Bioavailability of Belumosudil (KD025) in Healthy Male Subjects

• Sponsor: Kadmon Corporation, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02557139
• Collaborator: Quotient Clinical (Other)
• Enrollment: 23
• Location: 1
• Arms: 3
• Duration (Months): 1.3
• Patients Per Site Per Month: 17.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Bioavailability	Drug: Belumosudil Tablet; Drug: Belumosudil Capsule	Phase 1

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: 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
• Study Start Date: Sep 1, 2015
• Actual Primary Completion Date: Oct 12, 2015
• Actual Study Completion Date: Oct 12, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Regimen A Single-dose belumosudil 200 mg tablet in the fasted state	Drug: Belumosudil Tablet; Other Names: Rezurock (brand) SLx-2119
Experimental: Regimen B Single-dose belumosudil 200 mg tablet in the fed state	Drug: Belumosudil Tablet; Other Names: Rezurock (brand) SLx-2119
Experimental: Regimen C Single-dose belumosudil capsules (administered as two 100-mg capsules) in the fed state	Drug: Belumosudil Capsule; Other Names: Rezurock (brand) SLx-2119

Outcome Measures

Primary Outcome Measures

1. Pharmacokinetics: Cmax of Dosing Regimen A (Tablets--Fasting) vs. Dosing Regimen B (Tablets--Fed) for KD025, KD025m1, and KD025m2 at 48 Hours Post-dose [Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose]

   Maximum concentration (Cmax) of parent drug (KD025), Metabolite 1 (KD025m1), and Metabolite 2 (KD025m2) when administering a single dose of belumosudil 200 mg tablet to subjects who are fasting (Regimen A) compared to administering a single dose of belumosudil 200 mg tablet to subjects who are fed (Regimen B) at 48 hours after dosing

2. Pharmacokinetics: AUCs of Dosing Regimen A (Tablets--Fasting) vs. Dosing Regimen B (Tablets--Fed) for KD025, KD025m1, and KD025m2 at 48 Hours Post-dose [Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose]

   Area under concentration-time curve from zero to last dose of belumosudil 200 mg tablets (AUC[0-last]) and from zero to infinity (AUC[0-inf]) for Metabolite 1 (KD025m1), and Metabolite 2 (KD025m2) when administering a single dose of belumosudil 200 mg tablet to subjects who are fasting (Regimen A) compared to administering a single dose of belumosudil 200 mg tablet to subjects who are fed (Regimen B) at 48 hours after dosing

Secondary Outcome Measures

1. Pharmacokinetics: Cmax for the Relative Bioavailability of Regimen B/Regimen A and Regimen B/Regimen C by Ratio of the Adjusted Geometric Means at 48 Hours Post-dose [Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose]

   Analysis of the maximum concentration (Cmax) of the relative bioavailability of Regimen B (belumosudil 200 mg tablet-fed) vs. Regimen A (belumosudil 200 mg tablet-fasting) and for Regimen B vs. Regimen C (belumosudil 200 mg capsule-fed) utilizing the Ratio of the Adjusted Geometric Means at 48 hours after dosing

2. Pharmacokinetics: AUCs for the Relative Bioavailability of Regimen B/Regimen A and Regimen B/Regimen C by Ratio of the Adjusted Geometric Means at 48 Hours Post-dose [Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose]

   Analysis of the area under concentration-time curve for zero to infinity (AUC[0-inf]), and zero to last dose (AUC[0-last]) of the relative bioavailability of Regimen B (belumosudil 200 mg tablet-fed) vs. Regimen A (belumosudil 200 mg tablet-fasting) and for Regimen B vs. Regimen C (belumosudil 200 mg capsule-fed) utilizing the Ratio of the Adjusted Geometric Means at 48 hours after dosing

3. Pharmacokinetics: Cmax of Dosing Regimen A (Tablets--Fasting) vs. Dosing Regimen B (Tablets--Fed) vs. Dosing Regimen C (Capsules--Fed) for KD025, KD025m1, and KD025m2 at 48 Hours Post-dose [Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose]

