Clinical trial NCT02317627: Phase 2, Open-label, Study of KD025 in Subjects With Psoriasis Vulgaris Who Failed First-line Therapy
Official title: A Phase 2, Open-Label, Dose-finding Study to Evaluate the Safety, Tolerability, and Activity of KD025 in Subjects With Psoriasis Vulgaris Who Failed First-line Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Psoriasis Vulgaris
Lead sponsor: Kadmon Corporation, LLC
Sponsor class: INDUSTRY
First posted: 2014-12-16
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study was performed to evaluate the safety, tolerability, activity, pharmacokinetics (PK), and daily dose regimen of KD025 administered orally (PO) for 12 weeks to subjects with psoriasis vulgaris who failed at least one line of systemic therapy.

Detailed description: Study KD025-206 was a phase 2, open-label, dose-finding, safety, tolerability, activity, and PK study of KD025 in subjects with psoriasis who had failed at least 1 line of systemic therapy or phototherapy.

Subjects received KD025 PO for 12 weeks. Planned enrollment was 36 subjects in 3 cohorts, 12 subjects per cohort:

* Cohort 1 (12 subjects): KD025 400 mg once daily (QD) PO for 12 weeks
* Cohort 2 (12 subjects): KD025 200 mg PO twice daily (BID) for 12 weeks
* Cohort 3 (12 subjects): KD025 400 mg BID PO for 12 weeks

Subjects were initially enrolled simultaneously in Cohort 1 and Cohort 2 according to a randomization schedule, with safety reviewed before any subjects. If safety guidelines were met, Cohort 3 was added to explore the efficacy and safety of KD025 at a dose of 400 mg PO BID.

Subjects underwent safety evaluations: medical history evaluations; physical examinations (PEs); vital sign measurements; weight measurements; adverse event (AE) assessments; concomitant medication assessments; blood sample collection for hematology, chemistry, and coagulation; lipid panel; thyroid-stimulating hormone; measurements of antinuclear antibody; anti-double-stranded deoxyribonucleic acid; Complement C; antiphospholipid antibody; liver ultrasound (US); pregnancy testing for females of childbearing potential; PK sampling (subset of subjects only); urinalysis; and electrocardiogram (ECG).

Subjects underwent efficacy evaluations: Psoriasis Area and Severity Index (PASI) scoring; Physicians Global Assessment (PGA) scoring; and Dermatologic Life Quality Index (DLQI) scoring.

Subjects participating in PK sampling were admitted to the clinic on Month 1 Day 1 (M1D1) for PK procedures and were discharged on M2D2. Blood samples for PK analyses were collected on M2D1 and Month 3 Day 1 (M3D1) on an outpatient basis. Subjects were not to take their morning dose until after blood samples were drawn.

A Follow-Up visit occurred 30 ± 3 days after the last dose of study drug.

The endpoints for efficacy were PASI, PGA, and DSQI scores.

1. Psoriasis Area and Severity Index (PASI): The PASI is a measure of the psoriasis disease severity using the average redness, thickness, and scaliness of the lesions (each graded on a 0 to 4 scale), which is weighted by the area of involvement. The PASI combines the assessment of the severity of lesions and the area affected into a single score ranging from 0 (no disease) to 72 (maximal disease).
2. Physicians Global Assessment (PGA): The relative PGA documents the physician's assessment of the subject's psoriasis status. Consideration was given to the percent of body involvement as well as overall induration, scaling, and erythema. The PGA was assessed relative to baseline condition and defined as: (1) clear; (2) excellent; (3) good; (4) fair; (5) poor; and (6) worse.
3. Dermatology Life Quality Index (DLQI): The DLQI is a skin disease-specific instrument designed to assess the impact of the disease on a subject's quality of life (QOL). It is a 10-item questionnaire that assesses 6 different aspects of quality of life: symptoms and feelings, daily activities, leisure, work or school performance, personal relationships, and treatment. Possible DLQI scores range from 0 (no detectable impairment on a subject's QOL) to 30 (extremely large effect on a subject's QOL).

