A Phase I Study to Evaluate the Taste of Belumosudil Oral Suspensions & Assess Relative Bioavailability

A 2-Part, Phase I Study to Evaluate the Taste Profile of Belumosudil Oral Suspensions & Assess Relative Bioavailability of the Selected Belumosudil Oral Suspension Formulation Compared With Oral Tablets in Healthy Male Subjects

This is a single-center, randomized, open-label, 2-part study in healthy male subjects to evaluate the taste profile of different belumosudil oral suspensions and the relative bioavailability of those chosen oral suspensions of belumosudil compared to oral tablets of belumosudil.

Part 1 is an open-label, randomized single-period study of oral suspensions of belumosudil 40 mg/mL delivered in 6 different vehicles. Approximately 12 healthy male subjects, 2 subjects in each of 6 groups, will be administered a single dose of belumosudil 40 mg/mL in 6 different vehicles (Vehicles 1, 2, 3, 4, 5, and 6) in corresponding Regimens A, B, C, D, E, and F in different sequences of the 6 vehicles. All subjects will receive 1 dose of all belumosudil in all 6 vehicles which are as follows: ABFCED; BCADFE; CDBEAF; DECFBA; EFDACB; and FAEBDC.

Part 2 is a single-center, open-label, randomized, 3-period design to assess the relative bioavailability of a selected belumosudil suspension formulation compared to the oral belumosudil. Tablet reference and the effect of food on the selected belumosudil suspension formulation in 18 healthy male subjects. Subjects will be randomized prior to the administration of the first dose of IMP to 1 of 6 treatment sequences (GHI, HIG, IGH, IHG, GIH and HGI), with 3 subjects assigned to each treatment sequence where:

Regimen G--oral belumosudil 200 mg tablet (reference) with the subject fed; Regimen H--belumosudil powder 200 mg for oral suspension or belumosudil 200 mg oral suspension with the subject fasting; and Regimen I--belumosudil 200 mg powder for oral suspension or belumosudil 200 mg oral suspension with the subject fed.

PART 1

This is a single center, open-label, randomized, single period design to assess the taste profile of different novel regimens from bottles containing 1200 mg of belumosudil. Twelve healthy subjects will receive single doses of the 6 bottled oral formulations:

Regimen A: belumosudil 40 mg/mL delivered by Vehicle 1 (sterile water for irrigation); Regimen B: belumosudil 40 mg/mL delivered by Vehicle 2 (low sucralose solution); Regimen C: belumosudil 40 mg/mL delivered by Vehicle 3 (high sucralose solution); Regimen D: belumosudil 40 mg/mL delivered by Vehicle 4 (orange flavor with low sucralose solution); Regimen E: belumosudil 40 mg/mL delivered by Vehicle 5 (tropical fruit blend with low sucralose solution); Regimen F: belumosudil 40 mg/mL delivered by Vehicle 6 (lemon flavor with low sucralose solution)

Subjects will sip the belumosudil oral suspension and then spit it out. The maximum dose is belumosudil 200 mg.

On Day 1, two subjects each will be randomized to 1 of 6 treatment sequences with belumosudil:

ABFCED (2 subjects); BCADFE (2 subjects); CDBEAF (2 subjects); DECFBA (2 subjects); EFDACB (2 subjects); FAEBDC (2 subjects)

Subjects will undergo preliminary screening procedures to determine their eligibility for Part 1 of the study at a screening visit (Day -28 to Day -2 of Part 1). Subjects will be admitted to the clinical unit on the morning prior to investigational medicinal product (IMP) administration (Day -1) for confirmation of eligibility and baseline procedures. Prior to the first administration of IMP (either Day -1 or prior to the completion of breakfast [pre-dose] on Day 1), subjects will be given a training questionnaire using an example fluid (e.g., orange juice/squash).

In the evening of Day -1, subjects will receive a light snack and will then fast from all food and drink (except water). Following the overnight fast (approximately 8 hours), subjects will consume a standard breakfast. Following breakfast, subjects will brush their teeth using tap water (toothpaste will not be permitted). The first dose of IMP will be administered approximately 2 hours after breakfast has been completed.

Subjects will receive the test belumosudil from bottles in regimens according to a randomization schedule. Each regimen will follow the same study design. Subjects will receive a single dose of belumosudil 40 mg/mL as an oral suspension, which will be held in the mouth for approximately 1 minute before it is expectorated, and will subsequently complete a written taste/palatability questionnaire individually and privately. No belumosudil is to be consumed.

There will be a washout period of 30 min ± 10 min (minimum 20 min) between tasting each regimen (inclusive of palate cleansing). During this time, subjects will cleanse their palates using tap water (administered freely in 50 mL aliquots) and unsalted crackers before further tasting. It is expected that all regimens will be tasted on the same day.

A single plasma pharmacokinetic (PK) sample will be taken approximately 1 hour post-final dose (prior to discharge from the clinical unit). This sample will be retained and only analyzed in case of accidental swallowing of the formulation by a subject and/or for the purpose of investigating a possible treatment-emergent adverse event (TEAE) related to the IMP.