   Maximum concentration (Cmax) of parent drug (KD025), Metabolite 1 (KD025m1), and Metabolite 2 (KD025m2) when administering a single dose of belumosudil 200 mg tablet to subjects who are fasting (Regimen A) compared to administering a single dose of belumosudil 200 mg tablet to subjects who are fed (Regimen B) compared to a single dose of belumosudil 200 mg capsule (two 100-mg capsules) to subjects who are fed (Regimen C) at 48 hours after dosing

4. Pharmacokinetics: AUCs of Regimen A (Tablet--Fasting) vs. Dosing Regimen B (Tablet--Fed) vs. Dosing Regimen C (Capsule--Fed) for KD025, KD025m1, and KD025m2 for Belumosudil 200 mg at 48 Hours Post-dose [Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose]

   Area under concentration curve from zero to last dose (AUC[0-last]) and from zero to infinity (AUC[0-inf]) for parent drug (KD025), Metabolite 1 (KD025m1), and Metabolite 2 (KD025m2) when administering a single dose of belumosudil 200 mg tablet to subjects who are fasting (Regimen A) compared to administering a single dose of belumosudil 200 mg tablet to subjects who are fed (Regimen B) compared to administering a single dose of 200 mg capsule (two 100-mg capsules) to subjects who are fed at 48 hours after dosing

5. Pharmacokinetics: Lambda-z for Regimens A, B, and C for KD025, KD025m1, and KD025m2 at 48 Hours Post-dose [Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose]

   Slope of the regression line passing through the apparent elimination phase in a concentration-time plot (Lambda-z) for Regimen A, Regimen B, and Regimen C for for the parent drug (KD025), Metabolite 1 (KD025m1), and Metabolite 2 (KD025m2) at 48 hours after dosing

6. Pharmacokinetics: t(1/2), MRT(0-last), and MRT(0-inf) for Regimens A, B, and C for KD025, KD025m1, and KD025m2 at 48 Hours Post-dose [Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose]

   Apparent elimination half-life (t[1/2]), mean residence time from zero to last dose (MRT[0-last]), and MRT for zero to infinity (MRT[0-inf]) for Regimen A, Regimen B, and Regimen C for for the parent drug (KD025), Metabolite 1 (KD025m1), and Metabolite 2 (KD025m2) at 48 hours after dosing

7. Safety: Number of Subjects With TEAEs and SAEs [Approximately 1 month]

   Number of subjects with treatment-emergent adverse events (TEAEs), severity and relationship to belumosudil, serious adverse events (SAEs), TEAEs leading to withdrawal from study, and deaths. Treatment-emergent adverse events (TEAEs) are AEs that are not present before the first dose of IMP or that are present before the first dose of IMP but worsen in intensity during exposure to IMP. Severity: mild = 1; moderate = 2; severe = 3; life-threatening = 4; and death = 5. Related to belumosudil defined as possibly related, probably related, and related.

8. Safety: Total Number of Participants With TEAEs, Related TEAEs, Leading to Withdrawal, Severe, Serious, Leading to Death [Approximately 1 month]

   Total number of subjects who had treatment-emergent adverse events (TEAEs), TEAEs related to belumosudil, TEAEs leading to withdrawal of subject, severe TEAEs, serious TEAE (SAE), and TEAEs leading to death. Treatment-emergent adverse events (TEAEs) are AEs that are not present before the first dose of IMP or that are present before the first dose of IMP but worsen in intensity during exposure to IMP. Severity: mild = 1; moderate = 2; severe = 3; life-threatening = 4; and death = 5. Related to belumosudil defined as possibly related, probably related, and related.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

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

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

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

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

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

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

6. 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

7. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Quotient Clinical Limited	Ruddington Nottingham		United Kingdom	NG116JS

Sponsors and Collaborators

• Kadmon Corporation, LLC
• Quotient Clinical

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

• Schueller O, McDermott J, Evans P, Lohmer L, Alabanza A, Patel J. Phase 1 Studies to Evaluate the Food Effect and Relative Bioavailability of Tablet and Capsule Formulations of Belumosudil in Healthy Adult Subjects. Clin Pharmacol Drug Dev. 2022 Jul;11(7):807-814. doi: 10.1002/cpdd.1083. Epub 2022 Mar 2.

