Mitochondrial Disease Treatment Candidate KH176 Shows Potential, Study Finds

Khondrion’s mitochondrial disease treatment candidate KH176 has potential to be effective in a broad range of disorders, a new study reports.

The research, “KH176 Safeguards Mitochondrial Diseased Cells from Redox Stress-Induced Cell Death by Interacting with the Thioredoxin System/Peroxiredoxin Enzyme Machinery,“ was published in the journal Scientific Reports.

KH176 is a small, orally administered molecule that targets reactive oxygen species (ROS), or byproducts of mitochondria, the cells’ power plants. The compound belongs to a new class of potential mediators for the control of oxidative and redox harmful events, which are common in mitochondrial disease.

The scientists used patient-derived skin fibroblasts, a cell type responsible for generating connective tissue and crucial for skin repair. They tested several compounds for their ability to reduce ROS levels and protect against redox effects on cells. KH176, the lead compound, was tested in cells and also via computer simulation.

“Interestingly, we could demonstrate in several patient-derived cells that KH176 is an attractive candidate to correct both pathological phenotypes, illustrating its unique potential for this group of patients” Julien Beyrath, the study’s first author and COO at Khondrion, said in a press release.

The scientists also identified the antioxidant peroxiredoxin enzyme as the main target of KH176. The team is now assessing the precise processes involved in the interaction between KH176 and this enzyme.

“Due to its dual activity as antioxidant and redox modulator, KH176 offers a novel approach to the treatment of mitochondrial (-related) diseases,” the researchers wrote.

“The results presented highlight the potential of KH176 as a single molecule to be effective in a large group of heterogeneous [different] mitochondrial diseases, but also other diseases with underlying ROS and Redox perturbations” said Jan Smeitink, the study’s senior author and CEO at Khondrion.

 The work was conducted by Khondrion, the therapy’s developer, in collaboration with Inoviem Scientific and the Radboud University Medical Center, in the Netherlands.

Prior results showed that in a mouse model of Leigh disease — a progressive and severe mitochondrial disease — KH176 improved motor performance and gait. Also, results of a Phase 1 study (NCT02544217) testing multiple doses of KH176 revealed the treatment candidate is well-tolerated in healthy men.

In the KHENERGY Phase 2 clinical study (NCT02909400), KH176 showed a favorable safety profile and improved depression and migraine in carriers of a gene defect called m.3243A>G who have MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) or MIDD (maternally inherited diabetes and deafness) syndromes. The company is now planning a clinical program to confirm these benefits in patients with mitochondrial disease.

KH176 already received orphan drug designation for Leigh disease and MELAS in Europe and for all inherited mitochondrial respiratory chain diseases in the U.S.