A Safety and Tolerability Study of Belumosudil (KD025) Treatment in Subjects With Moderately Severe Psoriasis Vulgaris

• Sponsor: Kadmon Corporation, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02106195
• Collaborator: (none)
• Enrollment: 8
• Location: 1
• Arm: 1
• Duration (Months): 5
• Patients Per Site Per Month: 1.6

Study Details

Study Description

Brief Summary

The primary objective is to assess the safety and tolerability of 200 mg of belumosudil administered orally once daily for 28 days.

Condition or Disease	Intervention/Treatment	Phase
Psoriasis Vulgaris	Drug: Belumosudil	Phase 2

Detailed Description

This will be a Phase 2a, open-label, single-arm, safety and tolerability study of belumosudil given daily for treatment of psoriasis.

Eight subjects with moderately severe psoriasis who have failed at least 1 line of systemic therapy will be enrolled.

Treatment Period Eligible subjects who have failed at least 1 line of systemic therapy will be entered and treated for 4 weeks (28 days) with 200 mg of belumosudil given orally once daily (QD).

Subjects will undergo medical history evaluations, physical examinations, vital sign measurements, weight, adverse event assessments, concomitant medication assessments, and laboratory testing including but not limited to blood sample collection for hematology and chemistry, urinalysis, coagulation, lipid panel, electrocardiogram, pregnancy test for females of childbearing potential, testing with the Psoriasis Area and Severity Index (PASI) scale and Physician Global Assessment (PGA) scale, and pharmacokinetic sampling.

Follow-up Period:

Visit will occur 4 weeks after the last dose of study drug in the Treatment Period of the study. This visit must be done within ± 3 days of the scheduled visit. The same assessments will be performed as in the Treatment Period.

The duration of the study is 12 weeks: up to 4 weeks for screening, 4 weeks of treatment, and 4 weeks of follow-up.

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2a, Open-label Study to Evaluate the Safety and Tolerability of KD025 [Belumosudil] Treatment in Subjects With Moderately Severe Psoriasis Vulgaris Who Have Failed First-line Therapy
• Study Start Date: Apr 1, 2014
• Actual Primary Completion Date: Sep 1, 2014
• Actual Study Completion Date: Sep 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Belumosudil 200 mg Belumosudil 200 mg (two 100 mg capsules) orally once daily for 28 days	Drug: Belumosudil; Other Names: Rezurock (brand name) KD025 SLx-2119

Outcome Measures

Primary Outcome Measures

1. Number of Subjects Experiencing Adverse Events as a Measure of Safety and Tolerability [Up to 12 weeks:Up to 4 weeks screening (depending on signed informed consent + 4 weeks treatment + 4 weeks follow-up]

   To evaluate the safety and tolerability of 200 mg of belumosudil administered PO QD to subjects for treatment of psoriasis

Secondary Outcome Measures

1. Efficacy: Change in Overall PASI (Psoriasis Area and Severity Index) From Baseline to Week 4 and Week 8 [8 weeks: 4-week (28-day) treatment + 4-week (28-day) follow-up]

   The Psoriasis Area and Severity Index (PASI) is a composite score based on the degree of effect on body surface area of psoriasis and the extension of erythema (reddening), induration (thickness), desquamation (scaling) of the lesions and area affected as observed on the day of examination. The severity of each sign was assessed using a 5-point scale, where 0=no symptoms, 1=slight, 2=moderate, 3=marked, 4=very marked. The PASI score ranges from 0 to 72, where 0 indicates no psoriasis and 72 indicates very severe psoriasis. The measures are the changes in PASI score at Week 4 from baseline and Week 8 from baseline. Negative changes are favorable; positive changes are unfavorable.

2. Efficacy: Physician Global Assessment (PGA) at Week 4 and Week 8 [8 weeks: 4-week (28-day) treatment + 4-week (28-day) follow-up]

   PGA score after treatment with belumosudil 200 mg PO QD at 4 weeks (28 days treatment) and at 8 weeks (additional 4 weeks follow-up). Categories: 100% = clear; 75% to 99% clearing (Excellent) = marked improvement, nearly normal skin texture, some erythema may be present; 50% to 74% clear (Good) = moderate improvement, plaque has cleared to point of small scattered papules with normal intervening epidermis; 25% to 49% clearing (Fair) = slight improvement, decrease in scaling and softening of plaque; 0% to 24% clearing (Poor) = little or no change in scaling, erythema, or plaque elevation; Worse