• Responsible Party: Kadmon Corporation, LLC
• ClinicalTrials.gov Identifier: NCT02557139
• Other Study ID Numbers: KD025-106; 2015-002832-42
• First Posted: Sep 23, 2015
• Last Update Posted: May 25, 2022
• Last Verified: May 1, 2022

• Additional relevant MeSH terms: Belumosudil

Study Results

Participant Flow

Recruitment Details	Enrollment: 23 subjects

Arm/Group Title	Cohort ABC	Cohort BCA	Cohort CAB
Arm/Group Description	Period 1: Single-dose Belumosudil 200 mg tablet fasted (Regimen A); Washout; Period 2: Single-dose Belumosudil 200 mg tablet fed (Regimen B); Washout; Period 3: Single-dose Belumosudil two 100-mg capsules, i.e., 200 mg (Regimen C)	Period 1: Belumosudil 200 mg tablet fed; Washout; Period 2: Belumosudil 200 mg by capsule, i.e., two 100-mg capsules fed; Washout; Period 3: Belumosudil 200 mg tablet fasted	Period 1: Single-dose Belumosudil 200 mg by capsule, i.e., two 100-mg capsules fed; Washout; Period 2: Single-dose Belumosudil 200 mg tablet fasted; Washout; Period 3: Single-dose Belumosudil 200 mg tablet fed
Period Title: Overall Study
STARTED	8	8	7
COMPLETED	6	8	5
NOT COMPLETED	2	0	2

Baseline Characteristics

Arm/Group Title	Cohort ABC	Cohort BCA	Cohort CAB	Total
Arm/Group Description	Period 1: Single-dose Belumosudil 200 mg tablet fasted (Regimen A); Washout; Period 2: Single-dose Belumosudil 200 mg tablet fed (Regimen B); Washout; Period 3: Single-dose Belumosudil two 100-mg capsules, i.e., 200 mg (Regimen C)	Period 1: Belumosudil 200 mg tablet fed; Washout; Period 2: Belumosudil 200 mg by capsule, i.e., two 100-mg capsules fed; Washout; Period 3: Belumosudil 200 mg tablet fasted	Period 1: Single-dose Belumosudil 200 mg by capsule, i.e., two 100-mg capsules fed; Washout; Period 2: Single-dose Belumosudil 200 mg tablet fasted; Washout; Period 3: Single-dose Belumosudil 200 mg tablet fed	Total of all reporting groups
Overall Participants	8	8	7	23
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	34.1 (11.0)	32.3 (12.4)	43.0 (9.0)	36.2 (11.5)
Age (Years) [Median (Full Range) ]
Median (Full Range) [Years]	32.5	27.5	46.0	33.0
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%
Male	8 100%	8 100%	7 100%	23 100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	1 12.5%	1 12.5%	1 14.3%	3 13%
White	7 87.5%	7 87.5%	6 85.7%	20 87%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
BMI (body mass index) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.19 (2.67)	25.79 (2.43)	26.53 (3.35)	26.15 (2.70)
BMI (body mass index) (kg/m^2) [Median (Full Range) ]
Median (Full Range) [kg/m^2]	26.4	26.0	26.1	26.10

Outcome Measures

1. Primary Outcome

Title	Pharmacokinetics: Cmax of Dosing Regimen A (Tablets--Fasting) vs. Dosing Regimen B (Tablets--Fed) for KD025, KD025m1, and KD025m2 at 48 Hours Post-dose
Description	Maximum concentration (Cmax) of parent drug (KD025), Metabolite 1 (KD025m1), and Metabolite 2 (KD025m2) when administering a single dose of belumosudil 200 mg tablet to subjects who are fasting (Regimen A) compared to administering a single dose of belumosudil 200 mg tablet to subjects who are fed (Regimen B) at 48 hours after dosing
Time Frame	Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose

Outcome Measure Data

Analysis Population Description

Not all subjects received each regimen.

