Advances in Treating Friedreich Ataxia

AJMC^®: What is your experience in treating patients with Friedreich ataxia (FA)?

PERLMAN: I’m an adult neurologist with over 30 years of experience in an academic medical setting, primarily focusing on patients with FA. I first became interested in FA during my fellowship, when I conducted research on potential mitochondrial dysfunction in the condition. Our clinic has grown significantly since then. I’ve had the privilege of treating approximately 400 to 500 patients with FA during this time, and I’m currently following 125 of them.

Throughout the years, our understanding of FA’s molecular pathophysiology and disease progression has expanded. Additionally, there has been substantial growth in the development of potential symptomatic and disease-modifying agents over the last decade.

My dedication to patients with FA and their families has deepened over time, making it difficult to step away. I’m also a member of the collaborative Clinical Trials Network for FA, led by the Friedreich’s Ataxia Research Alliance at the Children’s Hospital of Philadelphia. This involvement has allowed me to contribute to natural history studies, biomarker research, and clinical trials for promising drugs over the past 15 to 20 years. Recently, I have been an investigator on the MOXIe trial and its open-label extension (OLE), which has studied the safety and tolerability of omaveloxolone in patients with FA.

AJMC^®: How do patients react to a diagnosis of FA?

PERLMAN: FA, a genetic disorder typically diagnosed in childhood, has historically had a profound impact not only on the affected child or young person but also on their parents and family members. It has been recognized for over a century as a slowly progressive, disabling disorder that affects various aspects such as upright stability, hand-eye coordination, speech, and more. This diagnosis has not only explained issues like clumsiness or unexplained falls at school, but also introduced a broader range of health concerns, including orthopedic complications, cardiac problems, and the risk of diabetes.

Traditionally, an initial diagnosis marked the beginning of a long-term investment in the child’s health with the hope of finding interventions to halt progression, enhance performance, and enable a relatively normal life alongside peers. Unfortunately, the grim adage that a patient with FA is in a wheelchair by the age of 20 years and dead by the age of 30 years persisted for over a century. Only recently, with improved cardiac management, have some patients with cardiac symptoms extended their lifespan into their forties. Nonetheless, the neurologic disability progression and the risk of early cardiac death remained significant challenges.

However, the recent FDA approval of omaveloxolone marks a pivotal moment. It is the first drug approved for FA, ending a series of pipeline disappointments in recent years. Omaveloxolone showed promising symptomatic benefits early on, which was followed by disease progression stabilization or slowing as patients continued treatment.¹ This approval has brought a sense of hope to the patient community, parents, and young individuals affected by FA. While it isn’t a cure, omaveloxolone holds the potential to change the course of the disease. It offers the prospect of altering that longstanding adage and providing positive impacts on neurologic and other facets of this condition.

AJMC^®: What are your treatment goals for patients with FA?

PERLMAN: The physical—and to some extent, cognitive—disability progression experienced by patients with FA poses significant challenges for individuals striving to achieve their career and life goals, especially for younger patients seeking acceptance and an equal footing with their peers.^2,3

The prospect of ending up in a wheelchair can be distressing. Consequently, our focus extends beyond academic and workplace performance to encompass emotional well-being and coping strategies for patients dealing with the ongoing challenges of a chronic, progressive neurologic illness.

In some cases, patients express modest goals, such as being able to walk across the stage at their high school graduation. Our commitment lies in empowering these individuals, both young and older patients, to regain a sense of control over their lives and future outcomes.

AJMC^®: For which patients with FA is omaveloxolone use appropriate?

PERLMAN: Omaveloxolone received FDA approval for use in patients with FA who are 16 years and older with no restrictions other than the age limit.⁴ This age limit was set due to the need to assess safety and potential differences in dosing and adverse effects in younger patients.