3. PK: Cmax and Cmin [Measured at Baseline (Day 1) and Week 4 (28 days): predose (0), 1, 2, 4, 8, and 24 hours post-dose]

   Pharmacokinetic measures: Cmax = maximum observed plasma concentration; Cmin = minimum observed plasma concentration over 1 dosing period; KD025 = Parent Drug KD025; M1 = Metabolite KD025 M1; KD025 M2 = Metabolite M2. Day 1 Cmax: 8 subjects each in KD025 and M2, and 6 subjects in M1. Day 28 Cmax: 4 subjects each in KD025 and M2, and 1 subject in M1. Day 1 Cmin: 8 subjects each in KD025 and M2, and 3 subjects in M1. Day 28 Cmin: 4 subjects each in KD025 and M2, and 1 subject in M1.

4. PK: AUC(0-24) and AUC(Inf) [Measured at Baseline (Day 1) and Week 4 (28 days): predose (0), 1, 2, 4, 8, and 24 hours post-dose]

   Pharmacokinetic measures: AUC(0-24) = area under concentration time-curve from pre-dose (time 0) to 24 hours post-dose; AUC(inf) = area under concentration time-curve extrapolated from Day 1 to infinity; KD025 = Parent Drug KD025; M1 = Metabolite KD025 M1; KD025 M2 = Metabolite M2.

5. PK: Tmax [Measured at Baseline (Day 1) and Week 4 (28 days): predose (0), 1, 2, 4, 8, and 24 hours post-dose]

   Pharmacokinetic measure: Tmax = time of maximum observed plasma concentration. Day 1 Tmax: 7 subjects each in KD025 and M2, and 5 subjects in M1. Day 28 Tmax: 4 subjects each in KD025 and M2, and 1 subject in M1.

6. PK: t(1/2) [Measured at Baseline (Day 1) and Week 4 (28 days): predose (0), 1, 2, 4, 8, and 24 hours post-dose]

   KD025 = Parent Drug KD025; KD025 M2 = Metabolite M2; t(1/2) = apparent terminal elimination half-life

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of moderately severe plaque psoriasis that has been stable for 6 months and has failed at least one line of systemic therapy and is a candidate for additional systemic therapy.

• Had a PASI of ≥12

• At least 10% of body surface area that is affected by plaque psoriasis.

• Willing to avoid tanning devices or sun bathing.

• Willing to forgo systemic and topical treatments for psoriasis during the course of the study.

• Adequate bone marrow function

• Negative urine pregnancy test (for women of childbearing potential)

• Agree to use a highly effective method of birth control (< 1% per year failure rate) during the study and for 1 month after the termination of the study.

• Willing to complete all study measurements and assessments in compliance with the protocol.

Exclusion Criteria:

• Non-plaque or drug-induced psoriasis

• Currently using corticosteroid or immunosuppressive therapy except for Class 5 or weaker topical corticosteroids to the face, groin, or scalp

• Using any topical therapy except for the following:

1. Class 5 or weaker steroids and phototherapy for 4 weeks prior to study entry

2. Immunosuppressive therapies for 4 weeks prior to study entry

3. Methotrexate, acitretin, or cyclosporine for 4 weeks prior to study entry

4. Biologic therapies for 3 months prior to study entry.

• Concomitant condition requiring treatment with moderate to high dose steroids in the 12 weeks prior to screening.

• Viral, fungal, or bacterial skin infection.

• Pregnant or lactating woman.

• Currently participating in another study with an investigational drug or within 28 days of study entry

• History or other evidence of severe illness or any other conditions that would make the subject, in the opinion of the investigator, unsuitable for the study

• History or presence of any of the following:

1. Hepatic disease and or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 × the upper limit of normal (ULN) at screening

2. Renal disease and/or serum creatinine > 1.5xULN at screening

• Has QTc(f) intervals of > 450 msec at the screening or pre-dose ECG

• Subject is receiving any drugs known to prolong the QTc interval, including any anti-arrhythmic medications within 2 weeks prior to screening

• Subject is receiving any drug that is a strong CYP enzyme inhibitor

• Subject is receiving any concomitant systemic drug that is metabolized by CYP enzyme

• Previous exposure to KD025 or known allergy/sensitivity to KD025 or any other ROCK-2 inhibitor.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UC Irvine Health, Dept of Dermatology	Irvine	California	United States	92697

