Experimental drugs for Friedrich’s ataxia: progress and setbacks in clinical trials

KEYWORDS:

• Clinical trial
• Friedreich‘s ataxia
• omaveloxolone
• primary endpoints
• outcome measures

1. Introduction

Friedreich’s ataxia (FA) (OMIM # 229300) is the most frequent inherited ataxia worldwide and a devastating multisystemic disease [1]. FA usually presents in adolescence with a slowly progressive coordination and balance disorder which can be accompanied by cardiomyopathy, scoliosis, and foot deformities [1]. Later, in the disease course, hearing loss, visual loss, and diabetes mellitus can occur [1].

The molecular genetics and phenotypic presentation of FA present several peculiarities. First, the culprit gene defect is intronic and consists of a GAA-trinucleotide expansion [2]. The majority of patients carry biallelic expansions in the first intron of the frataxin gene [2]. Approximately 4% of patients are compound heterozygous for an intronic GAA expansion and a canonical mutation [2]. Pathologically expanded alleles undergo gene silencing resulting in reduced levels of an otherwise normal protein. The length of the pathological GAA-expansions, above all of the shorter one (GAA1), inversely correlates with the residual frataxin levels and with the age at onset of the ataxic disorder [1]. Thus, atypical presentations can occur, with disease onset as early as in the first years of life or in adulthood, up to the seventh decade. Natural history data clearly show that, the earlier the onset of the disease, the fastest is the neurological progression [3,4].

Notably, frataxin is a ubiquitous mitochondrial protein, but its deficiency leads to the clinical affection of only few organs. From a clinical perspective, disease morbidity in FA is largely driven by the progressive neurological syndrome, while cardiac involvement represents the main determinant of premature mortality [5]. Up to date, the majority of clinical trials in FA addressed the neurological manifestations [6,7] and are the focus of the present editorial.

2. Progress in clinical trials in Friedreich’s ataxia

A milestone in FA was set in 2023 on the emblematic day of rare diseases. On 28 February, the U.S. Food & Drug Administration approved omaveloxolone (Skyclarys®, Biogen Inc.) as the first FA specific therapeutic [8]. Omaveloxolone is semi-synthetic triterpenoid drug that activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway [8]. Nrf2 is a master regulator of cellular redox homeostasis and mitochondrial function, which is pathologically suppressed in FA [9]. Omaveloxolone was approved based on the results of a double-blind, randomized, placebo-controlled, parallel-group trial with 103 FA patients recruited at 11 centers in the United States, Europe, and Australia (MOXIe) [10]. Primary endpoint of the trial was the change in the neurological scale modified Friedreich’s Ataxia Rating Scale (mFARS). Change from baseline in mFARS scores in omaveloxolone and placebo patients showed a difference between treatment groups of −2.40 ± 0.96 points (p = 0.014) [10]. At the end of the placebo-controlled phase, all the patients willing to continue the study were recruited in an open-label extension phase in which they all received omaveloxolone [11]. The ‘delayed-start’ analysis of the extension phase showed a sustained benefit of the patients who were started earlier on omaveloxolone versus those who received it for the first time in the extension phase [11].

Considering the numerous, negative, clinical trials concluded in FA, the exciting news of the omaveloxolone approval led us to reflect on the issues that made this step possible. Within the past 15 years, two research consortia, the Friedreich Ataxia Clinical Outcome Measures Study (FACOMS) in North America and the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS) in Europe, started independent multicentric prospective studies which contributed to unveil the natural history of FA and provided for the first-time sample size calculation for clinical trials based on validated endpoint measures [3,12]. Registry data clearly showed that the progression of the disease is faster in young, still ambulant individuals, implying a reduced sample size and/or study duration for a powered clinical trial in this patient group [6]. MOXIe is the first concluded trial in FA which took advantage of this precious natural history data and was designed to recruit young, mostly ambulant, patients.

The comparison with natural history data suggests that the magnitude of improvement in mFARS in the MOXIe trial is equivalent to approximately 2 years of disease progression [10]. Despite a statistically significant improvement in the mFARS, the actual clinical impact of this change remains to be defined. On the one hand, long-term data are needed to ultimately esteem the cumulative effect of a treatment in a slowly progressive disorder as FA. On the other hand, the ‘minimal significant clinical change’ of the currently used neurological scales in FA is not defined. This underscores the need to implement clinically meaningful outcome measures for future trials [13].

