A Phase IIb Double-blind, Randomised, Placebo-controlled, Multi-centre, Confirmative Three-way Cross-over Study on Cognitive Function With Two Doses of KH176 in Subjects With a Genetically Confirmed Mitochondrial DNA tRNALeu(UUR) m.3243A>G Mutation.

Mitochondrial diseases, estimated prevalence 1 in 4,300 adults, is caused by pathogenic mutations in genes finally encoding for mitochondrial proteins of the various enzyme complexes of the OXPHOS. Among these mutations, the 3243A>G nucleotide change in the mitochondrially encoded transfer RNALeu(UUR) leucine 1 gene (MT TL 1) is the most prevalent one. The OXPHOS dysfunction resulting from such mutations leads to increased production of reactive oxygen species (ROS), ultimately leading to irreversible oxidative damage of macromolecules, or to more selective and reversible redox modulation of cell signaling that may impact (adult) neurogenesis.

Despite advances in the understanding of mitochondrial disorders, treatment options are extremely limited and, to date, largely supportive. Therefore, there is an urgent need for novel treatments. KH176, a new active pharmaceutical ingredient (API), is an orally bio-available small molecule under development for the treatment of these disorders (see Section 1.4). The current study will further evaluate the effect of KH176 in various cognitive domains and evaluate the effect of different doses of KH176 (See Section 1.5).

In view of the growing recognition of the importance of mitochondrial function in maintaining cognitive processes in the brain, as well as the understanding of the safety profile and pharmacokinetics of KH176 following the two clinical studies described above, a more detailed study is indicated of the effects of KH176 in various cognitive domains, using the confirmed safe and well-tolerated KH176 dose of 100 mg bid, as well as a lower dose of 50 mg bid. The primary objective is an evaluation of KH176 in the attention domain of cognitive functioning, as assessed by the visual identification test score of the Cogstate computerised cognitive testing battery.