Thursday, October 15, 2015

Drugs in Clinical Pipeline: KH-176

KH-176 [(S)-6-hydroxy-2,5,7,8-tetramethyl-N-((R)-piperidin-3-yl)chroman-2-carboxamide] is a potent intracellular redox modulating agent targeting the reactive oxygen species which are important in the pathogenesis of disorders of mitochondrial oxidative phosphorylation. KH0176 is an orally bio-available small molecule developed by Khondrion for the treatment of mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS) syndrome and other mitochondrial respiratory chain/oxidative phosphorylation (OXPHOS) diseases.

KH-176 is capable of reducing intracellular reactive oxygen species (ROS) in cells. The compound was tested for its effect on decreasing the intracellular ROS levels in a patient cell line (S7-5175 cells, which are fibroblasts from a patient with a mutation in the NDUFS7 gene) with increased ROS levels, in a DCFDA assay. KH-176 reported an EC50 value in the range 0.1 - 1 uM.

In August, 2015 Khondrion, the Dutch biopharmaceutical company focusing on small molecule therapeutics for mitochondrial diseases, announced that the European Commission has granted Khondrion Orphan Drug Designation (ODD) for its front-runner compound KH-176 to treat mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS) syndrome.

The European Commission has already granted KH-176 an ODD for treatment of the mitochondrial disease, Leigh syndrome. The US Food and Drug Administration (FDA) granted KH-176 an ODD for all inherited mitochondrial respiratory chain disorders. KH-176 is currently being evaluated in randomized, double blind, placebo-controlled dose-escalating studies in healthy volunteers in Phase 1 Clinical Trials.

Mitochondria and its dysfunction

Mitochondria are essential organelles that constitute the 'powerhouses' of the cell. Defects in these organelles often lead to a variety of severe metabolic disorders affecting the organs that have a high-energy demand, such as muscle and brain. With an incidence of at least 1 in 5000 individuals it is recognized as the most common group of inborn errors of metabolism. Moreover, because programmed cell death (apoptosis) is triggered by mitochondria, defects in these organelles have consequences far beyond the diseases, which brought them initially to our attention and involvement in cancer and neurodegenerative diseases like Alzheimer and Parkinson has been demonstrated. Many commonly used drugs like the RTIs, certain antibiotics and anti-epileptic drugs, may cause mitochondrial dysfunction. So far no effective treatment is available to cure or improve these disease conditions.

One of the primary functions of mitochondria is oxidative phosphorylation (OXPHOS). The contribution of mitochondrial dysfunction to human disease was already recognized in the late 1980s, when maternally inherited point mutations, as well as deletions arising spontaneously during development, were found to be associated with rare neurological syndromes. Mitochondrial dysfunction contributes to various disease states. Some mitochondrial diseases are due to mutations or deletions in the mitochondrial genome. If a threshold proportion of mitochondria in the cell is defective, and if a threshold proportion of such cells within a tissue have defective mitochondria, symptoms of tissue or organ dysfunction can result. Practically any tissue can be affected, and a large variety of symptoms may be present, depending on the extent to which different tissues are involved. Some examples of mitochondrial diseases are Friedreich's ataxia (FRDA), Leber's Hereditary Optic Neuropathy (LHON), dominant optic atrophy (DOA); mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS), Myoclonus Epilepsy Associated with Ragged-Red Fibers (MERRF) syndrome, Leigh syndrome, and oxidative phosphorylation disorders. Most mitochondrial diseases involve children who manifest the signs and symptoms of accelerated aging, including neurodegenerative diseases, stroke, blindness, hearing impairment, diabetes, and heart failure [1].

Very few treatments are available for patients suffering from these mitochondrial diseases.

1. Blaauw, R. H.; et. al. Chromanyl derivatives for treating mitochondrial disease. WO2014011047A1