Safety, Tolerability, PK, PD and Preliminary Efficacy of ONO-4685

Study Overview
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Brief Summary
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This is an early phase study to assess the safety and tolerability of ONO-4685 in patients with psoriasis. In addition, the study will assess how the drug is distributed and eliminated by the body (pharmacokinetics) and how the drug affects the body (pharmacodynamics). This will be done by measuring the amount of drug in the blood and measuring other markers in the body that might have been affected by ONO-4685. The study will also look at preliminary information on whether ONO-4685 might be effective in treating psoriasis. The study will be split into three parts. Part A will assess a single dose of ONO-4685 in small groups of patients, each group planned to receive a higher dose than the last group. In Part B and C, patients will receive multiple doses of ONO-4685 over a period of 4 weeks.

Official Title
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A Randomised, Multi-centre, Double-blind, Placebo-controlled, Single Ascending Dose, Multiple Dose Study to Assess Safety, Tolerability, PK, PD & Preliminary Efficacy of IV Doses of ONO-4685 in Patients With Plaque Psoriasis

Conditions
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Plaque Psoriasis

Intervention / Treatment
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* Drug: ONO-4685
* Drug: Placebo
* Drug: ONO-4685
* Drug: Placebo
* Drug: ONO-4685
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Subjects must be willing and able to participate in the study A diagnosis of plaque-type psoriasis for ≥6 months. Plaque-type psoriasis involving ≥3% of body surface area (BSA) (Parts B and C). Willing to provide skin biopsies (Parts B and C). Subjects in good health, as judged by medical history, medical examination, vital signs, ECG and clinical laboratory tests. Subjects willing to comply with the contraception and sperm and ova donation requirements of the protocol. Exclusion Criteria Subjects with any clinically significant abnormality in screening tests. Guttate, erythrodermic or pustular psoriasis as sole or predominant form of the psoriasis, or other skin condition (eg eczema). Presence or history of alcohol or drugs abuse. Heavy smokers (more than 20 cigarettes or use more than ½ ounce (12.5 grams) of tobacco each day). Subjects have had any 'live' vaccines (excluding COVID-19 vaccine) during the 3 months before the first dose of study medicine. Subjects have had a first COVID-19 vaccine within 6 weeks or second and booster COVID-19 vaccinations within 2 weeks before the first dose of study medicine. Subjects have had any clinically significant disease or infection, including tuberculosis. Presence or history of malignancy (cancer) including lymphoproliferative disorders. Subject is pregnant, lactating, or breastfeeding. Subjects have received treatment with biologics in the last 3 months, immunosuppressant medicine or prescription medicine for psoriasis within 4 weeks before admission to the ward; have used phototherapy from 2 weeks before admission to the ward; have used highly potent or potent topical steroids within 2 weeks before admission to the ward. Subjects have used topical corticosteroids or Vitamin D analogues within 7 days before admission to the ward (Parts B and C).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This is a phase I, multi-centre study to assess the safety, tolerability, PK & PD of ONO-4685. This study consists of: Part A single ascending dose, Part B an assessment of multiple doses & Part C to undertake initial assessment of efficacy with multiple doses. The study will recruit patients, male & female, with mild or moderate psoriasis diagnosed for at least 6 months. Following screening activities, patients are admitted to a clinical unit 1 day ahead of dosing and will stay at the unit for 4 nights. For patients receiving multiple doses, they will attend the clinic on the day of dosing and will stay for 3 nights. All patients will be followed up, for up to 24 weeks from 1st dose. The study will recruit 6 patients per cohort for part A & B and 18 patients per cohort for part C. The overall active to placebo ratio will be 2:1.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A, Active<br> | Drug: ONO-4685<br>* -Part A: Single ascending doses of ONO-4685 as a single IV dose (Cohort A1-A5).<br>|
| Placebo Comparator: Part A, Placebo<br> | Drug: Placebo<br>* -Part A: Single ascending doses of placebo as a single IV dose (Cohort A1-A5).<br>|
| Experimental: Part B, Active<br> | Drug: ONO-4685<br>* -Part B: Multiple doses of ONO-4685 as IV doses over a 4-week treatment period (Cohort B1 and B2)<br>|
| Placebo Comparator: Part B, Placebo<br> | Drug: Placebo<br>* -Part B: Multiple doses of placebo as IV doses over a 4-week treatment period (Cohort B1 and B2).<br>|
| Experimental: Part C, Active<br> | Drug: ONO-4685<br>* -Part C: Multiple doses of ONO-4685 as IV doses over a 4-week treatment period (Cohort C1 and C2).<br>|
| Placebo Comparator: Part C, Placebo<br> | Drug: Placebo<br>* -Part C: Multiple doses of placebo as IV doses over a 4-week treatment period (Cohort C1 and C2).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment emergent adverse events (TEAEs) by severity | Number of participants with TEAEs. An adverse event is any untoward medical occurrence in a participant who receives study drug without regard to possible causal relationship. | End of Study (3 years) | 
