Dimethyl Fumarate
Dimethyl fumarate, a drug that has been approved for treatment of multiple sclerosis and psoriasis, has been shown to induce mitochondrial biogenesis in multiple sclerosis patients via activation of Nrf2 pathway. Because in Friedreich’s ataxia there are also impairments of Nrf2 activation and loss of mitochondria, treatment with dimethyl fumarate may be beneficial.
Stages of Dimethyl Fumarate Development
The drug development process can be thought of as a series of stages, and successful drugs must pass through each stage to become available to patients.
Dr. Gino Cortopassi at the University of California Davis and other groups have observed that Nrf2 (Nuclear factor (erythroid-derived 2)-like 2, a protein that is critical in a pathway to protecting the cell from oxidative stress) is paradoxically decreased in FA. Specifically, Dr. Cortopassi’s group has shown that Nrf2 protein is decreased in frataxin deficient cells and FA mouse models. Through a drug discovery program that screened a library of clinically approved drugs, the group identified several compounds that act as Nrf2 activators and rescue biochemical and cellular deficits related to frataxin deficiency.
One of the compounds identified though the screen was dimethyl fumurate. Dr. Cortopassi and colleagues have shown that dimethyl fumurate can induce mitochondrial biogenesis in cell models.
DMF has also undergone testing in preclinical models of FA, demonstrating an impact on frataxin levels.
Dr. Francesco Sacca at the University Federico II in Naples, Italy planned a clinical trial to further study DMF in individuals with FA. The clinical trial will investigate if dimethyl fumarate activates Nrf2 pathway, increases mitochondrial number (biogenesis), increases frataxin transcription and/or protein and will evaluate safety, tolerability, and other clinical endpoints. The initiation of this trial was delayed due to COVID-19.
DMF received approval from the EMA for the treatment of psoriasis based on the positive results of the BRIDGE trial (Mrowietz et al., 2017). DMF has also been considered for the treatment of MS (Gold et al., 2012) and was approved for the treatment of relapsing remitting MS.
The safety profile of DMF (trade name: Skilarence) is well-known and adverse events of special interest that have been considered for Skilarence are (EMA/412737/2017, 2017) leukocytopenia and lymphopenia, flushing, gastrointestinal disorders, hepatic injury, malignancies, renal injuries and proteinuria, and serious and opportunistic infections.
October 2023:The clinical study will investigate if DMF can increase the expression of the FXN gene and frataxin protein and ameliorate in-vivo detectable measures of mitochondrial dysfunction in FA. The study is composed of a screening visit and two sequential 12-week phases: a core phase and an extension phase. During the first phase (core), patients will be randomly assigned to either the DMF or a placebo group in a 1:1 ratio. During the first week, patients will receive a total daily dose of 240 mg of DMF or placebo; from the second week of treatment, the dose will be increased to two 120 mg tablets BID for a total daily dose of 480 mg. During the second phase (extension), all patients will be treated with DMF. Changes in frataxin mRNA and protein are the primary outcome measures. EudraCT number 2021-006274-23.
October 2024: The study described above has now been completed. The results are being analyzed and may be available publicly by the end of 2024.