The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended the granting of marketing authorisation for “Raxone” (idebenone), a novel therapy for the treatment of visual impairment in adolescent and adult patients with Leber’s Hereditary Optic Neuropathy (LHON). LHON is a genetic mitochondrial disorder often presenting early in life and is characterized by a rapid loss of central vision within months of the onset of symptoms. It is estimated that approximately 90% of LHON cases arise from one of three mitochondrial DNA (mtDNA) point mutations: m.3460G>A, m.11778G>A, and m.14484T>C, each of which affect the complex I subunits of the mitochondrial respiratory chain with varying severity. Raxone (idebenone) – a synthetic short-chain benzoquinone and a cofactor for the enzyme NAD(P)H – is understood to act by circumventing the complex I defect and restoring cellular energy levels in ganglion cells.
The newly approved compound is under development by Santhera Pharmaceuticals Holding AG, a Swiss pharmaceutical company with a therapeutic focus on mitochondrial and neuromuscular disease. The same compound (idebenone) is being developed by the company for a number of orphan indications, including Duchenne Muscular Dystrophy (DMD) and primary progressive Multiple Sclerosis (ppMS). In early 2013, the EMA refused marketing authorization for idebenone stating that in patients with LHON whose symptoms started in the previous five years, taking Raxone for six months did not lead to any significant improvement in vision, compared with placebo (patients taking Raxone were able to distinguish three more letters on the letter chart compared with patients taking placebo). The CHMP did not consider such a benefit to be significant. However, according to the company, the recent CHMP recommendation is based on a number of supporting data including results from a randomized, placebo controlled study, an Expanded Access Program by the company, and on comparative natural history data from case record surveys. In a press release on the milestone, the company stated that, “[t]he Committee considered that the totality of the data provided for an orphan disease as severe as LHON with no available treatment options warranted a recommendation for approval under Exceptional Circumstances. Santhera has undertaken to gather additional long-term efficacy and safety data in LHON patients as post-authorization measures.”
Commenting on the achievement Prof. Thomas Klopstock, MD at the University of Munich, and an LHON investigator and coordinator of the German network for mitochondrial disorders, (mitoNET) stated, “[t]his is a major breakthrough as it paves the way for the first medicinal product to become available for the treatment of a mitochondrial disease. LHON is a severe form of vision loss caused by mitochondrial dysfunction. Affected patients, usually young and otherwise healthy, rapidly lose central vision and become bilaterally blind within a few months from the onset of symptoms. Although there is a chance for partial or even full spontaneous recovery, most patients remain permanently blind if un-treated. The mode of action of idebenone provides a clear biochemical and medical rationale and the clinical data demonstrate that vision of affected patients can substantially improve upon treat-ment with Raxone. This recommendation is a landmark in mitochondrial disease research world-wide and will undoubtedly spur further research in this direction.”