| Clinical laboratory tests | Number of participants with clinical laboratory abnormalities (including haematology, clinical chemistry and urinalysis). | End of Study (3 years) | 
| Cytokines | Number of participants with elevated cytokines. | Up to day 8 post dosing day | 
| Lymphocytes | Number of participants with depleted lymphocytes. | End of Study (3 years) | 
| Vital signs (blood pressure) | Number of participants with clinically significant changes in vital signs (blood pressure) | End of Study (3 years) | 
| Vital signs (respiration rate) | Number of participants with clinically significant changes in vital signs (respiration rate) | End of Study (3 years) | 
| Vital signs (temperature) | Number of participants with clinically significant changes in vital signs (temperature) | End of Study (3 years) | 
| Vital signs (pulse rate) | Number of participants with clinically significant changes in vital signs (pulse rate) | End of Study (3 years) | 
| ECG parameters | Number of participants with ECG abnormalities. | End of Study (3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (Ceoi) | Assessment of the observed plasma concentration of ONO-4685 at the end of infusion (eoi). | Part A, Day 1 (day of dosing). Part B and C, Day 1 (day of first dose) and Day 15 or 22 (day of last dose) depending on weekly or bi-weekly dosing. | 
| Pharmacokinetics, Cmax | Assessment of the maximum observed plasma concentration of ONO-4685. | Part A up to day 85, Part B and Part C up to day 113 | 
| Pharmacokinetics, Tmax | Assessment of the time of maximum plasma concentration of ONO-4685. | Part A up to day 85, Part B and Part C up to day 113 | 
| Pharmacokinetics, AUC last | Assessment of the area under the plasma ONO-4685 concentration-time curve from time 0 to time of the last quantifiable concentration. | Part A up to day 85 | 
| Pharmacokinetics, AUCinf | Assessment of the area under the plasma ONO-4685 concentration-time curve from time 0 to infinity. | Part A up to day 85 | 
| Pharmacokinetics, CL (Clearance) | Assessment of the plasma clearance of ONO-4685. | Part A up to day 85 | 
| Pharmacokinetics, Vss | Assessment of the volume of distribution at steady state of ONO-4685 | Part A up to day 85 | 
| Pharmacokinetics, T1/2 | Assessment of the terminal elimination half-life of ONO-4685 in plasma. | Part A up to day 85, and after the last dose administration (Day 15 or 22) in Part B and Part C up to day 113. | 
| Pharmacokinetics, AUCtau | Assessment of the area under the plasma ONO-4685 concentration-time curve during the dosing interval. | Part B and C, after first (Day 1) and last (Day 15 or 22) dose | 
| Pharmacokinetics, Ctrough | Assessment of the trough concentration of ONO-4685 in plasma. | Part B and C, prior to administration of each dose | 
| Pharmacodynamics, lymphocytes | Assessment of total lymphocytes, including subsets CD4+ T cell, CD8+ T cell, B cell and NK cell. | Part A up to day 85, Part B up to day 113, Part C up to day 169 | 
| Pharmacodynamics, immunoglobulin | Assessment of total immunoglobulin, IgA, IgG and IgM. | Part A up to day 85, Part B up to day 113, Part C up to day 169 | 
| Pharmacodynamics, cytokines | Assessment of cytokines, including IL-2, IL-6, IL-10, TNF-α and INF-γ. | Part A up to day 8, Part B and Part C up to day 8 post last dose | 
| Immunogenicity, Anti-ONO-4685-antibodies (ADA) | Assessment of antibodies generated to ONO-4685 to measure potential immunogenicity. | Part A up to day 85, Part B and Part C up to day 113 | 
| Efficacy, Psoriasis Area and Severity Index (PASI) | Assessment of change in PASI from baseline. | Part A up to day 85, Part B up to day 113, Part C up to day 169 | 
| Efficacy, Psoriasis Area and Severity Index (PASI) 50 | Assessment of number of subjects that achieve PASI 50, a 50% reduction in PASI from baseline. | Part A up to day 85, Part B up to day 113, Part C up to day 169 | 
| Efficacy, Psoriasis Area and Severity Index (PASI) 75 | Assessment of number of subjects that achieve PASI 75, a 75% reduction in PASI from baseline. | Part A up to day 85, Part B up to day 113, Part C up to day 169 | 
| Efficacy, Psoriasis Area and Severity Index (PASI) 90 | Assessment of number of subjects that achieve PASI 90, a 90% reduction in PASI from baseline. | Part A up to day 85, Part B up to day 113, Part C up to day 169 | 
| Efficacy, Target Plaque Severity Score (TPSS) | Assessment of change in TPSS from baseline. | Part A up to day 85, Part B up to day 113, Part C up to day 169 | 
| Efficacy, Physician's Global Assessment (PGA) | Assessment of change in PGA from baseline. | Part A up to day 85, Part B up to day 113, Part C up to day 169 | 
| Efficacy, Physician's Global Assessment (PGA) 0/1 | Assessment of the number of subjects that achieve PGA 0/1. | Part A up to day 85, Part B up to day 113, Part C up to day 169 | 
| Efficacy, Physician's Global Assessment (PGA) 0/1 and a 2-point improvement | Assessment of the number of subjects that achieve PGA 0/1 and a 2-point improvement from baseline. | Part A up to day 85, Part B up to day 113, Part C up to day 169 | 
| Efficacy, Body Surface Area (BSA) | Assessment of the change in plaque BSA from baseline | Part A up to day 85, Part B up to day 113, Part C up to day 169 | 
| Patient Reported Outcome, Dermatology Life Quality Index (DLQI) | Assessment of the change in DLQI from baseline. | Part A up to day 85, Part B up to day 113, Part C up to day 169 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Psoriasis, ONO-4685, PD-1, Bi-specific antibody, PD-1 Receptor, PD-1 Agonist