Arm/Group Title	Regimen A	Regimen B
Arm/Group Description	Single-dose belumosudil 200 mg tablet in the fasting state	Single-dose belumosudil 200 mg tablet in the fed state Belumosudil Tablet
Measure Participants	23	20
Cmax: KD025	821 (129.5)	2100 (49.8)
Cmax: KD025m1	19.4 (51.6)	25.8 (42.0)
Cmax: KD025m2	173 (122.6)	412 (63.0)

2. Primary Outcome

Title	Pharmacokinetics: AUCs of Dosing Regimen A (Tablets--Fasting) vs. Dosing Regimen B (Tablets--Fed) for KD025, KD025m1, and KD025m2 at 48 Hours Post-dose
Description	Area under concentration-time curve from zero to last dose of belumosudil 200 mg tablets (AUC[0-last]) and from zero to infinity (AUC[0-inf]) for Metabolite 1 (KD025m1), and Metabolite 2 (KD025m2) when administering a single dose of belumosudil 200 mg tablet to subjects who are fasting (Regimen A) compared to administering a single dose of belumosudil 200 mg tablet to subjects who are fed (Regimen B) at 48 hours after dosing
Time Frame	Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose

Outcome Measure Data

Analysis Population Description

Not all subjects in either cohort had all AUC measurements

Arm/Group Title	Regimen A	Regimen B
Arm/Group Description	Single-dose belumosudil 200 mg tablet in the fasting state	Single-dose belumosudil 200 mg tablet in the fed state Belumosudil Tablet
Measure Participants	23	20
AUC(0-last): KD025	4520 (121.3)	9750 (49.3)
AUC(0-last): KD025m1	19.8 (150.6)	45.2 (95.3)
AUC(0-last): KD025m2	550 (133.3)	1320 (62.6)
AUC(0-inf): KD025	4910 (146.9)	10100 (52.9)
AUC(0-inf): KD025m1	153 (0)	98.7 (0)
AUC(0-inf): KD025m2	691 (76.7)	1370 (62.6)

3. Secondary Outcome

Title	Pharmacokinetics: Cmax for the Relative Bioavailability of Regimen B/Regimen A and Regimen B/Regimen C by Ratio of the Adjusted Geometric Means at 48 Hours Post-dose
Description	Analysis of the maximum concentration (Cmax) of the relative bioavailability of Regimen B (belumosudil 200 mg tablet-fed) vs. Regimen A (belumosudil 200 mg tablet-fasting) and for Regimen B vs. Regimen C (belumosudil 200 mg capsule-fed) utilizing the Ratio of the Adjusted Geometric Means at 48 hours after dosing
Time Frame	Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Regimen B/Regimen A	Regimen B/Regimen C
Arm/Group Description	Single-dose belumosudil 200 mg tablet fed (Regimen B) divided by single-dose belumosudil 200 mg tablet fasting (Regimen A)	Single-dose belumosudil 200 mg tablet fed (Regimen B) divided by single-dose belumosudil 200 mg capsule fed (Regimen C)
Measure Participants	20	20
Number (90% Confidence Interval) [Ratio of Adjusted Geometric Means]	225.02	119.38

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regimen A
	Comments	Cmax null hypothesis: Ratio of Adjusted Geometric Means = 100%
	Type of Statistical Test	Equivalence
	Comments	If the 90% confidence interval for the comparison of fed vs. fasted is within the acceptance range 80.00% to 125.00%, then it is concluded that there is no effect of food on belumosudil tablets.
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Ratio of Adjusted Geometric Means (%)
	Estimated Value	100
	Confidence Interval	(2-Sided) 90%; 80.00 to 125.00
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Intra-subject variability: 48.00%

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Regimen B
	Comments	Cmax null hypothesis: Ratio of Adjusted Geometric Means = 100%
	Type of Statistical Test	Equivalence
	Comments	If the 90% confidence interval for the comparison of belumosudil tablet (test drug) vs. the belumosudil capsule (reference drug) is within the acceptance range 80.00% to 125.00%, then it is concluded that there is no effect on the use of belumosudi tablet compared to belumosudil capsule.
Statistical Test of Hypothesis	p-Value	0.23
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Ratio of Geometric Means (%)
	Estimated Value	100
	Confidence Interval	(2-Sided) 90%; 80.00 to 125.00
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Intra-subject variability: 48.00%

4. Secondary Outcome

Title	Pharmacokinetics: AUCs for the Relative Bioavailability of Regimen B/Regimen A and Regimen B/Regimen C by Ratio of the Adjusted Geometric Means at 48 Hours Post-dose
Description	Analysis of the area under concentration-time curve for zero to infinity (AUC[0-inf]), and zero to last dose (AUC[0-last]) of the relative bioavailability of Regimen B (belumosudil 200 mg tablet-fed) vs. Regimen A (belumosudil 200 mg tablet-fasting) and for Regimen B vs. Regimen C (belumosudil 200 mg capsule-fed) utilizing the Ratio of the Adjusted Geometric Means at 48 hours after dosing
Time Frame	Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose

Outcome Measure Data

Analysis Population Description

Not all subjects were available for all bioavailability measurements.

