJMC^®: What mechanisms are being targeted by investigational agents?

KUO: The primary investigational mechanisms in FA treatment are focused on frataxin protein replacement or enhancement, targeting the deficiency through protein replacement or splicing regulators to boost frataxin expression. Gene therapy using viruses to restore frataxin expression is also under consideration. Omaveloxolone, on the other hand, targets mitochondrial dysfunction downstream, demonstrating slowed disease progression. Future advancements are likely to concentrate on mitochondrial pathways due to their potential to showcase clinical efficacy. Early studies on frataxin protein replacement show promise, increasing frataxin levels in blood and saliva by delivering the replacement protein into various compartments. ◆

References

1. Ayala IN, Aziz S, Argudo JM, et al. Review of riluzole for the treatment of hereditary ataxias: a systematic review. Brain Sci. 2022;12(8):1040. doi:10.3390/brainsci12081040
2. Parkinson MH, Schulz JB, Giunti P. Co-enzyme Q19 and idebenone use in Friedreich’s ataxia. J Neurochem. 2013;126(suppl 1):125-141. doi:10.1111/jnc.12322