Abstract Details

Title Efficacy and Safety of Dimethyl Fumarate in Friedreich Ataxia: Primary Results From the Phase Two, Randomized, Double-blind, Placebo-controlled DMF-FA-201 Trial

Topic Movement Disorders

Presentation(s) S26 - Movement Disorders: Clinical Trials and Therapeutics (2:24 PM-2:36 PM)

Poster/Presentation
Number 008

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.

Authors/Disclosures
Francesco Sacca, MD, FAAN (University Federico II) PRESENTER	Dr. Sacca has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Alexion. Dr. Sacca has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Argenx. Dr. Sacca has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lexeo. Dr. Sacca has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Sacca has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genpharm. Dr. Sacca has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Sacca has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Medpharma. Dr. Sacca has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Madison Pharma. Dr. Sacca has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Zai Lab. Dr. Sacca has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Dianthus. Dr. Sacca has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Reata. Dr. Sacca has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sandoz. Dr. Sacca has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neopharm Israel. Dr. Sacca has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Johnson&Johnson. Dr. Sacca has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. Dr. Sacca has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Astrazeneca. The institution of Dr. Sacca has received research support from AIFA. The institution of Dr. Sacca has received research support from FARA.
Martina Gramaglia, MD	Dr. Gramaglia has nothing to disclose.
Alessio Sarnataro, MD	Dr. Sarnataro has nothing to disclose.
Alessia Bonfini Rendina, PA	Miss Bonfini Rendina has nothing to disclose.
Giorgia Puorro	Giorgia Puorro has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Elma Research. Giorgia Puorro has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Alexion.
Angela Marsili	Angela Marsili has nothing to disclose.
Chiara Pane, MD	Dr. Pane has nothing to disclose.
Caterina Giannini, MD, PhD	Prof. Giannini has nothing to disclose.
Cosimo Linguetta, MD	Dr. Linguetta has nothing to disclose.
Giorgia Esposito, Jr., MD	Dr. Esposito has nothing to disclose.
Andrea De Mare, Jr., MD	Dr. De Mare has nothing to disclose.
Vittoria Giordano, MD	Dr. Giordano has nothing to disclose.
Ludovica Aliberti	No disclosure on file
ANTONIO CITTADINI, MD	Prof. CITTADINI has received personal compensation in the range of $500-$4,999 for serving as a Consultant for MERCK.
Alberto M. Marra, MD, PhD	Prof. Marra has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for MSD. Prof. Marra has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for De Grutyer.

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