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

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

Abstract

Background: Mitochondrial 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.

Results: KH176 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.

Conclusion: The 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 registration: NCT02544217 . Registered. ISRCTN43372293 . Retrospectively registered.

Keywords: Clinical trial phase 1; KH176; Mitochondrial disorder; Mitochondrial medicine; Orphan drugs; Pharmacokinetics; Randomized controlled trial; Rare disease; Redox; Safety.

Conflict of interest statement

Ethics approval and consent to participate

All studies were conducted at the Drug Research Unit Ghent in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines established by the International Conference on Harmonization (ICH). This protocol was approved by the local medical ethics committee (University Hospital of Ghent). All participants have signed informed consent prior to their enrolment.

This trial has been posted on clinicaltrials.gov prior to the conduction of the study (NCT02544217).

Consent for publication

Not applicable.

Competing interests

SK has no competing interests. FB is the founding CEO of AMPS. Jan Smeitink is the founding CEO of Khondrion BV.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Study design. a. SAD study. D = Dose; SD = Single dose; FU = follow-up. * Each dose was followed by an interim safety and 24-h PK evaluation, which determined the dose selection for the next dose. A washout period of at least 4 days had to be taken into account.b. MAD study. Gr = group; D = Dose; FU = follow-up * Each dose was followed by an interim 7-days safety and PK evaluation, which determined the dose selection for the next dose
Fig. 2
Fig. 2
Mean plasma concentrations of KH176 and its metabolite KH176m after single and multiple dose administration to healthy subjects. a. Plasma-concentration/time curve of KH176 for the SAD study (fasted state). b. Plasma-concentration/time curve of KH176m for the SAD study (fasted state). c. Plasma-concentration/time curve of KH176 for the MAD study. d. Plasma-concentration/time curve of KH176m for the MAD study. Loglinear scale
Fig. 3
Fig. 3
Dose-normalized individual values for Cmax and AUC0-inf of KH176 for the SAD and the MAD study. a. Dose normalized Cmax for the SAD study. b. Dose normalized AUC0-inf for the SAD study. c. Dose normalized Cmax for the MAD study. d. Dose normalized AUC0-inf for the MAD study. The horizontal lines depict the geometric mean value
Fig. 4
Fig. 4
Exposure-response analysis of KH176 plasma concentrations and a change from baseline for ECG derived TpTe intervals. The upper limit of normal (23.4 ms) is derived from the 95% confidence interval of the pre-dose values. In healthy subjects a dose of 100 mg BID resulted in maximum concentrations ranging from 303 to 458 ng/mL

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