Psoriasis Vulgaris
Conditions
Brief summary
The primary objective is to assess the safety and tolerability of 200 mg of belumosudil administered orally once daily for 28 days.
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.
Interventions
DRUGBelumosudil
Sponsors
Kadmon Corporation, LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
| 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. |
| 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. |
| 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 |
| 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. |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Belumosudil 200 mg PO QD Belumosudil 200 mg (two 100 mg capsules) orally once daily for 28 days | 8 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Protocol Violation | 1 |
Baseline characteristics
| Characteristic | Belumosudil 200 mg PO QD | — |
|---|---|---|
| Age, Continuous | 47.6 years STANDARD_DEVIATION 10.31 | — |
| Age, Customized | 49.5 years | — |
| BMI | 29.42 kg/m^2 STANDARD_DEVIATION 6.539 | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Sex: Female, Male Female | 0 Participants | — |
| Sex: Female, Male Male | 8 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 8 |
| other Total, other adverse events | 4 / 8 |
| serious Total, serious adverse events | 1 / 8 |
Outcome results
Primary
Number of Subjects Experiencing Adverse Events as a Measure of Safety and Tolerability
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
Population: Safety Population: All subjects who received at least 1 dose of belumosudil 200 mg
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Belumosudil 200 mg PO QD | Number of Subjects Experiencing Adverse Events as a Measure of Safety and Tolerability | Related SAEs | 0 Participants |
| Belumosudil 200 mg PO QD | Number of Subjects Experiencing Adverse Events as a Measure of Safety and Tolerability | AEs leading to discontinuation | 2 Participants |
| Belumosudil 200 mg PO QD | Number of Subjects Experiencing Adverse Events as a Measure of Safety and Tolerability | All AEs | 4 Participants |
| Belumosudil 200 mg PO QD | Number of Subjects Experiencing Adverse Events as a Measure of Safety and Tolerability | Related AEs | 1 Participants |
| Belumosudil 200 mg PO QD | Number of Subjects Experiencing Adverse Events as a Measure of Safety and Tolerability | Grade ≥3 AEs | 1 Participants |
| Belumosudil 200 mg PO QD | Number of Subjects Experiencing Adverse Events as a Measure of Safety and Tolerability | Grade ≥3 Related AEs | 0 Participants |
| Belumosudil 200 mg PO QD | Number of Subjects Experiencing Adverse Events as a Measure of Safety and Tolerability | Grade 4 AEs | 0 Participants |
| Belumosudil 200 mg PO QD | Number of Subjects Experiencing Adverse Events as a Measure of Safety and Tolerability | Deaths | 0 Participants |
| Belumosudil 200 mg PO QD | Number of Subjects Experiencing Adverse Events as a Measure of Safety and Tolerability | SAEs | 1 Participants |
Secondary
Efficacy: Change in Overall PASI (Psoriasis Area and Severity Index) From Baseline to Week 4 and Week 8
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
Population: All 8 subjects who received belumosudil 200 mg PO QD. 7 subjects available at follow-up visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Belumosudil 200 mg PO QD | Efficacy: Change in Overall PASI (Psoriasis Area and Severity Index) From Baseline to Week 4 and Week 8 | Baseline (Day 1) | 17.5 Score on a scale | Standard Deviation 8.41 |
| Belumosudil 200 mg PO QD | Efficacy: Change in Overall PASI (Psoriasis Area and Severity Index) From Baseline to Week 4 and Week 8 | Week 4 (Day 28) | 16.3 Score on a scale | Standard Deviation 9.49 |
| Belumosudil 200 mg PO QD | Efficacy: Change in Overall PASI (Psoriasis Area and Severity Index) From Baseline to Week 4 and Week 8 | Change from Baseline to Week 4 | -1.1 Score on a scale | Standard Deviation 3.04 |
| Belumosudil 200 mg PO QD | Efficacy: Change in Overall PASI (Psoriasis Area and Severity Index) From Baseline to Week 4 and Week 8 | Week 8 (Day 56) | 14.7 Score on a scale | Standard Deviation 3.41 |
| Belumosudil 200 mg PO QD | Efficacy: Change in Overall PASI (Psoriasis Area and Severity Index) From Baseline to Week 4 and Week 8 | Change from Baseline to Week 8 | 0.0 Score on a scale | Standard Deviation 1.54 |
p-value: 0.32495% CI: [-3.7, 1.4]t-test, 2 sided
Secondary
Efficacy: Physician Global Assessment (PGA) at Week 4 and Week 8
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
