Recent Advances in Friedreich Ataxia Management

Friedreich ataxia (FA) is a rare, hereditary neurodegenerative disease that causes difficulties with coordination and balance and reduces lifespan. The disease affects approximately 1 in 50,000 people in the United States.^1,2 This autosomal recessive disease which typically is diagnosed during childhood or adolescence affects males and females equally.³

As a progressive disease, FA typically leads to loss of ambulation and death before patients reach 40 years of age, and it has no cure.^3-5 Annual disease-related costs for US adults with FA are distinctly higher than are those incurred by US adults with 2 or more chronic conditions, such as upper respiratory infections, hypertension, nontraumatic joint disorders, diabetes, lipid metabolism disorders, and asthma.⁶ Total health care costs for patients with severe FA are dominated by paid homecare.⁷

Guidelines for the management of FA were published in November 2022.⁸ In February 2023, omaveloxolone became the first FDA-approved therapy for FA; it is indicated for use in patients 16 years and older.⁹ Several investigational agents are in clinical development, with the majority in early stage clinical trials.^10-16 This article describes the clinical and economic impact of FA and reviews the current treatment landscape.

Pathophysiology

Most cases of FA (95%) arise due to GAA trinucleotide repeat expansion mutations in the FXN gene, which result in diminished levels of frataxin, a protein involved in iron and DNA metabolism and mitochondrial regulation.^17-20 In patients with FA, low frataxin levels disrupt mitochondrial oxidative phospho­rylation, a process vital for proper functioning of the nervous, cardiac, and pancreatic tissues. Thus, FA pathologically affects these tissues.^18,21

Most patients with FA are homozygous for the GAA repeat expansion mutation. Larger nucleotide expansions correlate with earlier age of onset and more severe symptoms.^20,22,23 Heterozygous carriers of large GAA expansions are not symptomatic, which makes FA difficult to detect in the parents of patients with FA and other carriers.^18,19

Clinical Presentation

Timing of initial FA presentation and disease progression can vary.²⁴ Patients with this disease demonstrate a wide clinical spectrum of symptoms.^18,24,25

Time of Onset

Early diagnostic criteria for FA included onset in patients 25 years and younger and specific neurologic symptoms (eg, absence of lower-limb reflexes and pyramidal signs); the results of more recent studies, however, have demonstrated that the disease has a wider clinical spectrum.^18,24,25 Most commonly, the disease begins shortly after puberty, when patients present with gait instability.^18,26 Patients also may initially present with scoliosis, especially those with early onset of the disease.^18,26 Atypical presentations of FA, observed in approximately 25% of affected individuals, can occur in those with milder disease and FA without ataxia.³ For instance, patients can present with late-onset FA (LOFA) that occurs in patients 25 years or older and very late-onset FA (VLOFA) that occurs in patients older than 40 years.³ Those with LOFA or VLOFA typically present with spasticity and minimal ataxia.^18,27 Diagnosis is confirmed with genetic testing for expanded GAA mutations.¹⁸

Most Prevalent Complications and Comorbidities

The most prevalent complications and comorbid conditions that present in patients with genetically confirmed FA include scoliosis (60%-84% of patients), the foot deformity pes cavus (55%-76% of patients), and diabetes mellitus (8%-32% of patients) that often requires insulin therapy.^18,20,24,25 Most patients with FA (89%) will have abnor­malities in electro- or echo­cardiogram results and 59% to 82% will experience neurogenic bladder conditions (eg, incontinence, urinary tract manifestations, and urine retention).^18,25,28-30 Further, most patients experience dys­arthria (ie, difficulty speaking), and up to 90% of patients with FA will present with abnormal aural speech perception.^{18,24,25,28-30}

Disease Progression

The mean age of mortality among patients with FA is approximately 37 years.^3,5 The results of a retrospective analysis of patient records from the Friedreich Ataxia Parent Group, the Friedreich’s Ataxia Research Alliance (FARA) Pathology Database, and 5 academic centers that participated in a longitudinal study of FA showed that the most frequent cause of death in patients with FA was related to cardiovascular conditions (eg, congestive heart failure, arrhythmia, and stroke).⁵

