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

Open-label, 2-part Study Designated to Assess the Absolute Bioavailability of KD025 and to Determine the Mass Balance Recovery, Metabolite Profile and Identification of Metabolite Structures for [14C]-KD025 in Healthy Male Subjects

Human, absorption, metabolism and excretion study of belumosudil (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.

Inclusion Criteria:

1. Healthy males
2. Good state of health (mentally and physically) as indicated by a comprehensive clinical assessment (detailed medical history and a complete physical examination), electrocardiogram (ECG) and laboratory investigations (hematology, clinical chemistry and urinalysis)
3. Body weight ≥ 50 kg
4. Body mass index (BMI) of 18.0 to 35.0 kg/m^2
5. Must be willing and able to communicate and participate in the whole study
6. Must have regular bowel movements (i.e., average stool production of ≥ 1 and ≤ 3 stools per day)
7. Subjects must have participated in Part 1 in order to be eligible for Part 2
8. Must provide written informed consent
9. Must agree to adhere to the contraception requirements of the study

In addition to the above criteria, subjects must agree to the following restrictions:

• No alcohol during the 24 hours prior to screening and the 24-hour prior to each admission until discharge from each part of the study.
• No food or drinks containing grapefruit, cranberry, caffeine or other xanthines from 24 hours prior to each admission until discharge from each part of the study.
• No food containing poppy seeds for 48 hours prior to screening and for 48 hours prior to each admission until discharge from each part of the study.
• No unaccustomed strenuous exercise from the 72-hour period before the screening visit and then from 72 hours prior to each admission until discharge from each part of the study.

Exclusion Criteria:

1. Subjects who previously participated in any other investigational study drug trial in which receipt of an investigational study drug occurred within 90 days prior to dosing

2. Subjects who have previously participated in a study where subjects were dosed with belumosudil

3. Subjects who are study site employees or immediate family members of a study site or sponsor employee

4. Subjects with pregnant partners

5. History of any drug or alcohol abuse in the past 2 years

6. Regular alcohol consumption in males > 21 units per week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 Units = 125 mL glass of wine, depending on type)

7. Current smokers and those who have smoked within the last 12 months. A breath carbon monoxide reading of greater than 10 ppm at screening and admission

8. Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months

9. Radiation exposure, including that from the present study, excluding background radiation but including diagnostic x-rays and other medical exposures, exceeding 5 mSv in the last 12 months or 10 mSv in the last 5 years. No occupationally exposed worker, as defined in the Ionizing Radiation Regulations 2017.

10. Subjects who have been enrolled in an ADME/IV microtracer study in the last 12 months

11. Subjects who do not have suitable veins for multiple venepunctures/cannulation

12. Clinically significant abnormal biochemistry, hematology or urinalysis. Subjects with blood platelet count, hemoglobin and red blood cells lower than the reference range

13. Confirmed positive drugs of abuse test result

14. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab), or human immunodeficiency virus (HIV) results

15. Evidence of renal impairment at screening as indicated by an estimated creatinine clearance of < 80 mL/min using the Cockcroft-Gault equation

16. History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal (GI) disease, neurological or psychiatric disorder, as judged by the Investigator

17. Subject has a history or presence of any of the following:

    • Active GI disease requiring therapy
    • Hepatic disease and/or alanine aminotransaminase or aspartate aminotransaminase > upper limit of normal (ULN)
    • Renal disease and/or serum creatinine > upper limit of normal (ULN)
    • Other condition known to interfere with the absorption, distribution, metabolism or excretion of drugs

18. Subject has QT interval corrected using Fridericia's formula (QTcF) intervals > 450 msec at screening or admission

19. Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients

20. Presence or history of clinically significant allergy requiring treatment

21. Donation or loss of greater than 400 mL of blood within the previous 3 months

22. Subjects who are taking, or have taken, any prescribed or over-the-counter drug or herbal remedies in the 14 days before study drug administration.

23. Failure to satisfy the Investigator of fitness to participate for any other reason