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

Overview

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.