A Phase 2, Double-blind, Placebo-controlled Study of the Efficacy and Safety of Belumosudil in Subjects With Moderate/Severe Chronic Plaque Psoriasis

This phase 2, two-period, dose-finding, placebo-controlled study is performed on adult male and female subjects to evaluate the efficacy and safety of subjects with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy.

Period 1: Double-blind, Placebo-controlled Treatment Period

Approximately 110 subjects are planned to be randomly assigned to each of 5 dose cohorts in a 1:1:1:1:1 manner. Each cohort is planned to have 22 subjects who meet eligibility criteria. Subjects are treated with oral (PO) belumosudil tablets or placebo tablets as follows:

• 200 mg belumosudil once daily (QD) (Cohort 1) = one 200 mg belumosudil tablet and 1 matching placebo in the morning and 1 matching placebo in the evening
• 200 mg belumosudil twice daily (BID) (Cohort 2) = one 200 mg belumosudil tablet in the morning and one matching placebo in the morning, and one 200 mg belumosudil tablet in the evening
• 400 mg belumosudil QD (Cohort 3) = two 200 mg belumosudil tablets in the morning and one matching placebo in the evening
• 600 mg/day belumosudil (Cohort 4) = two 200 mg belumosudil tablets in the morning and one 200 mg belumosudil tablet in the evening
• Matching placebo BID (Cohort 5) = 2 matching placebo tablets in the morning and 1 matching placebo tablet in the evening

Subjects in each of the 5 cohorts in Period 1 are treated with study medication for a period of 16 weeks.

Note: Originally, a sample size of 36 subjects per cohort was planned to provide approximately 90% probability ≥ 1 subject in the 5 cohorts would experience an adverse event (AE) that had an underlying rate of ≥ 6% and approximately an 80% probability of ≥ 1 subject in the cohort experiencing an AE that had an underlying rate of ≥ 4%. However, due to a newly available plaque psoriasis treatment, the study is terminated early with 110 subjects.

Period 2: Open-label Treatment Period (with Belumosudil)

All subjects treated for 16 weeks, regardless of treatment with belumosudil (Cohorts 1 through 4) or placebo (Cohort 5) are given the option to receive 400 mg belumosudil QD for an additional 32 weeks (Week 16 through Week 48).

Follow-up Period

All subjects have a safety evaluation 30 days after the last dose of study drug.

Efficacy is assessed by the following scores at scheduled time points throughout the study:

• Psoriasis Area and Severity Index (PASI): Measure of psoriasis disease severity using average redness, thickness, and scaliness of lesions (each lesion graded 0 to 4), combined into single score ranging on a scale from 0 (no disease) to 72 (maximum disease)
• Physician's Global Assessment (PGA): Physician's assessment of a subject's psoriasis, relative to baseline, ranging on a scale from 1 (100% clearing of psoriasis) to 6 (poor to no clearing)
• Dermatology Life Quality Index (DLQI): Skin disease-specific instrument for assessing impact of disease on subject's quality of life ranging on a scale from 0 (no effect on subject's life) to 30 (extremely large effect on subject's life)

Safety is assessed by;

• AEs and serious AE (SAEs)
• Physical examination
• Vital sign measurements
• Clinical laboratory evaluations
• Electrocardiogram
• Reasons for discontinuation due to toxicity analyses

The maximum duration for subjects who complete Period 1 (Double-blind, Placebo-controlled) is 24 weeks (up to 4-week Screening, 16-week Period 1 treatment, and 4-week Follow-up). The maximum duration for subjects who complete Period 2 (Open-label) is 56 weeks (up to 4-week Screening, 16-week Double-blind Treatment Period, 32-week Open-label Treatment Period, and 4-week Follow-up).