Arm/Group Title	Regimen B/Regimen A	Regimen B/Regimen C
Arm/Group Description	Single-dose belumosudil 200 mg tablet fed (Regimen B) divided by single-dose belumosudil 200 mg tablet fasted (Regimen A)	Single-dose belumosudil 200 mg tablet fed (Regimen B) divided by single-dose belumosudil 200 mg capsule fed (Regimen C)
Measure Participants	20	20
AUC(0-inf)	179.58	118.43
AUC(0-last)	187.92	117.57

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regimen A
	Comments	AUC(0-inf) Null Hypothesis: Ratio of Adjusted Geometric Means = 100%
	Type of Statistical Test	Equivalence
	Comments	If the 90% confidence interval for the comparison of fed vs. fasted is within the acceptance range 80.00% to 125.00%, then it is concluded that there is no effect of food on belumosudil tablets.
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Ratio of Adjusted Geometric Means (%)
	Estimated Value	100
	Confidence Interval	(2-Sided) 90%; 80.00 to 125.00
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Intra-subject variability: 34.25%

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Regimen B
	Comments	AUC(0-inf) Null Hypothesis: Ratio of Adjusted Geometric Means = 100%
	Type of Statistical Test	Equivalence
	Comments	If the 90% confidence interval for the comparison of belumosudil tablet (test drug) vs. the belumosudil capsule (reference drug) is within the acceptance range 80.00% to 125.00%, then it is concluded that there is no effect on the use of belumosudi tablet compared to belumosudil capsule.
Statistical Test of Hypothesis	p-Value	0.16
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Ratio of Adjusted Geometric Means (%)
	Estimated Value	100
	Confidence Interval	(2-Sided) 90%; 80.00 to 125.00
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Intra-subject variability;

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Regimen A
	Comments	AUC(0-last) Null Hypothesis: Ratio of Adjusted Geometric Means = 100%
	Type of Statistical Test	Equivalence
	Comments	If the 90% confidence interval for the comparison of fed vs. fasted is within the acceptance range 80.00% to 125.00%, then it is concluded that there is no effect of food on belumosudil tablets.
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Ratio of Adjusted Geometric Means (%)
	Estimated Value	100
	Confidence Interval	(2-Sided) 90%; 80.00 to 125.00
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Intra-subject variability = 38.16%

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Regimen B
	Comments	AUC(0-last) Null Hypothesis: Ratio of Adjusted Geometric Means = 100%
	Type of Statistical Test	Equivalence
	Comments	If the 90% confidence interval for the comparison of belumosudil tablet (test drug) vs. the belumosudil capsule (reference drug) is within the acceptance range 80.00% to 125.00%, then it is concluded that there is no effect on the use of belumosudi tablet compared to belumosudil capsule.
Statistical Test of Hypothesis	p-Value	0.18
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Ratio of Adjusted Geometric Means (%)
	Estimated Value	100
	Confidence Interval	(2-Sided) 90%; 80.00 to 125.00
	Parameter Dispersion	Type: Value:
	Estimation Comments	Intra-subject variability = 38.16%
Other Statistical Analysis		Intra-subject variability = 38.16%

5. Secondary Outcome

Title	Pharmacokinetics: Cmax of Dosing Regimen A (Tablets--Fasting) vs. Dosing Regimen B (Tablets--Fed) vs. Dosing Regimen C (Capsules--Fed) for KD025, KD025m1, and KD025m2 at 48 Hours Post-dose
Description	Maximum concentration (Cmax) of parent drug (KD025), Metabolite 1 (KD025m1), and Metabolite 2 (KD025m2) when administering a single dose of belumosudil 200 mg tablet to subjects who are fasting (Regimen A) compared to administering a single dose of belumosudil 200 mg tablet to subjects who are fed (Regimen B) compared to a single dose of belumosudil 200 mg capsule (two 100-mg capsules) to subjects who are fed (Regimen C) at 48 hours after dosing
Time Frame	Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose

Outcome Measure Data

Analysis Population Description

Based on PK Population: Not all subjects received each regimen.