The neurologic symptoms and heart function of patients with FA worsen over time.^5,18,31,32 Results of a longitudinal study found that individuals with the disease demonstrated a pattern of motor decay whereby patients with FA sequentially lost the ability to stand with their feet apart and eyes closed, to stand with their feet together, and to stand normally.³¹ Patients with early onset FA (ie, before 15 years of age) were shown to lose ambulation at a median of 11.5 years (IQR, 8.6-16.2 years) after disease onset.³¹ Left ventricular ejection fraction, which independently predicts mortality in FA, also declines over time in patients with FA.^18,32

Several measures have been developed to track disease progression in FA. These include the International Cooperative Ataxia Rating Scale, the Scale for the Assessment and Rating of Ataxia, and the Friedreich Ataxia Rating Scale (FARS), a validated tool designed by the Cooperative Ataxia Group.^23,31 The modified FARS (mFARS) was developed for use in clinical trials; it contains bulbar, upper limb, lower limb, and upright stability subscales and requires patient participation.^23,31,33 Scores on the mFARS scale range from 0 to 99, with lower scores representing better neurologic function.³⁴ Investigators involved in a longitudinal natural history study conducted across 12 US-based centers used the mFARS to measure mean neurologic function in 812 patients with FA over 1 year. The results showed that mFARS scores for the studied population deteriorated by +1.91 points (SD, 6.34).²³

Functional Impairments and Quality of Life

Patients with FA have worse physical functioning and overall health-related quality of life (QOL) relative to those without neurologic symptoms or with other conditions and experience impairment in general health, vitality, social functioning, and mental health.^35,36 Progression-free survival (PFS) correlates significantly with age, length of the GAA repeat, age of onset, and duration; older age and a longer GAA repeat length predict worse PFS scores.³⁶ Patients needing to use mobility devices (eg, wheelchair, walker, or cane) have shown worse QOL outcomes and lower physical, emotional, social, and academic functioning than have control groups.^37,38 Adult patients with FA have demonstrated physical functional impairments associated with body pain and role limitations and have demonstrated lower physical functioning scores than have matched-control groups of patients with epilepsy, lymphedema, and organ transplantation.^35,36 Pediatric patients with FA also have shown impairments in QOL measures of physical health, psychosocial health, emotional functioning, social functioning, and general fatigue.³⁷

Health Care Resource Utilization and Costs of Care

There are few high-quality studies that have examined the economic impact of FA.^39,40 Results from a 2010 analysis of survey data collected from 197 US patients with FA have been most relevant.⁷ The mean total annual health care costs for these patients was $12,850 (95% CI, $9224-$16,477). Adjusted for inflation, this translates to $18,018 (2023 US$) (95% CI, $12,934-$23,104). (Note: these adjusted numbers are based only on the dollar amount without consideration of other factors, such as new therapies.)^7,41 Excluding costs of devices, stays in long-term care facilities, and car and home adaptations, costs among patients 19 years and older with FA were numerically higher than were those incurred by US adults with 2 or more chronic conditions (mean 95% CI, $11,860-$25,670 vs $6674-$7628, respectively) (all study costs inflated to 2023 US$).^7,41

The range of total health care costs was nearly 4 times greater for patients with severe FA compared to those with milder disease ($0-$253,979 vs $140-$66,661) (all costs inflated to 2023 US$).^7,41 In those with severe FA, total health care costs were dominated by paid homecare. Compared with those with milder disease, patients with severe disease incurred significantly higher costs for homecare, prescription medications, and car modifications.Those with milder disease had highest mean annual costs for therapist visits, physician visits, and medication; costs for therapist visits were significantly higher among patients with milder disease than for those with severe disease.⁷

Guideline Recommendations

In November 2022, guidelines for the management of FA were published that were developed by 70 expert clinicians in collaboration with the FARA.⁸ These guidelines provide clinical management direction in 15 topic areas ranging from neurologic components of the disease to cardiovascular and mental health considerations for patients.^8,18 Guideline authors emphasize the importance of early diagnosis, which may mitigate disease burden. Diagnosis often begins with patient complaints of neurologic symptoms and is confirmed with genetic testing.¹⁸

