Christian Rummey

Objective: Inherited ataxias are clinically diverse neurodegenerative diseases, complicating the choice of outcome measures for trials. In spinocerebellar ataxia (SCA), regulatory concerns about the Scale for the Assessment and Rating of Ataxia (SARA) caused a shift toward functional SARA (f‐SARA), contributing to pivotal trial failure. We investigated whether the Upright Stability Score (USS), validated in Friedreich ataxia (FRDA), retains its psychometric properties in SCA, and how it compares with SARA, f‐SARA, and the Friedreich Ataxia Activities of Daily Living scale (FA‐ADL). Methods: Cross‐sectional data from ambulatory participants in two large international natural‐history studies (CRC‐SCA and UNIFAI) were analyzed with correlation‐based psychometric methods, comparing score distributions across scales and genotypes. Results: Data from 406/343 participants in CRC‐SCA/UNIFAI were analyzed. In SCA, the USS captured a wider spectrum of balance performance, while in FRDA, early proprioceptive deficits—particularly impaired stance with eyes closed—constrained score variability. USS correlated strongly with SARA, f‐SARA, and FA‐ADL in both cohorts. SARA showed moderate skew, and f‐SARA showed pronounced floor effects in mildly affected SCA, whereas USS and FA‐ADL preserved discrimination at the low end. FA‐ADL distributions were broadly comparable across genotypes. Interpretation: USS showed cross‐sectional convergent validity with established measures across ambulatory FRDA and SCA, reflecting perceived disease burden (FA‐ADL) at least as well as SARA. f‐SARA is poorly discriminating in ambulatory SCA and is unlikely to work as an outcome measure, in particular in early cohorts. USS showed the potential to serve as a primary outcome assessment in pivotal SCA trials, but longitudinal evidence is required. Limitations include cross‐sectional design and a substantial age difference between cohorts.

Background: Novel therapeutics for Friedreich ataxia employ diverse strategies to increase frataxin protein levels, and a better understanding of the relation to clinical outcomes could strengthen their use as pharmacodynamic markers, and potentially as surrogate endpoint in therapeutic development. An elaborate modelling framework was developed to evaluate the suitability of frataxin as a biomarker across assays, tissues and disease stages. Methods: Frataxin levels generated previously through two distinct assay platforms and from two separate clinical cohorts: whole blood frataxin was measured by a lateral-flow immunoassay (LF cohort), and a triple-quadrupole LC-MS/MS method (TQ cohort), which enables separate quantification of mature frataxin (FXN-M) and erythrocyte-specific frataxin (FXN-E). Results were compared descriptively with control and heterozygous carriers, and several distinct modelling strategies were employed to correlate them with clinical function. Results: Both cohorts represented the relevant disease spectrum, with minor differences in both genetic and clinical severity, which correlated with frataxin levels. Heterozygous carriers showed intermediate levels. Modelling confirmed the predictive value of frataxin across multiple clinical assessments, such as age of symptom onset, age at loss of ambulation and long-term progression. GAA1, the shorter repeat expansion, was confirmed as the dominant predictor of frataxin itself, and, in most situations, clinical function. Discussion and conclusion: Although isoform biology and tissue-specific expression remain important considerations, peripheral frataxin quantification provides biologically grounded measure of the pathophysiology and disease progression, with strong potential for application in therapeutic trials. Frataxin is a valid clinical biomarker, and our findings support advancing its candidacy as a surrogate endpoint in Friedreich ataxia.

The placebo response in clinical trials in ataxias complicates outcome interpretation and potentially obscures genuine treatment effects. We analyzed placebo group data from past trials in Friedreich Ataxia and observed notable responses in appendicular items, in contrast to minimal changes in axial function, as measured by respective subscores of the modified Friedreich Ataxia Rating Scale (mFARS). The effect increased with the number of consecutive tests, shorter testing intervals, and older group ages. This has implications for trial design and endpoint selection, thus strengthening the utility of the Upright Stability Score (USS), a sub‐score of mFARS, as an independent measure.