Arm/Group Title	Regimen A	Regimen B	Regimen C
Arm/Group Description	Single-dose belumosudil 200 mg tablet in the fasting state	Single-dose belumosudil 200 mg tablet in the fed state Belumosudil Tablet	Single-dose belumosudil 200 mg capsule (two 100-mg capsules) in the fed state
Measure Participants	23	20	22
Cmax: Parent Drug KD025	821 (129.5)	2100 (49.8)	1750 (38.2)
Cmax: KD025m1	19.4 (51.6)	25.8 (42.0)	20.6 (38.2)
Cmax: KD025m2	173 (122.6)	412 (63.0)	289 (76.5)

6. Secondary Outcome

Title	Pharmacokinetics: AUCs of Regimen A (Tablet--Fasting) vs. Dosing Regimen B (Tablet--Fed) vs. Dosing Regimen C (Capsule--Fed) for KD025, KD025m1, and KD025m2 for Belumosudil 200 mg at 48 Hours Post-dose
Description	Area under concentration curve from zero to last dose (AUC[0-last]) and from zero to infinity (AUC[0-inf]) for parent drug (KD025), Metabolite 1 (KD025m1), and Metabolite 2 (KD025m2) when administering a single dose of belumosudil 200 mg tablet to subjects who are fasting (Regimen A) compared to administering a single dose of belumosudil 200 mg tablet to subjects who are fed (Regimen B) compared to administering a single dose of 200 mg capsule (two 100-mg capsules) to subjects who are fed at 48 hours after dosing
Time Frame	Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose

Outcome Measure Data

Analysis Population Description

Not all subjects in either cohort had all AUC measurements

Arm/Group Title	Regimen A	Regimen B	Regimen C
Arm/Group Description	Single-dose belumosudil 200 mg tablet in the fasted state	Single-dose belumosudil 200 mg tablet in the fed state Belumosudil Tablet	Single-dose belumosudil 200 mg capsule (two 100-mg capsules) in the fed state
Measure Participants	23	20	22
AUC(0-last): KD025	4520 (121.3)	9750 (49.3)	8650 (42.7)
AUC(0-last): KD025m1	19.8 (150.6)	45.2 (95.3)	33.6 (106.9)
AUC(0-last): KD025m2	550 (133.3)	1320 (62.6)	1000 (95.5)
AUC(0-inf): KD025	4910 (146.9)	10100 (52.9)	8710 (42.2)
AUC(0-inf): KD025m1	153 (0)	98.7 (0)	213 (0)
AUC(0-inf): KD025m2	691 (76.7)	1370 (62.6)	1420 (47.7)

7. Secondary Outcome

Title	Pharmacokinetics: Lambda-z for Regimens A, B, and C for KD025, KD025m1, and KD025m2 at 48 Hours Post-dose
Description	Slope of the regression line passing through the apparent elimination phase in a concentration-time plot (Lambda-z) for Regimen A, Regimen B, and Regimen C for for the parent drug (KD025), Metabolite 1 (KD025m1), and Metabolite 2 (KD025m2) at 48 hours after dosing
Time Frame	Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose

Outcome Measure Data

Analysis Population Description

Not all subjects had PK parameter lambda-z analyzed

Arm/Group Title	Regimen A	Regimen B	Regimen C
Arm/Group Description	Single-dose belumosudil 200 mg tablet in the fasted state	Single-dose belumosudil 200 mg tablet in the fed state	Single-dose belumosudil capsules (administered as two 100-mg capsules) in the fed state
Measure Participants	23	20	22
KD025	0.0622 (1.5848)	0.0993 (1.5293)	0.0967 (1.4594)
KD025m1	0.3618 (0)	0.3608 (0)	0.1275 (0)
KD025m2	0.4159 (1.5248)	0.3291 (1.7326)	0.2523 (1.7385)