Sponsors and Collaborators

• Kadmon Corporation, LLC

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Kadmon Corporation, LLC
• ClinicalTrials.gov Identifier: NCT02106195
• Other Study ID Numbers: KD025-205
• First Posted: Apr 8, 2014
• Last Update Posted: Mar 23, 2022
• Last Verified: Mar 1, 2022

• Additional relevant MeSH terms: Psoriasis; Belumosudil

Study Results

Participant Flow

Recruitment Details	Open-label, Phase 2a, single-arm study of subjects with moderately severe plaque psoriasis who had been stable for 6 months and had failed at least 1 line of systemic therapy. Subjects were recruited at 1 site in the U.S.
Pre-assignment Detail	Screening assessments occurred within 28 days prior to assignment and included informed consent, medical/demographic history, physical exam, vital signs, clinical laboratory tests, ECG, urine pregnancy, skin punch biopsy, PK, Psoriasis Area and Severity Index (PASI) scoring, Physician Global Assessment (PGA) scoring, and concomitant AE assessments.

Arm/Group Title	Belumosudil 200 mg PO QD
Arm/Group Description	8 subjects with moderately severe psoriasis who had failed at least 1 line of systemic therapy administered belumosudil 200 mg orally QD for 4 weeks
Period Title: Overall Study
STARTED	8
COMPLETED	5
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Belumosudil 200 mg PO QD
Arm/Group Description	Belumosudil 200 mg (two 100 mg capsules) orally once daily for 28 days
Overall Participants	8
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.6 (10.31)
Age, Customized (years) [Median (Full Range) ]
Median (Full Range) [years]	49.5
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	8 100%
Race and Ethnicity Not Collected (Count of Participants)
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	29.42 (6.539)
BMI (kg/m^2) [Median (Full Range) ]
Median (Full Range) [kg/m^2]	27.61

Outcome Measures

1. Primary Outcome

Title	Number of Subjects Experiencing Adverse Events as a Measure of Safety and Tolerability
Description	To evaluate the safety and tolerability of 200 mg of belumosudil administered PO QD to subjects for treatment of psoriasis
Time Frame	Up to 12 weeks:Up to 4 weeks screening (depending on signed informed consent + 4 weeks treatment + 4 weeks follow-up

Outcome Measure Data

Analysis Population Description

Safety Population: All subjects who received at least 1 dose of belumosudil 200 mg

Arm/Group Title	Belumosudil 200 mg PO QD
Arm/Group Description	Subjects who received at least 1 dose of belumosudil 200 mg orally daily
Measure Participants	8
All AEs	4 50%
Related AEs	1 12.5%
Grade ≥3 AEs	1 12.5%
Grade ≥3 Related AEs	0 0%
Grade 4 AEs	0 0%
Deaths	0 0%
SAEs	1 12.5%
Related SAEs	0 0%
AEs leading to discontinuation	2 25%

2. Secondary Outcome

Title	Efficacy: Change in Overall PASI (Psoriasis Area and Severity Index) From Baseline to Week 4 and Week 8
Description	The Psoriasis Area and Severity Index (PASI) is a composite score based on the degree of effect on body surface area of psoriasis and the extension of erythema (reddening), induration (thickness), desquamation (scaling) of the lesions and area affected as observed on the day of examination. The severity of each sign was assessed using a 5-point scale, where 0=no symptoms, 1=slight, 2=moderate, 3=marked, 4=very marked. The PASI score ranges from 0 to 72, where 0 indicates no psoriasis and 72 indicates very severe psoriasis. The measures are the changes in PASI score at Week 4 from baseline and Week 8 from baseline. Negative changes are favorable; positive changes are unfavorable.
Time Frame	8 weeks: 4-week (28-day) treatment + 4-week (28-day) follow-up

Outcome Measure Data

Analysis Population Description

All 8 subjects who received belumosudil 200 mg PO QD. 7 subjects available at follow-up visit.