Background: Friedreich ataxia is a rare genetic disorder caused by mutations in the FXN gene, typically presenting with balance and coordination difficulties between ages 7 and 15 years. Neurologic symptoms are progressive and lead to loss of ambulation and especially in children other symptoms such as cardiomyopathy, scoliosis, and fatigue are common. The FACHILD natural history study aimed to expand knowledge about the disease course and evaluate clinical outcome assessments in children. We report on functional performance testing, clinical rating scales, and patient-reported outcomes as clinical outcome assessments for Friedreich ataxia. Over a 3-year period, all tests and assessments were conducted to evaluate their sensitivity to progression and correlate with established measures such as neurologic rating scales. Methods: Individuals with genetically confirmed Friedreich ataxia, aged 7-18 years, were enrolled from October 2017 to November 2022. This analysis focused on ambulatory individuals, including timed walks (25-foot, 1 minute, and 6 minutes), the timed up and go, and the 9-hole pegboard test. Additionally, the Berg Balance Scale and FA-Activities of Daily Living were assessed. Progression data were analyzed using mixed models for repeated measures, with detailed analyses of intermittent missing data. Data from the Friedreich Ataxia Clinical Outcome Measures Study was used to augment analyses when available. Findings and Interpretation: Functional performance outcome measures are sensitive and clinically relevant tools for assessing disease progression in children with Friedreich ataxia. In early to moderately affected populations, the 1-Minute Walk demonstrated promising properties, showing comparable sensitivity to the modified Friedreich Ataxia Rating Scale and the Upright Stability Score.

Objectives: Friedreich ataxia (FRDA) is a rare genetic disorder caused by mutations in the FXN gene, leading to progressive coordination loss and other symptoms. The recently approved omaveloxolone targets this condition but is limited to patients over 16 years of age, highlighting the need for pediatric treatments due to the disorder's early onset and more rapid progression in children. This population also experiences increased non‐neurological complications; the FACHILD study aimed to augment and expand the knowledge about the natural history of the disease and clinical outcome assessments for trials in children in FRDA.Methods: The study enrolled 108 individuals aged 7–18 years with a confirmed FRDA diagnosis, with visits occurring from October 2017 to November 2022 across three institutions. Several measures were introduced to minimize the impact of the COVID‐19 pandemic, including virtual visits. Outcome measures centered on the mFARS score and its subscores, and data were analyzed using mixed models for repeated measures. For context and to avoid misinterpretation, the analysis was augmented with data from patients enrolled in the Friedreich's Ataxia Clinical Outcome Measures Study.Results: Results confirmed the general usefulness of the mFARS score in children, but also highlighted issues, particularly with the upper limb subscore (FARS B). Increased variability, limited homogeneity across study subgroups, and potential training effects might limit mFARS application in clinical trials in pediatric populations.Interpretation: The FARS E (Upright Stability) score might be a preferred outcome measure in this patient population.

Objective: Most individuals with Friedreich ataxia (FRDA) have homozygous GAA triplet repeat expansions in the FXN gene, correlating with a typical phenotype of ataxia and cardiomyopathy. A minority are compound heterozygotes carrying a GAA expansion on one allele and a mutation on the other. The study aim was to examine phenotypic variation among compound heterozygotes.Methods: Data on FXN mutations were obtained from the Friedreich Ataxia Clinical Outcome Measures Study (FA‐COMS). We compared clinical features in a single‐site FA‐COMS cohort of 51 compound heterozygous and 358 homozygous patients, including quantitative measures of cardiac, neurologic, and visual disease progression.Results: Non‐GAA repeat mutations were associated with reduced cardiac disease, and patients with minimal/no function mutations otherwise had a typical FRDA phenotype but with significantly more severe progression. The partial function mutation group was characterized by relative sparing of bulbar and upper limb function, as well as particularly low cardiac involvement. Other clinical features in this group, including optic atrophy and diabetes mellitus, varied widely depending on the specific type of partial function mutation.Interpretation: These data support that the typical FRDA phenotype is driven by frataxin deficiency, especially severe in compound heterozygotes with minimal/no function mutations, whereas the heterogeneous presentations of those with partial function mutations may indicate other contributing factors to FRDA pathogenesis.