Safety was assessed by standard clinical and laboratory tests (hematology, serum chemistry, and urinalysis), PEs, and reporting of treatment-emergent adverse events (TEAEs). Toxicity grades were defined using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. In addition, subjects had liver ultrasound and liver functioning testing assessed for possible steatosis.

Blood samples for determination of PK plasma concentrations of KD025 and its metabolites were collected for maximum concentration (Cmax); time of maximum concentration (Tmax); area under the concentration-time curve (AUC) at 0 to 24 hours, 0 to last, and 0 to infinity (0 to 24, 0 to last, 0 to infinity \[inf\]); half-life (t1/2); and accumulation ratio (metabolic-to-parent drug ratio).

Eligibility criteria: Inclusion Criteria:

* Able to provide written informed consent prior to the performance of any study specific procedures
* Diagnosis of moderately severe plaque psoriasis that has been moderately stable for 6 months and failed at least 1 line of systemic or phototherapy and is a candidate for additional systemic therapy
* PASI of ≥ 12 within the 24-hour period prior to the first dose of study drug
* At least 10% of body surface area affected by plaque psoriasis within the 24-hour period prior to the first dose of study drug
* Willing to avoid tanning devices
* Willing to forgo other systemic and topical treatments for psoriasis during the course of the study
* Adequate bone marrow function: absolute neutrophil count \> 1500/mm\^3; hemoglobin \> 9.0 g/dL; platelets \> 100,000/mm\^3
* Negative urine pregnancy test (for women of childbearing potential) documented within the 24-hour period prior to the first dose of study drug
* 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. Effective birth control included implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence, or vasectomized partner
* 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 is taking angiotensin II receptor blockers or beta blockers doses had to be stable for 6 months prior to study entry)
* Use of corticosteroid or immunosuppressive therapy within 4 weeks prior to study entry except for Class 5 or weaker topical corticosteroids or immunosuppressive therapies to the face, groin, or scalp.
* Use of methotrexate, acitretin, or cyclosporine within 4 weeks prior to study entry
* Use of phototherapy within 4 weeks prior to study entry
* Use of biologic therapies, including antibodies to IL-17, within 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
* History of gastrointestinal (GI) surgery including bariatric surgery, or any GI condition that might interfere with drug absorption
* 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 (such as poorly controlled psychiatric disease or coronary artery disease)
* Regular and excessive use of alcohol within the 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 equals one "drink" unit. One unit equals 1 ounce of distilled spirits, one 12-ounce beer, or one 4-ounce glass of wine
* History or presence of any of the following:

  1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 2.0 × the upper limit of normal (ULN) at screening. (Subjects with an isolated AST elevation of any magnitude, or a ratio of AST:ALT \> 1.5 interviewed regarding use of alcohol, have levels repeated and participation in the study should be discussed with the medical monitor.)
  2. Renal disease and/or serum creatinine \> 1.5 × ULN at screening
* QTc(F) interval (QT interval data corrected using Fridericia's formula) \> 450 msec at the screening or predose ECG
* Previous exposure to KD025 or known allergy/sensitivity to KD025 or any other ROCK-2 inhibitor