There are no contraindications or restrictions based on factors such as foot deformity, ambulatory ability, or cardiovascular status. The FDA did not establish an upper age limit or restrictions based on patient Friedreich Ataxia Rating Scale (FARS) or modified FARS (mFARS) scores.⁴ Such restrictions could have limited access for older or more severely affected patients.

The primary warnings and monitoring considerations include aminotransaminase levels, which may elevate within the first month or 2 of starting the drug but that are not indicative of liver disease. Elevation of BNP (B-type natriuretic peptide), a heart-related biomarker, has also been observed, but it does not necessarily signal cardiac damage. Lipid abnormalities have been reported and should be monitored.⁴

Omaveloxolone can be initiated in most patients, but caution is advised for individuals with significantly elevated transaminase levels or unstable heart conditions. In such cases, it may be necessary to adjust the dosage, temporarily discontinue the drug, and closely monitor liver function and cardiac health before considering restart.⁴

Patients with symptomatic heart disease should be carefully monitored, and starting the drug may be delayed until their cardiac issues are stabilized, especially if they exhibit declining ejection fractions or unstable arrhythmias.⁴

AJMC^®: The mFARS has been developed to monitor FA disease progression in clinical trials. How, if at all, is it used in clinical practice?

PERLMAN: Using mFARS in day-to-day clinical practice can be challenging due to its time-intensive nature. Completing the mFARS examination typically takes around 20 minutes. During an average patient visit in which various assessments and discussions are required, this can be quite cumbersome. As a result, clinicians often rely on alternative methods to effectively monitor FA disease progression.

One such approach involves closely listening to the patient’s self-reported experiences. For instance, if a patient mentions an improvement in speech clarity, the clinician can refer to previous notes to assess whether their speech has indeed improved. Similarly, if a patient reports better stability while standing, the clinician can review past records to compare their previous performance (eg, whether they were previously reliant on support) with their current abilities.

In essence, clinicians combine patient-reported changes with their observations to track disease progression effectively. This approach allows for a more patient-centric and practical method of monitoring FA progression as opposed to the detailed and time-consuming mFARS examination typically reserved for clinical trials.

AJMC^®: Treatment with omaveloxolone was shown to slow disease progression by an mFARS score of 2.4 points vs placebo in the MOXIe trial.¹ What does this mean for the daily life of a patient with FA?

PERLMAN: The mFARS consists of 4 components, including measures of speech, upper extremity performance, lower extremity performance, and upright stability (standing and walking), with an additional fifth part examining peripheral nerve muscle and reflex activity. In the second part of the MOXIe trial (NCT02255435), improvements were most notable in the upright stability component, specifically in standing and walking and, to some extent, in upper extremity performance and arm coordination.¹

A 2.4-point improvement vs placebo in mFARS can translate to significant changes in a patient’s daily life. For instance, in terms of upright stability, this improvement might mean an increased ability to stand with feet together from 15 seconds to 45 seconds or even a full minute. It could signify enhanced walking capabilities, such as being able to walk down a hallway with only occasional handrail or wall support as opposed to needing constant assistance.

This scoring system is closely tied to clinically meaningful performance measures. In this study, the improvement was particularly noticeable in the aspect of upright stability.¹ A 2.4-point improvement in mFARS vs placebo could result in reduced falling, increased mobility, and greater participation in community activities, thus enhancing patients’ daily lives and their ability to cope with their chronic neurologic disease.

What’s particularly remarkable about the 2.4-point improvement in mFARS vs placebo observed in the first year of treatment is that, based on natural history data, patients with FA typically experience a slow decline over time rather than improvement.⁵ Achieving a 2.4-point improvement vs placebo in the first year is akin to reversing the clock by 2 years in a context where deterioration is the norm. Furthermore, the study showed stabilization in the treatment group beyond the first year, maintaining their improved level and slowing progression, albeit with some gradual decline noted after the third or fourth year that was still at a significantly reduced rate compared to the matched natural history data.

AJMC^®: What is the clinical value of omaveloxolone in patients who have wheelchair dependence?

