A three-part, double-blind, placebo-controlled, phase I/Ib study of the safety, tolerability and pharmacokinetics of single and multiple ascending doses of IMU-935 in healthy volunteers and Psoriasis Patients.

INTERVENTION: This is a double‐blind, placebo controlled, ascending dose, multi‐cohort trial. The study will be conducted in three parts: a single ascending dose (SAD) part in healthy volunteers, followed by a multiple ascending dose (MAD) part in healthy volunteers and a repeat dose 2‐dose level treatment in moderate‐to‐severe psoriasis patients. The study is subdivided in 3 parts, Part A, Part B and Part C. In Part A, healthy volunteers will be enrolled to receive single ascending doses of IMU‐935 or placebo (oral capsule). In Part B, healthy volunteers will be enrolled to receive multiple ascending doses of IMU‐935 or placebo (oral capsule). In Part C, psoriasis patients will be enrolled to receive two different dose levels of IMU‐935 or placebo (oral capsule). The decision to escalate between dose levels and proceed to each of study parts (Parts A, B and C) will be based upon review of the available Adverse Event, clinical laboratory and Pharmacokinetic data by the Safety Monitoring Group. The starting dose, dose increments and dose range are based on available pre‐clinical data. Part A: In Part A, IMU‐935 dose levels in the range of 25 – 400 mg will be investigated in a total of six cohorts. Each cohort participant receiving a single (one) dose. The 8 participants in each cohort will be randomized to receive either IMU‐935 or placebo (ratio 3:1). Cohorts 1, 3, 4, 5 and 6 will receive IMU‐935 under fasted conditions only. Cohort 2 participants will receive IMU‐935 under fasted and fed conditions (controlled in‐house within the Phase I unit through monitoring and controlling meal times). Dosing in each dose level cohort will start with two sentinel participants with one of the two participants randomized to receive IMU‐935 and the other participant randomized to receive placebo. The safety and tolerability of each sentinel participant will be monitored until Day 4 and will be reviewed prior to dosing the remainder of participants in each CONDITION: Psoriasis; ; Psoriasis Skin ‐ Dermatological conditions PRIMARY OUTCOME: To assess the safety and tolerability of IMU‐935 when administered as a single oral dose in healthy adult volunteers, as a 14‐day repeat oral dose to healthy volunteers and as a 28‐day oral dose in psoriasis patients.[Clinical observations, safety laboratories, assessments, ECGs and Vitals.; ; Part A; Physical Exam: Screening, Day ‐1, Day 1, Pre‐dose, Day 1 (3h and 6h), Day 2, Day 3 and Day 4. ; ECGs and Vitals: Day ‐1, Day 1, Pre‐dose, Day 1 (3h and 6h), Day 2, Day 3 and Day 4; Safety laboratories (Hematology, Biochemistry and Urine samples): Screening, Day ‐1, Day 1(6hr), Day 2, Day 4 and End of Study; ; ; ; ] SECONDARY OUTCOME: Exploratory Objective: ; ; To investigate pharmacodynamic marker changes associated with administration of IM‐935 in healthy volunteers and psoriasis patients.[Cytokine Detection Assay. ; ; Part C: Day 1 and Day 28, Early Termination Visit if Applicable.] To assess the effects of IMU‐935 on skin disease in moderate‐to‐severe plaque psoriasis patients.