These guidelines present 130 recommendations and 95 best practice statements for disease management.^8,18 Among these are 18 strong recommendations, of which none is supported by a high level of evidence. The authors acknowledge both a lack of high-quality clinical studies in FA and a very low level of evidence for certain topics. As shown in Table 1, 6 of the strong recommendations are supported by low or moderate levels of evidence.⁸ Table 2 clarifies select best practice statements for more prevalent complications, comorbidities, and procedures related to FA.¹⁸

Advancement in Management Strategies

In February 2023, omaveloxolone became the first FDA-approved therapy for FA.^8,9 Several investigational therapies also are being explored and are in various stages of clinical development.^10-15

Omaveloxolone

Omaveloxolone is a small-molecule, semisynthetic oleanolic triterpenoid. It is the only FDA-approved treatment for FA and is indicated for use in patients 16 years and older.^9,42,43 Although its precise mechanism of action on FA is unknown, omaveloxolone has been shown to activate the NRF2 pathway in vitro and in vivo in animals and in humans. This pathway is implicated in the cellular response to oxidative stress.⁴² FDA approval was based on positive results from part 2 of the MOXIe study (NCT02255435) and its open-label extension (OLE) follow up.^9,34,42,44

MOXIe Trial

MOXIe was a randomized, double-blind, phase 2 trial, in which treatment with omaveloxolone was shown to be statistically significant in improving neurologic function as measured by mFARS and relative to treatment with placebo in patients with FA.³⁴

In the study, patients aged 16 to 40 years with genetically-confirmed FA who were able to complete exercise testing on a recumbent stationary bicycle and who had baseline mFARS scores of 20 to 80 were recruited from 11 clinical centers across Australia, Europe, and the United States. Those with interfering medical conditions, uncontrolled diabetes, clinically significant cardiac disease, active infections, or significant laboratory abnormalities were excluded. If patients developed diabetes or cardiac disease (eg, arrhythmias), they were allowed to remain in the study until they chose to withdraw. Patients with pes cavus were limited to 20% of enrolled participants.³⁴

A total of 103 participants were randomly assigned 1:1 to receive 150 mg/d of oral omaveloxolone or placebo. This number represented the set of all randomized patients (ARP). ARP were included in the safety analyses. Primary analysis of efficacy was completed in a subset of patients with at least 1 postbaseline measurement but without pes cavus. This was the full analysis set (FAS). The primary outcome was change from baseline in mFARS compared with placebo at 48 weeks. Ninety-one percent of patients completed treatment through week 48.³⁴

The results indicated that at 48 weeks, patients in the FAS who were randomly assigned to placebo (n = 42) showed a mean increase in mFARS of 0.85 points (SEM ± 0.64; 95% CI, –0.43 to 2.13), whereas patients randomly assigned to omaveloxolone (n = 40) had a mean decrease from baseline in mFARS of −1.55 points (± 0.69; 95% CI, –2.93 to –0.18), a difference between groups of –2.40 points (± 0.96; 95% CI, –4.31 to –0.5) (P = .014).³⁴

Rates of adverse events (AEs) were similar between the treatment and placebo groups. All study participants reported at least 1 AE. The rates of any serious AE (SAE) in the omaveloxolone and placebo groups were 10% and 6%, respectively; rates of discontinuing treatment due to AEs were 8% and 4%, respectively. The following AEs occurred more frequently in the omaveloxolone group than in the placebo group: headache (37% vs 25%), excoriation (26% vs 23%), nausea (33% vs 14%), fatigue (22% vs 14%), diarrhea (20% vs 10%), abdominal pain (22% vs 6%), as well as increased levels of alanine aminotransferase (37% vs 2%) and aspartate aminotransferase (22% vs 2%).³⁴

MOXIe Delayed Start OLE

Patients who completed part 2 of the MOXIe trial through 48 weeks of treatment and a safety visit at 52 weeks were eligible to enroll in a delayed-start OLE study. In the OLE, patients who initially were randomly assigned to receive omaveloxolone continued on the drug (omaveloxolone-omaveloxolone), whereas those initially given placebo were switched to omaveloxolone therapy (placebo-omaveloxo­lone). The investigators then compared mFARS scores at the end of MOXIe part 2 with scores at 72 weeks.⁴⁴

