KH176 under development for rare mitochondrial disease: a first in man randomized controlled clinical trial in healthy male volunteers

Saskia Koene,Jan Smeitink,Fabio Badilini,Edwin Spaans,Griet Van Lancker,Luc Van Bortel,Julien Beyrath,Brant Delafontaine

doi:10.1186/s13023-017-0715-0

Abstract

BackgroundMitochondrial disorders are a clinically, biochemically and genetically heterogeneous group of multi-system diseases, with an unmet medical need for treatment. KH176 is an orally bio-available small molecule under development for the treatment of mitochondrial(−related) diseases. The compound is a member of a new class of drugs, acting as a potent intracellular redox-modulating agent essential for the control of oxidative and redox pathologies. The aim of this randomized, placebo controlled, double-blinded phase 1 study was to test safety, tolerability and pharmacokinetics of single and multiple doses of KH176 in healthy male volunteers. Putative effects on redox related biomarkers were explored.ResultsKH176 was well tolerated up to and including a single dose of 800 mg and multiple doses of 400 mg b.i.d. for 7 Days. However, when the QT interval was corrected for heart rate, administration of single doses of 800 and 2000 mg and at a multiple dose of 400 mg KH176 had marked effects. Post-hoc analysis of the ECGs showed clear changes in cardiac electrophysiology at single doses of 800 and 2000 mg and multiple doses of 400 mg b.i.d.. At lower doses, detailed ECG analysis showed no changes in electrophysiology compared to placebo. Exposure-response modelling of the cardiac intervals revealed an exposure range of KH176 without effects on cardiac conduction and provided a threshold of 1000 ng/mL above which changes in intervals could occur. After single- and multiple-dose administration, the pharmacokinetics of KH176 was more than dose proportional. KH176 accumulated to a small extent and food only slightly affected the pharmacokinetics of KH176, which was considered clinically irrelevant. Renal excretion of unchanged KH176 and its metabolite represents a minor pathway in the elimination of KH176. As expected in healthy volunteers no effects on redox biomarkers were observed.ConclusionThe study deemed that KH176 is well tolerated up to single doses of 800 mg and multiple doses of 400 mg b.i.d. and has a pharmacokinetic profile supportive for a twice daily dosing. Only at high doses, KH176 causes clinically relevant changes in cardiac electrophysiology, including prolonged QTc interval and changes in T wave morphology. A Phase 2 clinical trial (100 mg b.i.d., orally) has been conducted recently of which the final results are expected Q1 2018.Trial registrationNCT02544217. Registered. ISRCTN43372293. Retrospectively registered.

Highlights

Mitochondrial disorders are a clinically, biochemically and genetically heterogeneous group of multisystem diseases, with an unmet medical need for treatment
Many treatment strategies have been attempted, including gene therapy, exercise and nutritional therapy, modulation of cell signalling and the manipulation of reactive oxygen species [5,6,7]. The latter has been subject of many studies and clinical trials [8, 9], since it has been recognised that cell redox imbalance play a key role in the pathogenesis of many of the clinical manifestations of mitochondrial diseases [5, 10,11,12]
This study aims to test the safety, tolerability and pharmacokinetics of KH176 in human subjects after oral administration of a single dose (SD) as well as multiple doses (MD), to obtain a safe and putatively efficacious dosing regimen of KH176 for a Proof of Concept study

Summary

Introduction

Mitochondrial disorders are a clinically, biochemically and genetically heterogeneous group of multisystem diseases, with an unmet medical need for treatment. Over 1150 genes have been identified to encode for proteins located in the mitochondria [1] Mutations in these genes, like those involved in oxidative phosphorylation, can cause mitochondrial disease. Many treatment strategies have been attempted, including gene therapy, exercise and nutritional therapy, modulation of cell signalling and the manipulation of reactive oxygen species [5,6,7] The latter has been subject of many studies and clinical trials [8, 9], since it has been recognised that cell redox imbalance play a key role in the pathogenesis of many of the clinical manifestations of mitochondrial diseases [5, 10,11,12]

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