Inclusion criteria

• Adult subjects between the ages of 18 and 65 years
• Able to provide written Informed Consent Form prior to the performance of any study-specific procedures
• Diagnosis of moderate to severe chronic plaque psoriasis and a candidate for systemic therapy or phototherapy
• PASI of ≥ 12 at screening and prior to the first dose of study drug, confirmed at Week 1 Day 1 (Baseline)
• ≥ 10% PASI body surface area involvement at screening and prior to the first dose of study drug, confirmed at Baseline
• Willing to avoid tanning devices
• Adequate bone marrow function:

• Absolute neutrophil count > 1500/mm^3
• Hemoglobin > 9.0 g/dL
• Platelets > 100,000/mm^3
• Adequate safety laboratory values:

• Serum total bilirubin within normal limits (WNL)
• Aspartate aminotransferase (AST) and alalnine aminotransferase (ALT) < 2 × upper limit of normal (ULN)
• Serum creatinine < 1.5 × ULN
• Female subjects of childbearing potential with a negative pregnancy test at screening. Females of childbearing potential were defined as sexually mature women without prior hysterectomy or who had any evidence of menses in the past 12 months. However, women who had been amenorrheic for 12 or more months were still considered to be of childbearing potential if the amenorrhea was possibly due to prior chemotherapy, antiestrogens, or ovarian suppression

• Women of childbearing potential (i.e., menstruating women) had to have a negative urine pregnancy test (positive urine tests were to be confirmed by serum test) documented within the 24-hour period prior to the first dose of study drug
• Sexually active women of childbearing potential enrolled in the study had to agree to use 2 forms of accepted methods of contraception during the course of the study and for 3 months after their last dose of study drug. Effective birth control included: (a) intrauterine device plus 1 barrier method; (b) on stable doses of hormonal contraception for at least 3 months (e.g., oral, injectable, implant, transdermal) plus one barrier method; and (c) 2 barrier methods. Effective barrier methods were male or female condoms, diaphragms, and spermicides (creams or gels that contained a chemical to kill sperm); or (d) a vasectomized partner
• For male patients who were sexually active and who were partners of premenopausal women: agreed to use 2 forms of contraception as defined above during the treatment period and for at least 3 months after the last dose of study drug
• Willing to complete all study measurements and assessments in compliance with the protocol

Exclusion criteria

• Non-plaque or drug-induced (antimalarials, lithium) psoriasis (If subject was taking angiotensin II receptor blockers or beta blockers doses must have been stable for 6 months prior to study entry)
• Used systemic corticosteroids within 12 weeks prior to study entry
• Used topical corticosteroids except to the face, groin, or scalp
• Used methotrexate, retinoids (such as acitretin), or calcineurin inhibitors (such as cyclosporine) within 4 weeks prior to study entry
• Phototherapy within 4 weeks prior to study entry
• Biologic therapies, including antibodies to IL-17; anti-tumor necrosis factor-alpha; and anti-IL-12 & IL-23 within 3 months prior to study entry
• Current use of an inhibitor or inducer of CYP3A4
• Active viral, fungal, or bacterial skin infection (other than nail fungal infection).
• Pregnant or lactating woman
• History of gastrointestinal (GI) surgery including any bariatric surgery, or any GI condition that might interfere with drug absorption
• Participating in another study with an investigational drug or within 28 days or 5 half-lives of the investigational drug (whichever was longer) 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
• Regular and/or excessive use of alcohol within 2 years prior to study entry defined as alcohol intake > 14 drinks per week in a man or > 7 drinks per week in a woman. Approximately 10 g of alcohol equaled one "drink" unit. One unit equaled 1 ounce of distilled spirits, one 12-ounce beer, or one 4-ounce glass of wine
• QT interval data corrected using Fridericia's formula (QTcF) > 450 msec (average of 3 readings) during screening
• Exposure to belumosudil or known allergy/sensitivity to belumosudil within the last 6 months prior to study entry or any other ROCK-2 inhibitor
• History or presence of any of the following:

• ALT or AST > 2.0 × ULN at screening
• Renal disease and/or serum creatinine > 1.5 × ULN at screening