Arm/Group Title	Belumosudil 200 mg PO QD
Arm/Group Description	Subjects receiving 200 mg of belumosudil daily
Measure Participants	8
Baseline (Day 1)	17.5 (8.41)
Week 4 (Day 28)	16.3 (9.49)
Change from Baseline to Week 4	-1.1 (3.04)
Week 8 (Day 56)	14.7 (3.41)
Change from Baseline to Week 8	0.0 (1.54)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Belumosudil 200 mg PO QD
	Comments
	Type of Statistical Test	Superiority
	Comments	Change from Baseline to Day 28
Statistical Test of Hypothesis	p-Value	0.324
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.1
	Confidence Interval	(2-Sided) 95%; -3.7 to 1.4
	Parameter Dispersion	Type: Standard Deviation; Value: 3.04
	Estimation Comments

3. Secondary Outcome

Title	Efficacy: Physician Global Assessment (PGA) at Week 4 and Week 8
Description	PGA score after treatment with belumosudil 200 mg PO QD at 4 weeks (28 days treatment) and at 8 weeks (additional 4 weeks follow-up). Categories: 100% = clear; 75% to 99% clearing (Excellent) = marked improvement, nearly normal skin texture, some erythema may be present; 50% to 74% clear (Good) = moderate improvement, plaque has cleared to point of small scattered papules with normal intervening epidermis; 25% to 49% clearing (Fair) = slight improvement, decrease in scaling and softening of plaque; 0% to 24% clearing (Poor) = little or no change in scaling, erythema, or plaque elevation; Worse
Time Frame	8 weeks: 4-week (28-day) treatment + 4-week (28-day) follow-up

Outcome Measure Data

Analysis Population Description

All 8 subjects had PGA scoring at Day 29 and at the follow-up visit (30 days after last dose of study drug)

Arm/Group Title	Belumosudil 200 mg PO QD
Arm/Group Description	Subjects receiving belumosudil 200 mg orally once daily for up to 28 days
Measure Participants	8
4 weeks: 75% to 100%	0 0%
4 weeks: 50% to 74% clearing	1 12.5%
4 weeks: 25% to 49% clearing	1 12.5%
4 weeks: 0 to 24% clearing	4 50%
4 weeks: Worse	2 25%
8 weeks: 75% to 100%	0 0%
8 weeks: 50% to 74% clearing	0 0%
8 weeks: 25% to 49% clearing	0 0%
8 weeks: 0% to 24% clearing	6 75%
8 weeks: Worse	1 12.5%
8 weeks: Missing (no data)	1 12.5%

4. Secondary Outcome

Title	PK: Cmax and Cmin
Description	Pharmacokinetic measures: Cmax = maximum observed plasma concentration; Cmin = minimum observed plasma concentration over 1 dosing period; KD025 = Parent Drug KD025; M1 = Metabolite KD025 M1; KD025 M2 = Metabolite M2. Day 1 Cmax: 8 subjects each in KD025 and M2, and 6 subjects in M1. Day 28 Cmax: 4 subjects each in KD025 and M2, and 1 subject in M1. Day 1 Cmin: 8 subjects each in KD025 and M2, and 3 subjects in M1. Day 28 Cmin: 4 subjects each in KD025 and M2, and 1 subject in M1.
Time Frame	Measured at Baseline (Day 1) and Week 4 (28 days): predose (0), 1, 2, 4, 8, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

One subject excluded from all the descriptive statistics due to a mix-up of samples between predose and 4 hours (KD025, M1 and M2); Two subjects had no measurable concentrations observed in their profiles for M1 at Day 1

Arm/Group Title	Parent Drug KD025	Metabolite M1	Metabolite M2
Arm/Group Description	Study drug belumosudil	Metabolite KD025 M1 of parent drug KD025.	Metabolite KD025 M2 of parent drug KD025.
Measure Participants	8	6	8
Cmax: Day 1	1240 (704)	21.3 (10.9)	221 (165)
Cmax: Day 28	810 (475)	15.0 (NA)	131 (152)
Cmin: Day 1	59.6 (29.3)	18.7 (9.16)	21.1 (6.13)
Cmin: Day 28	35.9 (22.9)	10.7 (NA)	17.6 (7.36)

5. Secondary Outcome

Title	PK: AUC(0-24) and AUC(Inf)
Description	Pharmacokinetic measures: AUC(0-24) = area under concentration time-curve from pre-dose (time 0) to 24 hours post-dose; AUC(inf) = area under concentration time-curve extrapolated from Day 1 to infinity; KD025 = Parent Drug KD025; M1 = Metabolite KD025 M1; KD025 M2 = Metabolite M2.
Time Frame	Measured at Baseline (Day 1) and Week 4 (28 days): predose (0), 1, 2, 4, 8, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

AUC(0-24) Day 1: 7 subjects in KD025 and 3 subjects in M2. AUC(0-24) Day 28: 4 subjects in KD025 and 2 subjects in M2. AUC(inf): 6 subjects in KD025 and 3 subject in M2. Neither AUC(0-24) nor AUC(inf) were calculated for M1.