[PASI Scale ; ; 1. Absolute and relative change of PASI scores at Days 8, 15, 22 and 28 compared to baseline (Day 1 pre‐dose); ; 2. Proportion of patients to achieve: ; • PASI 90 (i.e., 90% reduction from baseline PASI score); ; • PASI 75 (i.e., 75% reduction from baseline PASI score); ; • PASI 50 (i.e., 50% reduction from baseline PASI score); ; • PASI 25 (i.e., 25% reduction from baseline PASI score). ; 3. Change from baseline in DLQI at Day 28 compared to baseline (Day 1 pre‐dose); ; 4. Change in serum cytokine and biomarker levels (including but not restricted to: IL‐17A, IL‐17F, IL‐12, IL‐22, IL‐23, TNF?) at Day 28 (or ETV) compared to baseline (Day 1 pre‐dose); ; [Drug detection assay using a volunteer plasma. ; 5. Change in skin immune cells and other relevant biomarker levels (including but not restricted to: Th17, Th1, Treg, granulocytes, B cells) from skin biopsy samples collected at baseline (Day 1 pre‐dose) and Day 28; ; 6. Change in gene expression markers from whole blood at Day 15 and Day 28 compared to baseline (Day 1 pre‐dose).] To assess the pharmacokinetics of IMU‐935 following administration of a single dose and a 14‐day repeat dose in healthy volunteers. ; ; PK collections collected at: ; Part A Cohorts 1, 3, 4, 5, 6 = Pre‐dose, 1, 2, 3, 4, 5, 6, 8, 10, 14, 24, 48 and 72h post‐dose. ; Part A Cohort 2 = Pre‐dose, 1, 2, 3, 4, 5, 6, 8, 10, 14, 24, 48 and 72h post‐dose (collected at Fed and Fasted Periods) ; Part B: Pre‐dose, 1, 2, 3, 4, 5, 6, 8, 10, 14, 24, 48 and 72h post dose 1 and Pre‐dose, 1, 2, 3, 4, 5, 6, 8, 10, 14, 24, 48 and 72h post dose 14. ; ; The following pharmacokinetic parameters will be determined: ; • Time to maximum concentration (Tmax); ; • Maximum concentration (Cmax); ; • Area under the concentration‐time curve from time 0 to last measurable time‐point (AUC0–t); ; • Area under the concentration‐time curve from time 0 to infinity (AUC0–inf); ; • Terminal Elimination Rate Constant (kel); ; • Terminal half‐life (t1/2); ; • Terminal clearance (CL); ; • Volume of distribution (Vd). ; ; For Part A (SAD): ; • Area under the concentration‐time curve from time 0 to 24 hours following dose administration (AUC0‐24h); ; • Amount of drug excreted in urine in each collection interval. ; • The food effect of the capsule: ; o AUC capsule fed/ AUC capsule fasted ; o Cmax capsule fed/ Cmax capsule fasted ; For Part B (MAD): ; • Area under the concentration���time curve from time 0 to 24 hours following dose administration (AUC0‐24h) and 0 to 72 hours (AUC0‐72h) following the last dose on Day 14; ; • Accumulation factor; ; • Pre‐dose trough on Days 2, 3, 4, 7, and 14; ; ] To assess the trough plasma concentration levels of IMU‐935 in psoriasis patients treated in a 28‐day dose schedule. ; ; [Drug detection assay using a volunteer plasma. ; ; PK collections collected at: ; Part C: Day 1, Day 8, Day 15, Day 22 and Day 28. Early Termination Visit if Applicable.] To compare the pharmacokinetic profile of IMU‐935 capsule administered under fasted and fed conditions.[Drug detection assay using a volunteer plasma. ; ; Part A Cohort 2 = Pre‐dose, 1, 2, 3, 4, 5, 6, 8, 10, 14, 24, 48 and 72h post‐dose (collected at Fed and Fasted Periods)] INCLUSION CRITERIA: Part A and Part B: Healthy Volunteers 1. Participants must have given written informed consent before any study‐related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects; 2. Adult males and females, 18 to 55 years of age (inclusive) at screening; 3. Body Mass Index (BMI) greater than or equal to 18.0 and less than or equal to 32.0 kg/m2, with a body weight greater than or equal to 55 kg at screening; 4. Be non‐smokers (including tobacco, e‐cigarettes and marijuana) for at least 1 month prior to participation in the study; 5. Medically healthy without clinically significant abnormalities at the screening, including: a. Physical examination without any clinically relevant findings; b. Systolic blood pressure in the range of 90 to 160 mmHg (inclusive) and diastolic blood pressure in the range of 50 to 95 mmHg (inclusive) after 5 minutes in su