All participants received 150 mg/d of oral omaveloxolone. Similar to how part 2 was conducted, the FAS included individuals without pes cavus whereas the ARP included all patients enrolled in part 2.⁴⁴

mFARS assessments occurred on day 1 and then every 24 weeks. Mean baseline mFARS scores in the FAS were 38.8 in the placebo-omaveloxolone group (n = 42) and 40.9 in the omaveloxolone-omaveloxolone group (n = 40). Thirty-one patients had mFARS assessments at 72 weeks and results showed that the least-squares (LS) mean difference in mFARS between groups was –2.91 points (SE 1.437; P = .0433). Patients who were randomly assigned to receive omaveloxolone in part 2 continued to show no worsening in mFARS scores relative to the extension baseline through 144 weeks.⁴⁴

There were no deaths during the extension study, and SAE rates among the ARP were similar between the placebo-omaveloxolone and omaveloxolone-omaveloxo­lone groups (7.5% vs 11.6%, respectively). No patients discontinued treatement due to an SAE and no SAE was considered to be related to use of the study drug.⁴⁴

Investigational Agents in Clinical Development

As of October 2023, 6 treatments for FA were being investigated in phase 2, phase 3, or equivalent stage clinical trials.^10-15

Vatiquinone (PTC-743)

Vatiquinone (PTC-743, previously EPI-743) was granted fast track and orphan drug designations for FA by the FDA in 2014.^45,46 The small molecule agent inhibits 15-lipo­xygenase and helps mitigate outcomes from mitochondrial dysfunction and oxidative stress. It can be taken orally, and it has been shown to readily enter the central nervous system.^18,47,48

Vatiquinone is being studied in the phase 3, placebo-controlled MOVE-FA trial (NCT04577352) to assess its safety and efficacy in children and young adults with FA.^15,49 The primary end point is a statistically significant change in the mFARS score from baseline to 72 weeks. In May 2023, the agent’s manufacturer reported topline results, noting that the primary end point had not been met among the 146 pediatric patients with FA enrolled in the study.⁴⁹ However, the manufacturer stated that vatiquinone demonstrated statistically and clinically significant benefits over placebo in key secondary end points, including those using bulbar and upright stability subscales and the Modified Fatigue Scale. Moreover, in those who completed the study protocol, the primary end point was reached, with vatiquinone treatment demonstrating a 2.31-point mFARS improvement over placebo—or a 75% slowing in disease progression—over 72 weeks. According to these topline results, the agent was well tolerated.⁴⁹ The manufacturer anticipates a type C meeting with the FDA in the second half of 2023 to discuss a regulatory pathway.⁵⁰

Elamipretide

Elamipretide was granted orphan drug designation for FA by the FDA in 2022.⁵¹ The agent is a peptide compound that binds to cardiolipin in the inner mitochondrial membrane, increasing mitochondrial respiration and potentially reversing the damage of oxidative stress.⁵²

Elamipretide is being studied in the phase 2 ELViS-FA trial (NCT05168774), which is comparing the effects of high-dose (40-60 mg) vs low-dose (20-30 mg) elamipretide on vision loss as measured by high-contrast visual acuity after 52 weeks in patients aged 16 years and older who have received a diagnosis with FA. The study, which is taking place at the Children’s Hospital of Philadelphia, is estimated to conclude at the end of 2024 and is no longer recruiting. It will have an estimated enrollment of 18 participants older than 16 years with disease onset before age 18.¹⁴

Leriglitazone (MIN-102)

The FDA granted leriglitazone (MIN-102) orphan drug designation in FA in 2019.⁵³ The agent is a PPARγ agonist that has been shown to increase frataxin levels and, in humans, cross the blood–brain barrier, where it efficiently engages with PPARγ in the central nervous system.^18,54,55

Leriglitazone was studied in the phase 2, placebo-controlled FRAMES trial (NCT03917225), which aimed to assess the safety and efficacy of the agent in patients with FA aged 12 to 60 years. The primary end point was a statistically significant change in the spinal cord area (C2-C3) after 48 weeks as measured using MRI. In December 2022, investigators reported that the trial of 39 enrolled patients did not meet the primary end point. However, leriglitazone demonstrated clinically significant benefit over placebo in key secondary end points, including iron accumulation in the dentate nucleus (LS mean change [SE], 0.10 [1.33] vs 4.86 [1.84] ppb; P = .05). Improvements in the total N-acetylaspartate–to-myoinositol ratio were also observed (LS mean change [SE], 0.03 [0.02] vs –0.002 [0.03], P = .25).⁵⁶