8. Secondary Outcome

Title	Pharmacokinetics: t(1/2), MRT(0-last), and MRT(0-inf) for Regimens A, B, and C for KD025, KD025m1, and KD025m2 at 48 Hours Post-dose
Description	Apparent elimination half-life (t[1/2]), mean residence time from zero to last dose (MRT[0-last]), and MRT for zero to infinity (MRT[0-inf]) for Regimen A, Regimen B, and Regimen C for for the parent drug (KD025), Metabolite 1 (KD025m1), and Metabolite 2 (KD025m2) at 48 hours after dosing
Time Frame	Pre-dose (0), and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours post-dose

Outcome Measure Data

Analysis Population Description

Not all subjects had all PK parameters analyzed

Arm/Group Title	Regimen A	Regimen B	Regimen C
Arm/Group Description	Single-dose belumosudil 200 mg tablet in the fasted state	Single-dose belumosudil 200 mg tablet in the fed state	Single-dose belumosudil capsules (administered as two 100-mg capsules) in the fed state
Measure Participants	23	20	22
KD025: t(1/2)	11.16 (1.58)	6.98 (1.53)	7.16 (1.46)
KD025m1: t(1/2)	1.92 (0)	1.92 (0)	5.44 (0)
KD025m2: t(1/2)	1.67 (1.52)	2.11 (1.73)	2.75 (1.74)
KD025: MRT(0-last)	7.25 (1.39)	5.70 (1.27)	6.21 (1.22)
KD025m1: MRT(0-last)	1.70 (1.61)	2.45 (1.61)	2.79 (1.57)
KD025m2: MRT(0-last)	3.03 (1.32)	3.99 (1.45)	4.44 (1.34)
KD025: MRT(0-inf)	9.35 (1.33)	6.40 (1.27)	7.18 (1.24)
KD025m1: MRT(0-inf)	3.38 (0)	4.39 (0)	8.26 (0)
KD025m2: MRT(0-inf)	3.46 (1.30)	4.35 (1.46)	4.86 (1.40)

9. Secondary Outcome

Title	Safety: Number of Subjects With TEAEs and SAEs
Description	Number of subjects with treatment-emergent adverse events (TEAEs), severity and relationship to belumosudil, serious adverse events (SAEs), TEAEs leading to withdrawal from study, and deaths. Treatment-emergent adverse events (TEAEs) are AEs that are not present before the first dose of IMP or that are present before the first dose of IMP but worsen in intensity during exposure to IMP. Severity: mild = 1; moderate = 2; severe = 3; life-threatening = 4; and death = 5. Related to belumosudil defined as possibly related, probably related, and related.
Time Frame	Approximately 1 month

Outcome Measure Data

Analysis Population Description

All subject who received at least one dose of belumosudil

Arm/Group Title	Regimen A	Regimen B	Regimen C	Overall
Arm/Group Description	Single-dose belumosudil 200 mg tablet in the fasted state Belumosudil Tablet	Single-dose belumosudil 200 mg tablet in the fed state Belumosudil Tablet	Single-dose belumosudil capsules (administered as two 100-mg capsules) in the fed state Belumosudil Capsule	Subjects who received Regimen A and/or Regimen B and/or Regimen C
Measure Participants	23	20	22	23
At least 1 TEAE	6 75%	3 37.5%	5 71.4%	9 39.1%
Reporting belumosudil-related TEAEs	1 12.5%	0 0%	0 0%	1 4.3%
TEAEs Leading to Withdrawal	3 37.5%	0 0%	0 0%	3 13%
Severe TEAEs	1 12.5%	0 0%	0 0%	1 4.3%
Serious TEAEs	0 0%	0 0%	0 0%	0 0%
TEAEs Leading to Death	0 0%	0 0%	0 0%	0 0%

