Human Absorption, Distribution and Metabolism Study (hAME) [14C]-KD025

This is an open-label, 2-part study designed to assess the absolute bioavailability of belumosudil (KD025) and to determine the mass balance recovery, metabolite profile, and identification of metabolite structures for [14C]-KD025 in healthy male subjects.

Primary Objectives

• To determine the absolute oral bioavailability of KD025 (Part 1)
• To determine the mass balance recovery after a single oral dose of [14C]-KD025 (Part 2)
• To provide plasma, urine, and fecal samples for metabolite profiling and structural identification (Part 2)

Secondary Objectives

• To obtain information regarding the oral PK of total radioactivity, KD025 and its metabolites KD025m1 and KD025m2, in plasma
• To obtain information regarding the intravenous (IV) pharmacokinetics (PK) of [14C]-KD025 in plasma (Part 1)
• To determine the routes and rates of elimination of [14C]-KD025 and associated total radioactivity (Part 2)
• To evaluate the extent of distribution of total radioactivity into blood cells (Part 2)
• To assess the qualitative and quantitative metabolic profile of [14C]-KD025 and carry out the structural elucidation of the main metabolites in plasma (accounting for ≥ 10% of circulating total radioactivity) and in urine and fecal samples accounting for ≥ 10% of administered dose (Part 2)
• To provide additional safety and tolerability information for belumosudil

PART 1:

Part 1 is an open-label, non-randomized single oral dose followed by an IV microtracer assessment in 5 healthy male subjects. Subjects receive a single oral dose of belumosudil (KD025) 200 mg Tablet (Treatment A), in the fed state following a standard breakfast on the morning of Day 1. Subjects then receive an IV dose of 100 μg [14C]-KD025 (a 'microdose') containing not more than (NMT) 37 kBq (kilobecquerel; 1000 nanocurie [nCi]) [14C], as a 15 min IV infusion (Treatment B), beginning 1.75 hours (h) after the oral dose administration (Treatment A), i.e., 15 minutes [min] before the expected time of maximum concentration [Tmax] 2 h) for the oral dose.

Planned enrollment is to be 6 subjects to ensure 4 evaluable subjects. An evaluable subject for Part 1 will be defined as a subject who had sufficient data for evaluation of the primary oral bioavailability objective of the study.

All subjects are to undergo preliminary screening procedures to determine their eligibility for Part 1 and Part 2 at the screening visit (Day -28 to Day -2 of Part 1). Subjects are to be admitted to the clinical unit on the evening prior to investigational medicinal product (IMP) administration (Day -1 of Part 1) for confirmation of eligibility and baseline procedures. Subjects will be dosed on the morning following admission (Day 1 of Part 1). Following an overnight fast (approximately 10 h), subjects are to consume a standard breakfast and receive a single dose of Belumosudil 200 mg Tablet (Treatment A) 30 min after the start of breakfast. At 1 h 45 min (1.75 h) after Treatment A administration, subjects are to receive an IV infusion of [14C]-KD025 solution, 100 µg (Treatment B). Subjects are to remain resident in the clinic until up to 48 hours post-oral dose (up to Day 3). The minimum washout period between dose administrations in Part 1 and 2 is 7 days.

PART 2:

Part 2 is an open-label, non-randomized absorption, distribution, metabolism, and elimination (ADME) assessment in 5 healthy male subjects. Following a minimum washout period of 7 days, subjects who participated in Part 1 of the study are to be admitted to the clinical unit for participation in Part 2 of the study. Subjects are to receive a single oral administration of [14C]-KD025 200 mg Capsule containing NMT 9.8 MBq (266 µCi) [14C] (Treatment C) in the fed state following a standard breakfast on the morning of Day 1.

A subject in Part 2 will be considered evaluable if they had provided biological samples for up to 168 hours after drug administration or demonstrates >90% mass balance recovery, or < 1% of the administered dose eliminated in excreta for 2 consecutive days, whichever was sooner.

Approximately 7 days after subjects are discharged from Part 1 of the study, subjects are to be admitted to the clinical unit on the evening of the day prior to IMP administration (Day -1 of Part 2) for confirmation of eligibility and baseline procedures.

Subjects are to be dosed on the morning following admission (Day 1 of Part 2). Following an overnight fast (approximately 10 h), subjects consume a standard breakfast and receive a single dose of [14C]-KD025 200 mg Capsule (Treatment C) 30 min after the start of breakfast. Subjects are to remain in the clinic until up to 168 hours after dosing (up to Day 8 of Part 2). The plan is for subjects to be released as a group when all subjects had achieved a mass balance cumulative recovery of > 90% or if < 1% of the dose administered had been collected in urine and feces within 2 separate consecutive 24-hour periods. This may result in the subjects being discharged as a group prior to completion of the planned residency period. Once the discharge criteria or the planned residency period is achieved, the subjects are to undergo discharge assessments; collection of all samples (blood, urine and feces) is stopped.

If mass balance criteria has not been met by all subjects on Day 8, the residency period for the subjects not achieving the release criteria may be extended up to a maximum of 216 h post-dose (Day 10 of Part 2). During the additional residency period, only urine and/or feces are to be collected. If the criterion is still not met by Day 10, or if additional residency not considered appropriate or necessary, then home collections of urine and/or feces may be requested at the discretion of the Investigator for individual subjects. To ensure ongoing well-being of subjects, a follow-up phone call will take place 5 to 7 days post-discharge from the study or after the end of the last collection period.