Dataset Information

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

ABSTRACT:

Objectives

Friedreich ataxia (FRDA) is a rare disorder with progressive neurodegeneration and cardiomyopathy. Luvadaxistat (also known as TAK-831; NBI-1065844), an inhibitor of the enzyme d-amino acid oxidase, has demonstrated beneficial effects in preclinical models relevant to FRDA. This phase 2, randomized, double-blind, placebo-controlled, parallel-arm study evaluated the efficacy and safety of oral luvadaxistat in adults with FRDA.

Methods

Adult patients with FRDA were randomized 2:1:2 to placebo, luvadaxistat 75 mg twice daily (BID), or luvadaxistat 300 mg BID for 12 weeks. The primary endpoint changed from baseline at week 12 on the inverse of the time to complete the nine-hole peg test (9-HPT^-1 ), a performance-based measure of the function of the upper extremities and manual dexterity. Comparisons between luvadaxistat and placebo were made using a mixed model for repeated measures.

Results

Of 67 randomized patients, 63 (94%) completed the study. For the primary endpoint, there was no statistically significant difference in change from baseline on the 9-HPT^-1 (seconds^-1 ) at week 12 between placebo (0.00029) and luvadaxistat 75 mg BID (-0.00031) or luvadaxistat 300 mg BID (-0.00059); least squares mean differences versus placebo (standard error) were -0.00054 (0.000746) for the 75 mg dose and -0.00069 (0.000616) for the 300 mg dose. Luvadaxistat was safe and well tolerated; the majority of reported adverse events were mild in intensity.

Interpretation

Luvadaxistat was safe and well tolerated in this cohort of adults with FRDA; however, it did not demonstrate efficacy as a treatment for this condition.

SUBMITTER: Wang H

PROVIDER: S-EPMC8164851 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionCurrently, no treatment that delays with the progression of Friedreich ataxia is available. In the majority of patients Friedreich ataxia is caused by homozygous pathological expansion of GAA repeats in the first intron of the FXN gene. Nicotinamide acts as a histone deacetylase inhibitor. Dose escalation studies have shown, that short term treatment with dosages of up to 4?g/day increase the expression of FXN mRNA and frataxin protein up to the levels of asymptomatic heterozygous gene carriers. The long-term effects and the effects on clinical endpoints, activities of daily living and quality of life are unknown.MethodsThe aim of the NICOFA study is to investigate the efficacy and safety of nicotinamide for the treatment of Friedreich ataxia over 24?months. An open-label dose adjustment wash-in period with nicotinamide (phase A: weeks 1-4) to the individually highest tolerated dose of 2-4?g nicotinamide/day will be followed by a 2 (nicotinamide group): 1 (placebo group) randomization (phase B: weeks 5-104). In the nicotinamide group, patients will continue with their individually highest tolerated dose between 2 and 4?g/d per os once daily and the placebo group patients will be receiving matching placebo. Safety assessments will consist of monitoring and recording of all adverse events and serious adverse events, regular monitoring of haematology, blood chemistry and urine values, regular measurement of vital signs and the performance of physical examinations including cardiological signs. The primary outcome is the change in the Scale for the Assessment and Rating of Ataxia (SARA) over time as compared with placebo in patients with Friedreich ataxia based on the linear mixed effect model (LMEM) model. Secondary endpoints are measures of quality of life, functional motor and cognitive measures, clinician's and patient's global impression-change scales as well as the up-regulation of the frataxin protein level, safety and survival/death.PerspectiveThe NICOFA study represents one of the first attempts to assess the clinical efficacy of an epigenetic therapeutic intervention for this disease and will provide evidence of possible disease modifying effects of nicotinamide treatment in patients with Friedreich ataxia.Trial registrationEudraCT-No.: 2017-002163-17, ClinicalTrials.gov NCT03761511.