KHENERGY study provides first data on safety and efficacy of KH176 in patients with mitochondrial disease. Results from phase IIa study of innovative reduction-oxidation modulator published in Clinical Pharmacology and Therapeutics.

NIJMEGEN, the Netherlands: Khondrion, the leading clinical-stage pharmaceutical company focusing on small molecule therapeutics for mitochondrial diseases, today announces that data from its KHENERGY phase IIa study, examining the safety and efficacy of KH176 in patients with mitochondrial disease, have been published in Clinical Pharmacology and Therapeutics.

KH176 is a new innovative cellular redox modulator that, based on extensive investigations in preclinical studies, has the potential to positively change the clinical burden of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) spectrum disorders and other mitochondrial diseases.

The study, in 18 patients with an m.3243A>G mutation in their mitochondrial genome, showed that KH176 was well tolerated and appeared safe at the 100mg twice-daily oral dosing regimen. No significant improvements in gait parameters were obtained but positive effects in mood related outcomes and alertness were observed and will be further investigated for clinical significance in future studies, given the prevalence of depressive symptoms among patients with mitochondrial disease.

Commenting on the study results, Prof. Dr. Jan Smeitink, Chief Executive Officer of Khondrion, said: “We are very pleased with the results from KHENERGY which reaffirm the positive profile of KH176 seen in earlier studies. While the study was exploratory in nature, we have seen early indications of the potential impact this medicine could have on the clinical symptoms of mitochondrial disease. Plans are now underway to progress towards pivotal studies to confirm a true treatment effect on mitochondrial disease-related symptoms.”

Mitochondria, the cell’s powerhouses, produce the energy necessary for life. Mitochondrial failure, due to either mutations in the mitochondrial genome or the nuclear DNA, is associated with a broad range of diseases, including orphan diseases of the oxidative phosphorylation system like Leigh disease, MELAS, MIDD and LHON syndromes as well as diseases like Parkinson’s Disease.

Patients with an m.3243A>G mutation in their mitochondrial genome show chronically progressive, often early fatal, multisystem disorders for which no clinically beneficial treatment is available.

Cellular consequences like abnormal mitochondrial architecture, reactive oxygen species production and alterations in the cellular redox-state are common findings in mitochondrial diseases. Khondrion’s drug development strategy is based on counteracting these cellular consequences to stop disease progression and to restore normal cellular function.

About the study

The KHENERGY study was a randomised, placebo-controlled single-center study to evaluate the tolerability, safety, and pharmacokinetics of KH176 in patients with m.3242A>G related mitochondrial disease and explore the effects of treatment with KH176 for 4 weeks on clinical signs and symptoms and biomarkers of mitochondrial disease. The data showed that twice daily oral 100mg KH176 was well tolerated and appeared safe.

About KH176

KH176 is an orally bio-available small molecule in development by Khondrion for the treatment of mitochondrial (-related) diseases. The compound is a member of a new class of potential Khondrion drugs essential for the control of oxidative and redox alterations. Preclinical studies in patient‐derived fibroblasts with a wide variability of genetic backgrounds showed that KH176 had a protective effect against redox perturbation in cells. In complex I deficient knockout mice (Ndufs4−/−), KH176 retained brain microstructural coherence in the external capsule in Ndufs4(−/−) mice and normalized the increased lipid peroxidation in this area and the cerebral cortex. Furthermore, KH176 treatment was able to significantly improve rotarod and gait performance and reduced the degeneration of retinal ganglion cells in Ndufs4(−/−) mice. A phase I clinical trial in healthy volunteers deemed that KH176 is well tolerated up to single doses of 800 mg and multiple doses of 400 mg. and had a pharmacokinetic profile supportive of a twice daily dosage. At blood concentrations >1,000 ng/ml, KH176 caused changes in cardiac electrophysiology, including prolonged QTc interval and changes in T‐wave morphology.

About Khondrion

Khondrion is an innovative clinical-stage pharmaceutical company, based in Netherland, focusing on developing small molecule therapeutics for mitochondrial (-related) diseases. The potential of several lead compounds to serve as new treatment modalities for mitochondrial disease is currently being explored. Khondrion’s KH176 has been granted Orphan Drug Designation (ODD) for Leigh disease and MELAS syndrome in Europe and for all inherited mitochondrial respiratory chain disorders in the USA. Thanks to its strategic partnership with the Radboud Center for Mitochondrial Medicine of the Radboud University Medical Center, Nijmegen, The Netherlands, Khondrion has access to all mitochondrial tools, technologies and expertise. Besides, Khondrion has established collaborations with patient organisations, patient advocacy groups and university research groups around the world as well as with small, medium and large enterprises. Khondrion is among others supported by the Dutch Foundations Energy4All, Join4Energy, Road4Energy, Ride4Kids, Tim Foundation, Zeldzame Ziekten Fonds, and National and European Governments. Khondrion has established a strong intellectual property position protecting its emerging product portfolio through the filing of multiple broad patent applications. For more information, please visit www.khondrion.com

Cautionary Note Regarding Forward-Looking Statements

This press release contains forward-looking statements. All statements, other than statements of historical facts, contained in this press release, including statements regarding our strategy, future operations, future financial position, future revenues, projected costs, prospects, plans and objectives of management, are forward-looking statements. The words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,” “target,” “potential,” “will,” “would,” “could,” “should,” “continue,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Khondrion. Risks and uncertainties include but are not limited to: challenges and uncertainties inherent in product development, including the uncertainties of clinical success and the timeline for the availability of KH176. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so, even if our views change.