A first-in-human study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of KM-819 (FAS-associated factor 1 inhibitor), a drug for Parkinson’s disease, in healthy volunteers

Abstract

Background

KM-819 is a novel FAS-associated factor 1 (FAF1) inhibitor, and a neuroprotective agent, under clinical development for the treatment of Parkinson’s disease as a disease-modifying drug.

Methods

This first-in-human, single and multiple ascending dose study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of KM-819 in healthy volunteers. Additionally, the effect of age on safety and pharmacokinetics were assessed. The starting dose was determined considering the no observed adverse effect level based on preclinical studies, and the dose escalations in subsequent cohorts were decided based on safety, tolerability, and pharmacokinetic data from previous dose cohorts.

Results

After a single dose, the KM-819 plasma exposure showed a less than dose-proportional increase across a dose range of 10–400 mg. After repeated dosing, KM-819 plasma exposure increased in an approximately dose-proportional manner across the evaluated dose range (30–400 mg once daily for 7 days). The mean elimination half-life was 1.8 to 4.8 h with the lower KM-819 doses (≤30 mg), which increased to around 9 h with the higher doses (100–400 mg). When administered to the elderly population, KM-819 plasma exposure increased to 102% after a 200 mg once-daily dosing for 7 days. No clear treatment-related effects on the estimated pharmacodynamic variables were observed. Single or multiple doses of KM-819 were generally well tolerated.

Conclusion

The data from this study can be used to guide rational drug dosing and choose therapeutic regimens in subsequent clinical studies.

Keywords:

• first-in-human
• KM-819
• pharmacokinetics
• pharmacodynamics
• safety

Data availability

The raw data of this study will not be shared because of confidentiality.

Acknowledgments

This study was funded by Kainos Medicine, Inc., Seongnam, Republic of Korea and supported by a grant of the Korea Health Technology R & D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant no: HI14C2750).

The abstract of this paper was presented at the 2018 Annual Meeting of American Society for Clinical Pharmacology and Therapeutics as a poster presentation with interim findings. The poster’s abstract was published in “Poster Abstracts” in Clinical Pharmacology and Therapeutics.

Author contributions

All authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

S Yoo, YT Chung, and JM Lee are the employees of Kainos Medicine Inc. J Hong, S Jhee and J Kim are the employees of PAREXEL, which performed work for this study under contract to Kainos Medicine Inc. The other authors report no conflicts of interest related to this work.

Supplementary materials

Table S1 Inclusion and exclusion criteria for KM-819 first-in-human study

Table S2 Summary of change from baseline (day 1 predose) to day 7 for PD parameters