Bioavailability of Belumosudil (KD025) in Healthy Male Subjects

A 3-way, Crossover, Randomized, Open-label Study in Healthy Subjects Comparing the Bioavailability of Belumosudil (KD025) Tablets in Fed and Fasted States and Relative Bioavailability of Tablets and Capsules in the Fed State

Phase 1 bioavailability study to evaluate the pharmacokinetics (PK) and tolerability/safety of the belumosudil tablet formulation in the fasted and fed states and compared to the belumosudil capsule formulation in the fed state.

This is a Phase 1, 3-way, crossover, randomized, open-label study in healthy subjects designed to compare the bioavailability of belumosudil (previously known as KD025) tablet formulation administered in the fed and fasted states and to assess the relative bioavailability of belumosudil tablet and capsule formulations in the fed state.

The primary objective of the study is to determine the PK parameters of belumosudil tablet formulation in the fed and fasted states.

The secondary objectives of the study are: (1) to assess the relative bioavailability of a tablet (test) to capsule (reference formulation of belumosudil; (2) to assess and compare the variability in the maximum concentration (Cmax) and area under the concentration-time curve (AUC) for belumosudil treatments (belumosudil 200 mg tablet in the fasting state, belumosudil 200 mg tablet in the fed state, and belumosudil as two 100 mg capsules in the fed state); and (3) to provide additional safety and tolerability information for belumosudil.

This is a single-center, open-label, randomized, single-dose, 3-period, 3-way, crossover study in healthy subjects.

In each of 3 study periods, each subject receives 1 of the following single-dose treatments:

• Regimen A: Belumosudil 200 mg tablet in the fasted state
• Regimen B: Belumosudil 200 mg tablet in the fed state
• Regimen C: Belumosudil 200 mg as two 100-mg capsules in the fed state

Subjects are randomized to receive 1 dose of investigational product (IP; belumosudil tablet or capsule) in the morning of Day 1 in a randomized manner following an overnight fast or a high-fat breakfast. Administration is performed on Day 1 with an appropriate interval between subjects based on logistical requirements. Start time is determined based on logistics.

Subjects undergo a screening visit in the 21 days preceding first dose. Subjects are admitted to the clinical unit on the evening prior to dosing (Day -1), remain on site until 24 hours post-dose, and return to the clinic at 36 and 48 hours post-dose for PK assessments.

There is a minimum washout period of 6 days between each dose administration. All other meals are standardized for each of the in-clinic phases of the 3 treatment periods. Each period follows the same study design.

The randomized cohorts for the 3-periods were as follows:

• Cohort ABC: Regimen A (Period 1); Regimen B (Period 2); Regimen C (Period 3)
• Cohort BCA: Regimen B (Period 1); Regimen C (Period 2); Regimen A (Period 3)
• Cohort CAB: Regimen C (Period 1); Regimen A (Period 2); Regimen B (Period 3)

A follow-up call is made 3 to 5 days after the final dose of IP.

Planned enrollment is 24 subjects to insure there are 20 evaluable subjects. A subject is considered evaluable if (s)he completes treatment with fasted and fed tablet formulations (Regimens A and B) without major protocol deviations.

Inclusion Criteria:

To be eligible for study entry subjects has to satisfy all of the following criteria:

1. Healthy males
2. Aged 18 to 55 years of age
3. Good state of health (mentally and physically) as indicated by a comprehensive clinical assessment (detailed medical history and a complete physical examination), ECG, and laboratory investigations (hematology, coagulation, clinical chemistry and urinalysis)
4. Body mass index 18.0-30.0 kg/m^2, or if outside the range, considered not clinically significant by the Investigator
5. Willing and able to communicate and participate in the whole study
6. Provide written informed consent
7. Agree to use an adequate method of contraception for up to 90 days post discharge

Exclusion Criteria

Subjects are excluded from the study if one of more of the following statements is applicable:

1. Participated in a clinical research study within the previous 3 months

2. Study site employees, or immediate family members of a study site or sponsor employee

3. Had been previously enrolled in this study

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

5. Regular alcohol consumption > 21 units per week (1 unit = ½ pint beer, 25 mL of 40% spirit or a 125 mL glass of wine)

6. Current smokers and those who had smoked within the last 12 months. A breath carbon monoxide (CO) reading of greater than 10 ppm at screening

7. Did not have suitable veins for multiple venepunctures/cannulation as assessed by the Investigator at screening

8. Clinically significant abnormal biochemistry, hematology, coagulation, or urinalysis as judged by the Investigator

9. Positive drugs of abuse test result or alcohol breath test

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

11. History of any clinically significant cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal (GI) disease that may have compromised the subject's safety or interfered with the objectives of the study as judged by the investigator

12. Subject had a history or presence of any of the following:

    • Active GI disease requiring therapy
    • Hepatic disease and/or alanine aminotransaminase (ALT) or aspartate aminotransaminase (AST) > 1.5 × upper limit of normal (ULN) at screening
    • Renal disease and/or serum creatinine > 1.5 × ULN at screening
    • Other condition known to interfere with the absorption, distribution, metabolism or excretion of drugs

13. QT interval corrected using Fridericia's formula (QTcF) > 450 msec at the screening or admission ECG

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

15. Known sensitivity to ROCK2 inhibitor agents or to any of the constituents of the belumosudil formulation

16. Presence or history of clinically significant allergy requiring treatment, as judged by the Investigator. Hayfever is permitted unless it is active.

17. Donation or loss of > 400 mL of blood within the previous 3 months

18. Taking or had taken any prescribed or over-the-counter drug (other than 4 g per day paracetamol) or herbal remedies in the 14 days before IP administration

19. Fails to satisfy the Investigator's discretion of fitness to participate or for any other reason

Additional Restrictions

1. Abstain from alcohol during the 24 h prior to each admission until discharge from the clinic in each study period
2. Not to drink liquids or eat food containing grapefruit, cranberry, caffeine, or other xanthines from 24 hours prior to each admission until 48 hours post-dose
3. Refrain from eating food containing any seeds (e.g., poppy) for 48 hours before the screening visit and then from 48 h prior to each admission until discharge from the clinic for each study period
4. Not to take part in any unaccustomed strenuous exercise from 72 hours prior to the screening visit and then from 72 hours prior to admission until discharge from the study