10. Secondary Outcome

Title	Safety: Total Number of Participants With TEAEs, Related TEAEs, Leading to Withdrawal, Severe, Serious, Leading to Death
Description	Total number of subjects who had treatment-emergent adverse events (TEAEs), TEAEs related to belumosudil, TEAEs leading to withdrawal of subject, severe TEAEs, serious TEAE (SAE), and TEAEs leading to death. Treatment-emergent adverse events (TEAEs) are AEs that are not present before the first dose of IMP or that are present before the first dose of IMP but worsen in intensity during exposure to IMP. Severity: mild = 1; moderate = 2; severe = 3; life-threatening = 4; and death = 5. Related to belumosudil defined as possibly related, probably related, and related.
Time Frame	Approximately 1 month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Regimen A	Regimen B	Regimen C	Overall
Arm/Group Description	Single-dose belumosudil 200 mg tablet in the fasted state Belumosudil Tablet	Single-dose belumosudil 200 mg tablet in the fed state Belumosudil Tablet	Single-dose belumosudil capsules (administered as two 100-mg capsules) in the fed state Belumosudil Capsule	Subjects who received Regimen A and/or Regimen B and/or Regimen C
Measure Participants	23	20	22	23
All TEAEs	7 87.5%	3 37.5%	6 85.7%	16 69.6%
TEAEs Related to Belumosudil	1 12.5%	0 0%	0 0%	1 4.3%
TEAEs Leading to Withdrawal	3 37.5%	0 0%	0 0%	3 13%
Severe TEAEs	1 12.5%	0 0%	0 0%	1 4.3%
Serious TEAEs (SAE)	0 0%	0 0%	0 0%	0 0%
TEAEs Leading to Death	0 0%	0 0%	0 0%	0 0%

Adverse Events

Time Frame	Approximately 1 month
Adverse Event Reporting Description	Adverse events were classified into two categories: 1.Pre-dose AEs: AEs recorded at screening or with a start date and time prior to the first does of IMP and either do not continue after or do not worsen in intensity after the first dose of IMP; 2. Treatment-emergent adverse events (TEAEs): AEs that are not present before the first dose of IMP or that are present before the first dose of IMP but worsen in intensity during exposure to IMP.
Arm/Group Title	Regimen A		Regimen B		Regimen C
Arm/Group Description	Single-dose belumosudil 200 mg tablet in the fasted state		Single-dose belumosudil 200 mg tablet in the fed state Belumosudil Tablet		Single-dose belumosudil 200 mg capsule (two 100-mg capsules) in the fed state
All Cause Mortality
	Regimen A		Regimen B		Regimen C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/20 (0%)		0/22 (0%)
Serious Adverse Events
	Regimen A		Regimen B		Regimen C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/20 (0%)		0/22 (0%)
Other (Not Including Serious) Adverse Events
	Regimen A		Regimen B		Regimen C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/23 (26.1%)		3/20 (15%)		5/22 (22.7%)
Cardiac disorders
Atrioventricular block--2nd degree	1/23 (4.3%)		0/20 (0%)		0/22 (0%)
General disorders
Fatigue	0/23 (0%)		0/20 (0%)		1/22 (4.5%)
Influenza-like illness	1/23 (4.3%)		0/20 (0%)		0/22 (0%)
Infections and infestations
Nasopharyngitis	0/23 (0%)		1/20 (5%)		0/22 (0%)
Viral upper respiratory tract infection	1/23 (4.3%)		0/20 (0%)		0/22 (0%)
Investigations
Alanine aminotransferase increased	1/23 (4.3%)		0/20 (0%)		0/22 (0%)
Blood creatinine phosphokinase increased	1/23 (4.3%)		0/20 (0%)		0/22 (0%)
Transaminase increased	1/23 (4.3%)		0/20 (0%)		0/22 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	0/23 (0%)		0/20 (0%)		1/22 (4.5%)
Nervous system disorders
Cervical radiculopathy	1/23 (4.3%)		0/20 (0%)		0/22 (0%)
Headache	0/23 (0%)		1/20 (5%)		1/22 (4.5%)
Paresthesia	0/23 (0%)		0/20 (0%)		1/22 (4.5%)
Somnolence	0/23 (0%)		0/20 (0%)		1/22 (4.5%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal	0/23 (0%)		1/20 (5%)		0/22 (0%)
Skin and subcutaneous tissue disorders
Rash macular	0/23 (0%)		0/20 (0%)		1/22 (4.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding results. The sponsor cannot require changes to the study results in the communication except to remove sponsor's confidential information. Sponsor cannot unilaterally extend the embargo.