Results of a randomized double‐blind study evaluating luvadaxistat in adults with Friedreich ataxia

Wang, Hao; Norton, J.B.; Xu, Lin; DeMartinis, Nicholas; Sen, Rohini; Shah, Ankit; Farmer, Jennifer M.; Lynch, David R.

doi:10.1002/acn3.51373

Cited by 9 publications

(17 citation statements)

References 21 publications

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“…2 Treatment-emergent AEs that were related to the study drug were observed in about 65% of the patients in the CEPO arm 28 and 55% patients in the luvadaxistat arm. 4 Other drugs such as vatiquinone, CoQ10, A0001, amantadine hydrochloride, EPO, rhuEPO, RT001, and IFN-gamma 1b have reported fewer AEs.…”

Section: Safety Resultsmentioning

confidence: 99%

“…A total of 32 2,4,21–50 publications were identified, of which 28 2,4,22–26,28–37,39–49 were unique studies. Overall, 22 RCTs 2,4,21,23,25,26,28,31–…”

Section: Resultsmentioning

confidence: 99%

“…Similarly, in a phase 2 trial of luvadaxistat, mFARS score improvement was higher among patients in the placebo group than among patients in the intervention group. 4 A short 6-month study of vatiquinone at two doses (200 and 400 mg) was not able to demonstrate statistically significant differences in the FARSneuro scores. However, patients were treated in an open-label extension where a decrease in FARS-neuro scores of 1.8 units was noted at 24 months.…”

Section: Efficacy Outcomesmentioning

confidence: 91%

“…A total of 32 2,4,21-50 publications were identified, of which 28 2,4,[22][23][24][25][26][28][29][30][31][32][33][34][35][36][37][39][40][41][42][43][44][45][46][47][48][49] were unique studies. Overall, 22 RCTs 2,4,21,23,25,26,28,31-36,38,40-43,46-50 , 5 open-label studies, 23,27,30,40,44 2 single-arm trials, 37,39 2 observational studies, 24,29 and 1 crossover study 45 (Table 1) were reviewed.…”

Section: Study Characteristicsmentioning

confidence: 99%

“…About 10-30% of FA patients experience diabetes. 3,4 FA is the most common form of hereditary ataxia, mostly prevalent in Europe (about 1 in 50,000); there are about 1.7 cases per 100,000 to 4 cases per 100,000 in the United States, Middle East, and South Asia. 3,[5][6][7] The age of disease onset generally ranges from 5 to 15 years, with most individuals experiencing wheelchair dependence within 15 years of diagnosis.…”

Section: Introductionmentioning

confidence: 99%

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Clinical evidence of interventions assessed in Friedreich ataxia: a systematic review

Jain¹,

Badgujar²,

Spoorendonk³

et al. 2022

Therapeutic Advances in Rare Disease

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Objectives: The rare inherited autosomal recessive disease Friedreich ataxia (FA) causes progressive neurodegenerative changes and disability in patients. A systematic literature review (SLR) was carried out to understand and summarize the published efficacy and safety of therapeutic interventions in this disease. Methods: Database searches were carried out in MEDLINE, Embase, and Cochrane by two independent reviewers. In addition, trial registries and conference proceedings were hand-searched. Results: Thirty-two publications were deemed eligible according to PICOS criteria. Twenty-four publications detail randomized controlled trials. The most frequently identified therapeutic intervention was idebenone ( n = 11), followed by recombinant erythropoietin ( n = 6), omaveloxolone ( n = 3), and amantadine hydrochloride ( n = 2). Other therapeutic interventions were investigated in one publication: A0001, CoQ10, creatine, deferiprone, interferon-γ-1b, the L-carnitine levorotatory form of 5-hydroxytryptophan, luvadaxistat, resveratrol, RT001, and vatiquinone (EPI-743). These studies included patients from 8 to 73 years old, and disease duration varied from 4.7 to 19 years. Disease severity as per the mean GAA1 and GAA2 allele repeat length ranged from 350 to 930 and 620 to 987 nucleotides, respectively. Most frequently reported efficacy outcomes were the International Cooperative Ataxia Rating Scale (ICARS, n = 10), the Friedreich Ataxia Rating Scale (modified FARS and FARS-neuro, n = 12), the Scale for Assessment and Rating of Ataxia (SARA, n = 7), and the Activities of Daily Living scale (ADL, n = 8). Each of these assesses the severity of disability in FA patients. In many studies, patients with FA deteriorated according to these severity scales regardless of treatment, or inconclusive results were found. Generally, these therapeutic interventions were well-tolerated and safe. Serious adverse events were atrial fibrillation ( n = 1), craniocerebral injury ( n = 1), and ventricular tachycardia ( n = 1). Conclusion: Identified literature showed a considerable unmet need for therapeutic interventions that halt or slow the deteriorating nature of FA. Novel efficacious drugs should be investigated that aim to improve symptoms or slow disease progression. Plain Language Summary A systematic review investigating the effectiveness and safety of treatments for Friedreich ataxia What is Friedreich ataxia? Friedreich ataxia (FA) is a rare genetic condition that causes nervous system damage and movement problems, including muscle weakness and impaired coordination (ataxia). Heart problems, vision problems, spine problems, and diabetes can occur, too. Within 10 to 20 years of the first symptoms, an individual with FA generally requires a wheelchair. Why was this study done? Currently there are no approved treatments for FA. Current treatments focus on relieving symptoms. This study was carried out to obtain a landscape view of all the published evidence about FA treatments. What did the researchers find? • Two scales were most frequently used to assess disease severity: the International Cooperative Ataxia Rating Scale (ICARS) and the FA Rating Scale (modified FARS and FARS-neuro). • Patients on idebenone at 1350 to 2550 mg per day showed improvement in ICARS and FARS scores over 6 months, but scores deteriorated after 12 months in ambulatory patients with FA. • Omaveloxolone at doses of 2.5 to 300 mg per day showed significant improvement in mFARS scores and FA Activity of Daily Living scores at 48 weeks compared with placebo. • Patients treated with vatiquinone showed significant improvements in FARS-neuro scores at 24 months versus natural disease progression. • Other treatments did not show evidence of significant improvement. What does this mean? FA leads to nervous system damage slowly, over an extended period. It is important to keep in mind that many of the studies reviewed here were of fairly short duration, meaning that the effects of a treatment may not have been detectable. Why is this important? This study was undertaken in the hopes that a comprehensive picture of the current treatment landscape for FA will help promote research that will eventually lead to effective treatments to slow down or reverse the damage caused by disease, which are vitally needed.