Population: All 8 subjects had PGA scoring at Day 29 and at the follow-up visit (30 days after last dose of study drug)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Belumosudil 200 mg PO QD | Efficacy: Physician Global Assessment (PGA) at Week 4 and Week 8 | 4 weeks: 75% to 100% | 0 Participants |
| Belumosudil 200 mg PO QD | Efficacy: Physician Global Assessment (PGA) at Week 4 and Week 8 | 4 weeks: 50% to 74% clearing | 1 Participants |
| Belumosudil 200 mg PO QD | Efficacy: Physician Global Assessment (PGA) at Week 4 and Week 8 | 4 weeks: 25% to 49% clearing | 1 Participants |
| Belumosudil 200 mg PO QD | Efficacy: Physician Global Assessment (PGA) at Week 4 and Week 8 | 4 weeks: 0 to 24% clearing | 4 Participants |
| Belumosudil 200 mg PO QD | Efficacy: Physician Global Assessment (PGA) at Week 4 and Week 8 | 4 weeks: Worse | 2 Participants |
| Belumosudil 200 mg PO QD | Efficacy: Physician Global Assessment (PGA) at Week 4 and Week 8 | 8 weeks: 75% to 100% | 0 Participants |
| Belumosudil 200 mg PO QD | Efficacy: Physician Global Assessment (PGA) at Week 4 and Week 8 | 8 weeks: 50% to 74% clearing | 0 Participants |
| Belumosudil 200 mg PO QD | Efficacy: Physician Global Assessment (PGA) at Week 4 and Week 8 | 8 weeks: 25% to 49% clearing | 0 Participants |
| Belumosudil 200 mg PO QD | Efficacy: Physician Global Assessment (PGA) at Week 4 and Week 8 | 8 weeks: 0% to 24% clearing | 6 Participants |
| Belumosudil 200 mg PO QD | Efficacy: Physician Global Assessment (PGA) at Week 4 and Week 8 | 8 weeks: Worse | 1 Participants |
| Belumosudil 200 mg PO QD | Efficacy: Physician Global Assessment (PGA) at Week 4 and Week 8 | 8 weeks: Missing (no data) | 1 Participants |
Secondary
PK: AUC(0-24) and AUC(Inf)
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Belumosudil 200 mg PO QD | PK: AUC(0-24) and AUC(Inf) | AUC(0-24): Day 1 | 7360 ng*hr/mL | Standard Deviation 3180 |
| Belumosudil 200 mg PO QD | PK: AUC(0-24) and AUC(Inf) | AUC(0-24): Day 28 | 5500 ng*hr/mL | Standard Deviation 3790 |
| Belumosudil 200 mg PO QD | PK: AUC(0-24) and AUC(Inf) | AUC(inf) from Day 1 | 8230 ng*hr/mL | Standard Deviation 3600 |
| Metabolite M1 | PK: AUC(0-24) and AUC(Inf) | AUC(0-24): Day 1 | 1040 ng*hr/mL | Standard Deviation 545 |
| Metabolite M1 | PK: AUC(0-24) and AUC(Inf) | AUC(0-24): Day 28 | 162 ng*hr/mL | Standard Deviation 2320 |
| Metabolite M1 | PK: AUC(0-24) and AUC(Inf) | AUC(inf) from Day 1 | 1120 ng*hr/mL | Standard Deviation 680 |
Secondary
PK: Cmax and Cmin
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Belumosudil 200 mg PO QD | PK: Cmax and Cmin | Cmin: Day 1 | 59.6 ng/mL | Standard Deviation 29.3 |
| Belumosudil 200 mg PO QD | PK: Cmax and Cmin | Cmax: Day 1 | 1240 ng/mL | Standard Deviation 704 |
| Belumosudil 200 mg PO QD | PK: Cmax and Cmin | Cmin: Day 28 | 35.9 ng/mL | Standard Deviation 22.9 |
| Belumosudil 200 mg PO QD | PK: Cmax and Cmin | Cmax: Day 28 | 810 ng/mL | Standard Deviation 475 |
| Metabolite M1 | PK: Cmax and Cmin | Cmin: Day 1 | 18.7 ng/mL | Standard Deviation 9.16 |
| Metabolite M1 | PK: Cmax and Cmin | Cmax: Day 28 | 15.0 ng/mL | — |
| Metabolite M1 | PK: Cmax and Cmin | Cmax: Day 1 | 21.3 ng/mL | Standard Deviation 10.9 |
| Metabolite M1 | PK: Cmax and Cmin | Cmin: Day 28 | 10.7 ng/mL | — |
| Metabolite M2 | PK: Cmax and Cmin | Cmin: Day 28 | 17.6 ng/mL | Standard Deviation 7.36 |
| Metabolite M2 | PK: Cmax and Cmin | Cmax: Day 1 | 221 ng/mL | Standard Deviation 165 |
| Metabolite M2 | PK: Cmax and Cmin | Cmax: Day 28 | 131 ng/mL | Standard Deviation 152 |
| Metabolite M2 | PK: Cmax and Cmin | Cmin: Day 1 | 21.1 ng/mL | Standard Deviation 6.13 |
Secondary
PK: t(1/2)
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Belumosudil 200 mg PO QD | PK: t(1/2) | t(1/2): Day 1 | 6.08 hours | Standard Deviation 0.681 |
| Belumosudil 200 mg PO QD | PK: t(1/2) | t(1/2): Day 28 | 5.27 hours | Standard Deviation 0.692 |
| Metabolite M1 | PK: t(1/2) | t(1/2): Day 28 | 2.26 hours | — |
| Metabolite M1 | PK: t(1/2) | t(1/2): Day 1 | 4.25 hours | Standard Deviation 3.95 |
Secondary
PK: Tmax
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
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Belumosudil 200 mg PO QD | PK: Tmax | Tmax: Day 28 | 4.00 hours |
| Belumosudil 200 mg PO QD | PK: Tmax | Tmax: Day 1 | 2.00 hours |
| Metabolite M1 | PK: Tmax | Tmax: Day 1 | 2.00 hours |
| Metabolite M1 | PK: Tmax | Tmax: Day 28 | 4.00 hours |
| Metabolite M2 | PK: Tmax | Tmax: Day 1 | 2.00 hours |
| Metabolite M2 | PK: Tmax | Tmax: Day 28 | 4.00 hours |