A recently published meta-analysis of therapeutic biomarkers in Friedrich ataxia (FA) showed significant improvement in combined clinical outcomes measures in Friedreich Ataxia Rating Scale scores and significant improvement of left ventricular mass index (LVMI) following treatment with medications that augmented mitochondrial function.1 Investigators concluded that the clinical importance of these changes remains to be clarified in well-designed randomized controlled trials in which the minimal clinically important change should be predefined.
Comprised of 1409 patients from 43 studies, 205 patients from 6 studies demonstrated a statistically significant improvement in combinined FARS and modified FARS following 15 months of therapies that augmented mitochondrial function (standardized mean difference [SMD] = - 0.32; 95% CI, -0.62 to -0.02). Using 261 patients from 10 studies, results also showed that patients had significant reduction in the LVMI following 28.5 months of treatment with medications that enhanced mitochondrial function (SMD = -0.34; 95% CI, -0.5 to -0.18). In an analysis of untreated patients, authors noted that LVMI remained stable following 6-month follow-up (SMD = 0.05; - 0.3 to 0.41).
Top Clinical Takeaways
- Medications augmenting mitochondrial function show promise in improving clinical outcomes and left ventricular mass index (LVMI) in patients with Friedreich Ataxia (FA).
- Caution is advised in interpreting results, given limitations such as short follow-up durations, heterogeneous patient populations, and potential bias from positive trials.
- The study recommends a comprehensive biomarker toolbox, including FA Rating Scale scores and LVMI assessments, for robust evaluation in future randomized controlled trials with extended durations.
“This result should be interpreted with caution because it was mainly driven by omaveloxolone’s positive trial and was characterized by very low quality of evidence. Low quality of evidence from the studies examining the patients supported a beneficial effect of drugs that augment mitochondrial function on cardiac structure measured by LVMI after 28.5 months,” senior author Vasilios K. Kimiskidis, MD, PhD, associate professor of neurology and Clinical neurophysiology at Aristotle University of Thessaloniki School of Medicine, in Greece, and colleagues wrote.1 “This result was driven by idebenone studies in combination with one trial of the iron chelator deferiprone. In contrast, all the remaining biomarkers examined did not change following any treatment or during the natural course of the disease. Of note, the median follow-up period for these outcome measures did not exceed 12-months.”
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In this qualitative synthesis, investigators searched PubMed, MEDLINE, and EMBASE databases up to June 2023 for any original study with at least 5 participants and at least 2 months' follow-up. Studies were included in the analysis if they reported on the effect of therapeutic interventions on any clinical, cardiac, biochemical, patient-reported outcome measures, imaging, or neurophysiologic biomarkers. The investigators also assessed the biomarkers' ability in the detection of subtle disease progression among patients not treated and calculated the pooled SMD using a random-effects model.
“An ideal valuable biomarker should be able to detect both subtle changes in the natural course of a slowly progressive disorder such as FA and concurrently be responsive to any treatment effect. Nevertheless, it is imperative that the observed alterations are also clinically meaningful,” Kimiskidis et al noted.1 “The pooled analysis in untreated patients showed that LVMI did not change over 12 months. The observed LVMI reduction following drugs that augment mitochondrial function without any parallel change in other cardiac or clinical biomarkers should be interpreted with caution.”
All told, the major limitations of this study included the observational nature of most of the included records in conjunction with lacking a control group, the short median follow-up duration in most outcomes, and the heterogeneity of the observed FA populations. The authors noted that they downgraded the quality of evidence of their estimates based on these major limitations. Additionally, the investigators noted the lack of inclusion of other interventions such as occupational and physical therapy, speech and swallowing therapy, psychological counseling.
“In view of these results, we suggest the use of a biomarker toolbox, for example, a combination of Friedreich Ataxia Rating Scale scores and LVMI assessment, evaluating different aspects of this disease as a primary outcome measure in future randomized controlled trials. Notably, study duration should be least 24 months considering that trials with shorter duration are unlikely to demonstrate any clinical benefit. Finally, the clinical meaningful change of the employed biomarkers should be predefined based on natural history studies,” Kimiskidis et al noted.1
REFERENCES
1. Gavriilaki M, Chatzikyriakou E, Moschou M, Arnaoutoglou M, Sakellari I, Kimiskidis VK. Therapeutic Biomarkers in Friedreich's Ataxia: a Systematic Review and Meta-analysis. Cerebellum. Published online October 27, 2023. doi:10.1007/s12311-023-01621-6