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Section: Safety Resultsmentioning

confidence: 99%

“…A total of 32 2,4,21–50 publications were identified, of which 28 2,4,22–26,28–37,39–49 were unique studies. Overall, 22 RCTs 2,4,21,23,25,26,28,31–…”

Section: Resultsmentioning

confidence: 99%

Section: Efficacy Outcomesmentioning

confidence: 91%

Section: Study Characteristicsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Clinical evidence of interventions assessed in Friedreich ataxia: a systematic review

Jain¹,

Badgujar²,

Spoorendonk³

et al. 2022

Therapeutic Advances in Rare Disease

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Therapeutic Biomarkers in Friedreich’s Ataxia: a Systematic Review and Meta-analysis

Gavriilaki,

Chatzikyriakou,

Moschou

et al. 2023

Cerebellum

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Although a large array of biomarkers have been investigated in Friedreich’s ataxia (FRDA) trials, the optimal biomarker for assessing disease progression or therapeutic benefit has yet to be identified. We searched PubMed, MEDLINE, and EMBASE databases up to June 2023 for any original study (with ≥ 5 participants and ≥ 2 months’ follow-up) reporting the effect of therapeutic interventions on any clinical, cardiac, biochemical, patient-reported outcome measures, imaging, or neurophysiologic biomarker. We also explored the biomarkers’ ability to detect subtle disease progression in untreated patients. The pooled standardized mean difference (SMD) was calculated using a random-effects model. The study’s protocol was registered in PROSPERO (CRD42022319196). In total, 43 studies with 1409 FRDA patients were included in the qualitative synthesis. A statistically significant improvement was observed in Friedreich Ataxia Rating Scale scores [combining Friedreich Ataxia Rating Scale (FARS) and modified FARS (mFARS): SMD = − 0.32 (− 0.62 to − 0.02)] following drugs that augment mitochondrial function in a sensitivity analysis. Left ventricular mass index (LVMI) was improved significantly [SMD = − 0.34 (− 0.5 to − 0.18)] after 28.5 months of treatment with drugs that augment mitochondrial function. However, LVMI remained stable [SMD = 0.05 (− 0.3 to 0.41)] in untreated patients after 6-month follow-up. None of the remaining biomarkers changed significantly following any treatment intervention nor during the natural disease progression. Nevertheless, clinical implications of these results should be interpreted with caution because of low to very low quality of evidence. Further randomized controlled trials of at least 24 months’ duration using a biomarker toolbox rather than a single biomarker are warranted.

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Targeting d-Amino Acid Oxidase (DAAO) for the Treatment of Schizophrenia: Rationale and Current Status of Research

2022

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Results of a randomized double‐blind study evaluating luvadaxistat in adults with Friedreich ataxia

Cited by 9 publications

References 21 publications

Clinical evidence of interventions assessed in Friedreich ataxia: a systematic review

Clinical evidence of interventions assessed in Friedreich ataxia: a systematic review

Therapeutic Biomarkers in Friedreich’s Ataxia: a Systematic Review and Meta-analysis

Targeting d-Amino Acid Oxidase (DAAO) for the Treatment of Schizophrenia: Rationale and Current Status of Research

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