Dimethyl fumarate — an approved therapy for multiple sclerosis and psoriasis — has been granted orphan drug designation by the European Medicines Agency for the treatment of adrenoleukodystrophy (ALD).
Orphan designation is given to new therapies with the potential to be a safe and effective treatment for rare, life-threatening, or chronically debilitating conditions with no approved treatments. It also is granted for conditions with approved treatments for which the investigational therapy shows significant benefit.
This designation is expected to provide regulatory support and financial benefits for dimethyl fumarate, and to accelerate its clinical development and review. It also ensures a 10-year period of marketing exclusivity in the EU upon regulatory approval.
ALD is a rare genetic disorder caused by mutations in the ABCD1 gene, which provides instructions for producing the adrenoleukodystrophy protein (ALDP). Increasing evidence points to oxidative stress and mitochondrial dysfunction as early hallmarks of ALD.
Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them, which can lead to cellular damage. Mitochondria are the cell organelles responsible for the production of energy. Since they produce about 90% of the chemical energy that cells need to survive, their malfunction can lead to several diseases.
Dimethyl fumarate is an activator of the protein NRF2 — nuclear factor erythroid 2‐like 2. NRF2 is involved in the production of new mitochondria, in antioxidant responses that protect against oxidative stress, and in the regulation of neuroinflammation. Several studies have shown that dimethyl fumarate promotes antioxidant, anti-inflammatory, and neuroprotective responses.
Since ALD’s early hallmarks include mitochondrial dysfunction and oxidative stress, the Center for Biomedical Network Research on Rare Diseases (CIBERER), in Barcelona, Spain, has been evaluating whether dimethyl fumarate can be repurposed for treating the disease.
Led by Aurora Pujol, MD, a team of researchers at the Bellvitge Biomedical Research Institute (IDIBELL), in Barcelona — integrated in CIBERER — discovered that NRF2’s activity was reduced in a mouse model of ALD, and in cells from ALD patients.
Notably, the team also found that oral treatment with dimethyl fumarate reverted oxidative damage, mitochondrial dysfunction, and neuroinflammation, and prevented neurodegeneration and motor dysfunction in these mice.
According to a press release from IDIBELL, “dimethyl fumarate normalizes oxidative stress, energetic production, inflammation, neural degeneration and associated locomotor disabilities in animal models of adrenoleukodystrophy, which suggest that DMF is an attractive therapeutic option for patients with this disorder.”
Dimethyl fumarate is sold by Biogen under the brand name Tecfidera as a treatment for the most common form of multiple sclerosis, and by Almirall as Skilarence for the treatment of psoriasis, an autoimmune skin condition.