PERLMAN: The typical disease progression in FA leads to wheelchair dependence within approximately 10 to 20 years after onset.⁵ For younger, ambulatory patients, we can use standard measures to assess potential improvements in various aspects. However, for patients who have progressed to the point of being nonambulatory and reliant on a wheelchair, it’s less likely that use of this drug will enable them to regain ambulation. While not impossible, it’s improbable.

Nevertheless, this drug has shown a staged progression of benefits. In the MOXIe OLE, we have found that omaveloxolone initially has positive impact on standing, walking, and leg performance. After 5 to 10 years, it extends its effects to hand coordination, speech, swallowing, vision, and hearing. Even for patients who are wheelchair-bound, this medication could offer improvements in hand coordination, speech, and, potentially, in vision and hearing. Additionally, it may have positive effects on other aspects not originally studied.

As a clinician, I prescribe this drug to eligible patients and closely monitor their condition, focusing on the relevant areas of their individual disease progression.

AJMC^®: Under what circumstances should omaveloxolone be discontinued in patients, if at all?

PERLMAN: I would discontinue therapy if a patient experiences a generalized allergic reaction to the medication.If extensive elevations in transaminase levels persist after dose reduction, discontinuation may also be required. Finally, if common adverse effects such as headache, nausea, abdominal pain, or fatigue persist and significantly bother the patient, discontinuing the medication may be appropriate. These adverse effects should resolve within a few weeks after starting the drug; otherwise, the patient’s well-being and comfort become key factors in the decision-making process.

AJMC^®: How might the results of the MOXIe trial and the FDA approval of omaveloxolone impact FA treatment and research?

PERLMAN: Omaveloxolone, as the lead and now approved member of a group of drugs targeting mitochondrial function in FA, holds significant potential impact for patients living with this condition.

In the short term, it has the potential to provide rapid symptomatic improvement within the first 6 months of treatment. Moreover, it may offer stabilization against disease progression over the next 2 to 3 years. However, the long-term durability of these effects remains uncertain, as we are yet to determine whether the underlying disease progression might eventually diminish the continued benefits of omaveloxolone.

Nonetheless, omaveloxolone is poised to extend the functional time that patients with FA can spend on their feet, enhance upper extremity coordination, and improve speech. Moreover, the recent FDA approval serves as a crucial stepping stone in FA treatment research, opening doors for the next phase of drug development. This next phase will focus on targeting the frataxin protein deficiency directly, either by replacing frataxin protein or enhancing the ability of FXN to produce protein despite the mutation.

Ultimately, omaveloxolone represents a significant advancement in FA treatment, and it has the potential to work in combination with drugs targeting the genetic root of the condition, offering hope for improved outcomes and quality of life for patients with FA. ◆

References

1. Lynch DR, Chin MP, Delatycki MB, et al. Safety and efficacy of omaveloxolone in Friedreich ataxia (MOXIe study). Ann Neurol. 2021;89(2):212-225. doi:10.1002/ana.25934
2. Dogan I, Tinnemann E, Romanzetti S, et al. Cognition in Friedreich’s ataxia: a behavioral and multimodal imaging study. Ann Clin Transl Neurol. 2016;3(8):572-587. doi:10.1002/acn3.315
3. Nieto A, Correia R, de Nóbrega E, Montón F, Hess S, Barroso J. Cognition in Friedreich ataxia. Cerebellum. 2012;11(4):834-844. doi:10.1007/s12311-012-0363-9
4. Skyclarys. Prescribing information. Reata Pharmaceuticals; 2023. Accessed September 21, 2023. https://www.skyclarys.com/docs/skyclarys_us_prescribing_information/
5. Friedreich ataxia. National Institute of Neurological Disorders and Stroke. Reviewed February 14, 2023. Accessed September 11, 2023. https://www.ninds.nih.gov/health-information/disorders/friedreich-ataxia