Subjects will remain on site until 1 hour post-final taste/palatability assessment. To ensure the ongoing well-being of the subjects, a follow-up phone call will take place 3 to 7 days after the final dose. If a subject reports any adverse events (AEs) after discharge which is a cause for concern, they will be required to attend the clinical unit for a follow-up assessment. This follow-up visit will be considered an unscheduled visit.

Following the completion of Part 1, an interim data review will be performed during which the taste/palatability assessment data will be reviewed to determine the flavor system that will be incorporated into the IMP formulation for administration in Part 2.

PART 2

This is a single-center, open-label, randomized, 3-period design to assess the relative bioavailability of a selected belumosudil suspension formulation from Part 1 compared to the belumosudil oral tablet. Eighteen subjects will receive single doses of the following:

Regimen G = 200 mg belumosudil tablet (reference drug) orally when subjects are fed; Regimen H = 200 mg belumosudil powder for oral suspension or belumosudil oral suspension when subjects are fasting; and Regimen I = 200 mg belumosudil powder for oral suspension or belumosudil oral suspension when subjects are fed.

On Day 1, three subjects each will be randomized to 1 of 6 treatment sequences with belumosudil:

GHI (3 subjects); HIG (3 subjects); IGH (3 subjects); IHG (3 subjects); GIH (3 subjects); HGI (3 subjects)

Subjects will undergo preliminary screening procedures to determine their eligibility for Part 2 of the study at a screening visit (Day -28 to Day -2 of Part 2). Subjects who have taken part in Part 1 of the study are permitted to take part in Part 2.

Each study period will follow a similar design. Subjects will be admitted to the clinical unit on the morning prior to the first IMP administration (Day -1 of Period 1) for confirmation of eligibility and baseline procedures. For Regimen H only, subjects will be given a training questionnaire using an example fluid (e.g., orange juice/squash) prior to IMP administration. This will be performed either on Day -1 (only applicable if Regimen H is administered in Period 2 or 3) or prior to the completion of breakfast (pre-dose) on Day 1.

Subjects will receive a single dose of IMP in the morning of Day 1 following an overnight fast of a minimum of 10 hours (Regimen H, fasted state) or following a standard breakfast (Regimens G and I, fed state). Blood samples will be collected at regular intervals for PK analysis. Following administration of Regimen H, subjects will complete a written taste/palatability questionnaire individually and privately.

Subjects will reside in the clinical unit for 10 consecutive nights that will cover all 3 treatment periods. All subjects will remain on site until 72 h post-final dose for safety and PK assessments. There will be a minimum washout period of 3 days between each IMP administration. To ensure the ongoing well-being of the subjects, a follow-up phone call will take place 3 to 7 days after the final dose. If a subject reports any AEs after discharge which is a cause for concern, they will be required to attend the clinical unit for a follow-up assessment. This follow-up visit will be considered an unscheduled visit.

Inclusion Criteria:

1. Healthy males
2. Aged 18 to 55 years inclusive at the time of signing informed consent.
3. Body mass index of 18.0 to 32.0 kg/m^2 at screening
4. Body weight ≥ 50 kg at screening
5. Must be willing and able to communicate and participate in the entire study
6. Must provide written informed consent
7. Must agree to adhere to the contraception requirements

Exclusion Criteria:

1. Subjects who have received any IMP in a previous clinical research study within the 90 days prior to Day 1 (Part 2 only)

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

3. Subjects who have previously been administered IMP in Part 2 of this study. Subjects who have taken part in Part 1 are permitted to take part in Part 2

4. Evidence of current SARS-CoV-2 infection

5. Clinically significant history or presence of acute or chronic bacterial, fungal, or viral infection (e.g., pneumonia, septicemia) within the 3 months or 90 days prior to screening

6. Any subject with clinically significant symptoms of COVID-19 in the last 4 weeks, including but not limited to fever, new and persistent cough, breathlessness or loss of taste or smell, as per the judgement of the investigator

7. Known or suspected malignancy, autoimmune disorder, or any history of known or suspected congenital or acquired immunodeficiency state or condition that would compromise the participant's immune status or any factor that would predispose participants to develop infection (e.g., open skin lesions, recurrent issues related to poor dentition, perianal fissures, history of splenectomy, primary immunodeficiency)

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

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

10. A confirmed positive alcohol breath test at screening or admission

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

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

13. Subjects with pregnant or lactating partners

14. Subjects who do not have suitable veins for multiple venipunctures/cannulation as assessed by the investigator or delegate at screening

15. Clinically significant abnormal clinical chemistry, hematology or urinalysis as judged by the investigator. Subjects with Gilbert's Syndrome are allowed.

16. Confirmed positive drugs of abuse test result.

17. Positive hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency virus antibody results

18. Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance (CLcr) of < 80 mL/min using the Cockcroft-Gault equation (Part 2 only)

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

20. Subject has a history or presence of any of the following (Part 2 only):

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

21. Subjects with a history of cholecystectomy or gall stones (Part 2 only)

22. Subject has QTcF intervals >450 msec at screening or admission (Part 2 only)

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

24. Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active

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

26. Subjects who are taking or have taken any prescribed or over-the-counter drug or herbal remedies (other than up to 4 g of paracetamol per day) in the 14 days prior to IMP administration, including proton pump inhibitors. Exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as determined by the investigator.

27. Failure to satisfy the investigator of fitness to participate for any other reason