Primary outcomes:
measure: Efficacy: Percentage of Subjects With ≥ 75% Decrease or ≥ 50% Decrease in PASI Score at EOT---ITT Population
timeFrame: 12 weeks
measure: Efficacy: Percentage of Subjects With ≥ 75% Decrease or ≥ 50% Decrease With PASI Score at EOT---Evaluable Population
timeFrame: 12 weeks
measure: Safety: Percentage of Subjects With AEs by Severity and Relationship to Belumosudil--ITT Population
timeFrame: 12 weeks
Secondary outcomes:
measure: Efficacy: Mean Change in PASI Score at 12 Weeks From Baseline--ITT Population
timeFrame: 12 weeks
measure: Efficacy: Mean Change in PASI Score at 12 Weeks From Baseline--Evaluable Population
timeFrame: 12 weeks
measure: Efficacy: Percentage of Subjects With a Decrease in PASI After 4 Weeks---ITT Population
timeFrame: 4 weeks
measure: Efficacy: Percentage of Subjects With a Decrease in PASI Score After 8 Weeks---ITT Population
timeFrame: 8 weeks
measure: Efficacy: Percentage of Subjects With a Decrease in PASI Score at EOT---ITT Population
timeFrame: 12 weeks
measure: Efficacy: Percentage of Subjects With a Decrease in PASI Score After 4 Weeks, 8 Weeks, and 12 Weeks---Evaluable Population
timeFrame: 12 weeks
measure: Efficacy: Mean Change in PASI Score After 4 Weeks---ITT Population
timeFrame: 4 weeks
measure: Efficacy: Mean Change in PASI Score After 8 Weeks---ITT Population
timeFrame: 8 weeks
measure: Efficacy: Mean Change in PASI Score at 4 and 8 Weeks---Evaluable Population
timeFrame: 8 weeks
measure: Efficacy: Percentage of Subjects With Improvement in PGA af 4 Weeks---ITT Population
timeFrame: 4 weeks
measure: Efficacy: Percentage of Subjects With Improvement in PGA af 8 Weeks---ITT Population
timeFrame: 8 weeks
measure: Efficacy: Percentage of Subjects With Improvement in PGA af EOT--ITT Population
timeFrame: 12 weeks
measure: Efficacy: Percentage of Subjects With Improvement in PGA af 4, 8, and 12 Weeks---Evaluable Population
timeFrame: 12 weeks
measure: Efficacy: Mean Changes in DLQI at EOT--ITT Population
timeFrame: 12 weeks
measure: Efficacy: Mean Changes in DLQI at 12 Weeks--Evaluable Population
timeFrame: 12 weeks
measure: Pharmacokinetics: Cmax of Parent Drug KD025, KD025m1, and KD025m2
timeFrame: 24 hours
measure: Pharmacokinetics: AUC of Parent Drug KD025, KD025m1, and KD025m2
timeFrame: 24 hours
measure: Pharmacokinetics: t(1/2) of KD025
timeFrame: 24 hours
measure: Pharmacokinetics: MR C(Max) and MR AUC(0-t) for KD025m1 and KD025m2
timeFrame: 24 hours
Other outcomes:
Locations:
city: Glendale
country: United States
facility: Arrowhead Health Centers
state: Arizona
city: Santa Ana
country: United States
facility: Southern California Dermatology, Inc.
state: California
city: Lake Charles
country: United States
facility: Shondra L. Smith
state: Louisiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Henderson
country: United States
facility: Clinical Studies Group, LLC
state: Nevada
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: High Point
country: United States
facility: High Point Clinical Trials Center
state: North Carolina
city: Duncansville
country: United States
facility: Altoona Center for Clinical Research
state: Pennsylvania
city: Dallas
country: United States
facility: Metroplex Clinical Research Center (MCRC)
state: Texas
Study officials:
References:
citation: Zanin-Zhorov A, Weiss JM, Trzeciak A, Chen W, Zhang J, Nyuydzefe MS, Arencibia C, Polimera S, Schueller O, Fuentes-Duculan J, Bonifacio KM, Kunjravia N, Cueto I, Soung J, Fleischmann RM, Kivitz A, Lebwohl M, Nunez M, Woodson J, Smith SL, West RF, Berger M, Krueger JG, Ryan JL, Waksal SD. Cutting Edge: Selective Oral ROCK2 Inhibitor Reduces Clinical Scores in Patients with Psoriasis Vulgaris and Normalizes Skin Pathology via Concurrent Regulation of IL-17 and IL-10. J Immunol. 2017 May 15;198(10):3809-3814. doi: 10.4049/jimmunol.1602142. Epub 2017 Apr 7.