3. Setbacks in clinical trials in Friedreich’s ataxia

Regardless of ongoing debates, MOXIe sets a first significant step on the path toward the definition of a treatment with a major effect on the disease burden. At the same time, several recent trials missed their primary endpoint or did not provide sufficient evidence to motivate advancement to larger studies. The list of compounds investigated in these studies encompasses the deuterated form of linoleic acid (RT001), interferon-γ 1b, vatiquinone, and leriglitazone [7,14]. These setbacks bring back into focus the definition of suitable outcome measures for clinical trials in FA [4]. A recent analysis of the FACOMS data [4] stressed the heterogeneity of neurological progression among subgroups with different genetic severities. Indeed, the progression of the mFARS score is the fastest in patients with ‘typical’ onset (i.e., between 8 and 14 years of age) and in this group is mostly driven by worsening of the stance and gait items. Capturing disease progression in the non-ambulatory status is more challenging. Disease progression is slower in older patients and displays a higher variability in early onset patients (<8 years), both issues which may hinder the detection of a statistically significant change and thus compromise the design of powered studies. Proposed strategies to overcome these hurdles are a selection of study populations based on the functional capacity (e.g., ambulatory status) and a strict age-based stratification. The first strategy may raise ethical concerns, and the second one is intrinsically challenging in the setting of a rare disease.

4. Expert opinion

Generally, therapeutic approaches in FA are divided in two categories [6]. One group of therapeutics (including gene therapy) aims at increasing/restoring frataxin levels. The second group encompasses those approaches aiming at reversing the consequence of frataxin loss at a tissue level, for instance mitochondrial failure. The first class of therapeutics may appear the most appealing as they intervene very early in the pathogenic cascade and may be potentially curative [6]. Currently, various gene therapy and genome editing strategies are explored in FA [15]. The likelihood of toxicity issues when overexpressing frataxin and the need for a delivery system with widespread distribution and low immunogenicity are among the hurdles to be addressed [15]. Beyond these biological hinders, it is however not clear when such treatments should be administered to guarantee a reversal or at least a substantial improvement of the clinical phenotype [6]. The presence of a developmental aspect as well as of a neurodegenerative kind of progression after onset suggest that the benefit of gene therapy/genome editing would be limited if applied beyond an early clinical phase [6]. Notably, omaveloxolone belongs to the second category of therapeutics, which do not target the primary cause of the disease but may potentially be beneficial also for FA patients in more advanced disease stages. In the future, a palette of therapeutics acting at different steps of the pathogenic cascade would most likely become the standard of treatment in FA. From this perspective, fostering research on ‘symptomatic,’ downstream-acting treatments remains extremely relevant also in the era of gene therapy. In this setting, the presence of good preclinical evidence along with comprehensive clinical data is fundamental to support pursuing a target pathway. The parable of iron chelation therapy in FA exemplifies this issue. A paramount work showing mitochondrial iron deposition in a yeast model of frataxin deficiency set the start for intensive iron-focused research in FA [16]. Based on the notion that iron deposition may trigger radical oxygen species production and thus sustain a vicious circle of mitochondrial dysfunction, iron chelation eventually advanced to clinical trials in FA. Therapeutic iron chelation did not lead to symptomatic improvement and, at higher doses, even result in a worsening of neurological deficits [17]. Notably, studies on iron metabolism in representative FA patient cohorts were missing and only very recently, clinical evidence of an iron starvation phenotype in FA has been provided (see Abstract of International Parkinson and Movement Disorder Society Congress 2023, ‘Systemic and Intracellular Iron Starvation Response in Friedreich’s Ataxia’ by Indelicato E et al [18], currently under revision). A decade of trials in FA likely failed because of both insufficient preclinical/clinical evidence and missing data on suitable outcome measures and sample size calculation [6]. Future trials need to include commonly accepted primary outcome measures which are meaningful for the patients as well as sensitive to changes in the selected study population and in the defined study time schedule. The conditio sine qua non for translation from bench to the bedside is solid preclinical evidence collected from both cellular/animal models as well as from examinations in patients, including analysis of accessible patients’ tissues [19]. Now that several lessons have been learned from previous trials, our effort to provide FA patients with valid therapeutics can be optimized when carefully using information that has been gathered in a cooperative world-wide effort. This is the rationale of the recently established platform Friedreich’s Ataxia Integrated Clinical Database (FAICD) curated by the Critical Path Institute [20]. Both academic institutions and collaborating companies are contributing to FAICD with natural history and clinical trial data, sharing the common aim of boosting the drug development in FA.

Declaration of interest

Sylvia Boesch received investigator fees from REATA and VICO Therapeutics. Elisabetta Indelicato is supported by the European Joint Programme on Rare Diseases (EJP-RD WP17 research mobility fellowship) and received funding by the Friedreich’s Ataxia Research Alliance (FARA), FARA Ireland, and FARA Australia as well as by the intramural funding program of the Medical University Innsbruck for young scientists MUI-START, Project 2022-1-3. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Sylvia Boesch and Elisabetta Indelicato are member of the European Reference Network for Rare Neurological Diseases—Project ID No 739510.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.