Arm/Group Title	Parent Drug KD025	Metabolite M2
Arm/Group Description	Study drug belumosudil	Metabolite KD025 M2 of parent drug KD025.
Measure Participants	7	7
AUC(0-24): Day 1	7360 (3180)	1040 (545)
AUC(0-24): Day 28	5500 (3790)	162 (2320)
AUC(inf) from Day 1	8230 (3600)	1120 (680)

6. Secondary Outcome

Title	PK: Tmax
Description	Pharmacokinetic measure: Tmax = time of maximum observed plasma concentration. Day 1 Tmax: 7 subjects each in KD025 and M2, and 5 subjects in M1. Day 28 Tmax: 4 subjects each in KD025 and M2, and 1 subject in M1.
Time Frame	Measured at Baseline (Day 1) and Week 4 (28 days): predose (0), 1, 2, 4, 8, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

Day 1: 7 subjects each in KD025 and M2, and 5 subjects in M1. Day 28: 4 subjects each in KD025 and M2, and 1 subject in M1.

Arm/Group Title	Parent Drug KD025	Metabolite M1	Metabolite M2
Arm/Group Description	Study drug belumosudil	Metabolite KD025 M1 of parent drug KD025.	Metabolite KD025 M2 of parent drug KD025.
Measure Participants	7	5	7
Tmax: Day 1	2.00	2.00	2.00
Tmax: Day 28	4.00	4.00	4.00

7. Secondary Outcome

Title	PK: t(1/2)
Description	KD025 = Parent Drug KD025; KD025 M2 = Metabolite M2; t(1/2) = apparent terminal elimination half-life
Time Frame	Measured at Baseline (Day 1) and Week 4 (28 days): predose (0), 1, 2, 4, 8, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

One subject was excluded from all descriptive statistics due to a mix-up of samples between pre-dose and 4 hours on Day 1. Three subjects were excluded from day 28 statistics due to varying protocol deviations. Four additional subjects were excluded from M1 Day 28. No data were collected for Metabolite M1.

Arm/Group Title	Parent Drug KD025	Metabolite M2
Arm/Group Description	Study drug belumosudil	Metabolite KD025 M2 of parent drug KD025.
Measure Participants	6	3
t(1/2): Day 1	6.08 (0.681)	4.25 (3.95)
t(1/2): Day 28	5.27 (0.692)	2.26 (NA)

Adverse Events

Time Frame	12 weeks: up to 4 weeks for screening, 4 weeks of treatment, and 4 weeks of follow-up.
Adverse Event Reporting Description	The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 was used. The Clinical Symptom and Adverse Event Grading scale was used for grading toxicities.
Arm/Group Title	Belumosudil 200 mg PO QD
Arm/Group Description	Subjects who received belumosudil 200 mg orally daily
All Cause Mortality
	Belumosudil 200 mg PO QD
	Affected / at Risk (%)	# Events
Total	0/8 (0%)
Serious Adverse Events
	Belumosudil 200 mg PO QD
	Affected / at Risk (%)	# Events
Total	1/8 (12.5%)
Gastrointestinal disorders
Nausea	1/8 (12.5%)	1
Vomiting	1/8 (12.5%)	2
Injury, poisoning and procedural complications
Anastomotic ulcer	1/8 (12.5%)	1
Renal and urinary disorders
Nephrolithiasis	1/8 (12.5%)	1
Other (Not Including Serious) Adverse Events
	Belumosudil 200 mg PO QD
	Affected / at Risk (%)	# Events
Total	4/8 (50%)
Gastrointestinal disorders
Nausea	1/8 (12.5%)	2
Vomiting	1/8 (12.5%)	2
Tooth ache	1/8 (12.5%)	1
General disorders
Pyrexia	1/8 (12.5%)	1
Injury, poisoning and procedural complications
Anastomotic ulder	1/8 (12.5%)	1
Rib Fracture	1/8 (12.5%)	1
Fall	1/8 (12.5%)	1
Investigations
Transaminase increased	2/8 (25%)	2
Metabolism and nutrition disorders
Hypokalemia	1/8 (12.5%)	1
Nervous system disorders
Somnolence	1/8 (12.5%)	1
Renal and urinary disorders
Nephrolithiasis	1/8 (12.5%)	1

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.