Efficacy and Safety of Dimethyl Fumarate in Friedreich Ataxia: Primary Results From the Phase Two, Randomized, Double-blind, Placebo-controlled DMF-FA-201 Trial
Francesco Sacca1, Martina Gramaglia1, Alessio Sarnataro1, Alessia Bonfini Rendina1, Giorgia Puorro1, Angela Marsili1, Chiara Pane1, Caterina Giannini1, Cosimo Linguetta1, Giorgia Esposito1, Andrea De Mare1, Vittoria Giordano1, Ludovica Aliberti1, Antonio Cittadini1, Alberto Maria Marra1
1University Federico II
Objective:
Evaluate the efficacy and safety of Dimethyl fumarate (DMF) in patients with Friedreich Ataxia (FA).
Background:
FA is an autosomal recessive neurodegenerative disease caused by the homozygote expansion of the GAA trinucleotide in the first intron of the FXN gene. Compared to controls, FXN gene expression is 20% in patients and 50% in healthy carriers. Treatment of multiple sclerosis patients with DMF is known to increase FXN expression by 70%.
Design/Methods:
We conducted a randomized, placebo-controlled, Phase II trial to test the efficacy of DMF on FXN gene transcription in patients with FA. Secondary objectives were the increase in frataxin protein, stimulation of the nrf2 pathway and mitochondrial biogenesis, safety and tolerability of DMF, and impact on clinical measures of disease. The study consisted of two sequential phases of 12 weeks each: a core phase (patients were randomized to receive DMF or placebo) and an extension phase (all patients were treated with DMF). EudraCT number: 2021-006274-23.
Results:
In total, 40 patients (female, 57.5%; mean [SD] age, 36.1 [12.6] years; disease duration 16.8 [6.9] years), were randomized (DMF n=20, placebo n=20). At the end of the core phase, 33 patients continued to the open-label extension. DMF significantly increased FXN gene expression after 12 weeks of treatment (difference compared to placebo +119.0% 95% CI +55.3, +182.7, p=0.018). In the DMF-DMF group FXN expression increased to +205% after 24 weeks compared to baseline (p<0.001). Frataxin protein and some clinical measures showed a non-significant trend towards improvement after treatment. The most frequent adverse events were gastrointestinal (heartburn, nausea, vomiting, diarrhea, abdominal pain), flushing, eosinophilia, lymphopenia, and elevated liver enzymes.
Conclusions:
DMF significantly increases transcription of the FXN gene, with long-term stability, to a degree that restores expression levels to those of healthy carriers. The drug appeared safe, with adverse events consistent with DMF pharmacovigilance.
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