Objective: The natural history of Friedreich ataxia is being investigated in a multi‐center longitudinal study designated the Friedreich ataxia Clinical Outcome Measures Study (FACOMS). To understand the utility of this study in analysis of clinical trials, we performed a propensity‐matched comparison of data from the open‐label MOXIe extension (omaveloxolone) to that from FACOMS.Methods: MOXIe extension patients were matched to FACOMS patients using logistic regression to estimate propensity scores based on multiple covariates: sex, baseline age, age of onset, baseline modified Friedreich Ataxia Rating scale (mFARS) score, and baseline gait score. The change from baseline in mFARS at Year 3 for the MOXIe extension patients compared to the matched FACOMS patients was analyzed as the primary efficacy endpoint using mixed model repeated measures analysis.Results: Data from the MOXIe extension show that omaveloxolone provided persistent benefit over 3 years when compared to an untreated, matched cohort from FACOMS. At each year, in all analysis populations, patients in the MOXIe extension experienced a smaller change from baseline in mFARS score than matched FACOMS patients. In the primary pooled population (136 patients in each group) by Year 3, patients in the FACOMS matched set progressed 6.6 points whereas patients treated with omaveloxolone in MOXIe extension progressed 3 points (difference = −3.6; nominal p value = 0.0001).Interpretation: These results suggest a meaningful slowing of Friedreich ataxia progression with omaveloxolone, and consequently detail how propensity‐matched analysis may contribute to understanding of effects of therapeutic agents. This demonstrates the direct value of natural history studies in clinical trial evaluations.

Objective: Friedreich ataxia (FRDA) is an inherited condition caused by a GAA triplet repeat (GAA‐TR) expansion in the FXN gene. Clinical features of FRDA include ataxia, cardiomyopathy, and in some, vision loss. In this study, we characterize features of vision loss in a large cohort of adults and children with FRDA.Methods: Using optical coherence tomography (OCT), we measured peripapillary retinal nerve fiber layer (RNFL) thickness in 198 people with FRDA, and 77 controls. Sloan letter charts were used to determine visual acuity. RNFL thickness and visual acuity were compared to measures of disease severity obtained from the Friedreich Ataxia Clinical Outcomes Measures Study (FACOMS).Results: The majority of patients, including children, had pathologically thin RNFLs (mean = 73 ± 13 μm in FRDA; 98 ± 9 μm in controls) and low‐contrast vision deficits early in the disease course. Variability in RNFL thickness in FRDA (range: 36 to 107 μm) was best predicted by disease burden (GAA‐TR length X disease duration). Significant deficits in high‐contrast visual acuity were apparent in patients with an RNFL thickness of ≤68 μm. RNFL thickness decreased at a rate of −1.2 ± 1.4 μm/year and reached 68 μm at a disease burden of approximately 12,000 GAA years, equivalent to disease duration of 17 years for participants with 700 GAAs.Interpretation: These data suggest that both hypoplasia and subsequent degeneration of the RNFL may be responsible for the optic nerve dysfunction in FRDA and support the development of a vision‐directed treatment for selected patients early in the disease to prevent RNFL loss from reaching the critical threshold.

The ever‐increasing body of ataxia research provides opportunities for large‐scale meta‐analyses, systematic reviews, and data aggregation. Because multiple standardized scales are used to quantify ataxia severity, harmonization of these measures is necessary for quantitative data pooling. We applied the modified Friedreich Ataxia Rating Scale (mFARS), the Scale for the Assessment and Rating of Ataxia (SARA), and the International Cooperative Ataxia Rating Scale (ICARS) to a large cohort of people with Friedreich's ataxia. We provide regression coefficients for scale interconversion and discuss the reliability of this approach, together with insights into the differential sensitivities of mFARS and SARA to disease progression.