The agent was well tolerated. At least 1 AE was reported in all patients. In patients treated with leriglitazone, 96.2% of AEs were treatment-related, and 88.5% were of mild or moderate severity. In leriglitazone-treated patients, peri­pheral edema and increased weight were the most common AEs (73.1% and 46.2% of patients, respectively).⁵⁶ Based on these results, the agent’s manufacturer noted, results involving secondary end points support assessment of leriglitazone in patients with FA in larger clinical studies.¹²

CTI-1601, frataxin replacement

In 2017, CTI-1601 received orphan drug designation for FA from the FDA.⁵⁷ The agent employs a TAT protein fragment to deliver synthetic frataxin directly to mitochondria.^18,58

CTI-1601 is being studied in a phase 2, placebo-controlled dose exploration trial (NCT05579691) to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of subcutaneous (SC) administration of the agent in adults with FA.⁵⁹ The primary end point is the number of participants with treatment-emergent AEs through study completion (average, 93 days). In May 2023, the agent’s manufacturer announced topline results from the trial’s 25-mg cohort (n = 13), who received either SC CTI-1601 (n = 9) or placebo (n = 4) given by SC injection daily for 2 weeks and every other day for 2 weeks thereafter. At this dose, CTI-1601 use was well tolerated and associated with increases in frataxin levels in skin and buccal cells relative to those at baseline when compared with levels in cells from patients in the placebo group.⁶⁰ Based on these results, in July 2023 the FDA cleared study of the trial’s 50-mg cohort and the OLE.¹¹

Etravirine

In 2008, the FDA approved the antiviral drug etravirine for the treatment of HIV infection.¹⁸ Use of the agent has been shown to increase frataxin in fibroblasts and lymphoblasts derived from patients with FA to levels comparable to those found in unaffected carrier cells.^18,61

Etravirine was studied in the phase 2, dose-finding FAEST1 trial (NCT04273165) to assess its safety and efficacy in patients with FA aged 10 to 40 years. The primary end point was a description and count of AEs and SAEs after 4 months of treatment with 200 mg/d or 400 mg/d of etravirine. The secondary outcome was the increase in the maximum volume of oxygen used during exertion (VO₂ max) after 12 months. Investigators aimed to recruit 30 participants. As of September 2023, the trial has been completed; however, no results have been posted.¹⁰

NAD+ and Exercise

Exercised muscles show an increase in NAD (NAD+) and, in animals lacking FXN, NAD+ precursors have been shown to restore deficient cardiac function.⁶² The hypothesis of the placebo-controlled NAD+ and Exercise in FA (ExRx in FA) trial (NCT04192136) is that exercise plus nicotinamide riboside (NR), a commercially available NAD+ precursor, will increase mitochondrial oxidative phosphorylation, muscle mass, and aerobic activity (VO₂ max) in patients with FA.¹³ Exercise has been demonstrated to improve mitochondrial respiratory capacity and oxidative phosphorylation.⁶³ The primary outcome of the ExRx in FA trial is the change in VO₂ max from baseline to 12 weeks. The study, which also takes place at the Children’s Hospital of Philadelphia, has an estimated enrollment of 72 patients with FA aged 10 to 40 years; it is recruiting as of August 14, 2023.¹³

Conclusions

FA is a rare disease with a progressive nature. It is associated with loss of patient ambulation, early age of mortality, and, in adults, greater health care utilization than for adults with 2 or more other chronic conditions. In the absence of a cure for FA, a current goal is to continue advances in the management of this chronic, progressive, and neurodegenerative condition. In February 2023, omaveloxolone became the first FDA-approved therapy for FA to slow its progression. Various treatments are being assessed in clinical trials, demonstrating the commitment to ongoing research in this field. Access to approved therapies is essential for managing this neurodegenerative disease and slowing disease progression. ◆

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