A Study of Experimental Medication BMS-986251, Taken by Mouth, in Healthy Participants and Patients With Average to Very Serious Psoriasis

Study Overview
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Brief Summary
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The purpose of this study is to investigate experimental medication BMS-986251 taken by mouth in healthy patients and patients with average to very serious Psoriasis (a condition characterized by itchy, dry skin with a scaly rash).

Official Title
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A Double-Blind Randomized Placebo-Controlled Single and Multiple Ascending Doses Study of the Safety and Tolerability, Pharmacokinetics (Including Bioavailability Comparison and Food Effect) and Pharmacodynamics of Oral BMS-986251 Administration in Healthy Subjects, With Efficacy Assessment of Multiple Doses in Patients With Moderate-to-Severe Psoriasis

Conditions
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Rheumatoid Arthritis, Psoriasis, Ankylosing Spondylitis, Inflammatory Bowel Diseases, Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: BMS-986251
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria (Healthy Patients): Males and females, ages 18 to 55 years, inclusive, at screening Healthy subjects, as determined by no clinically significant deviations from normal in medical history, physical examination, 12-lead ECGs, vital signs, and clinical laboratory results Body mass index (BMI) of 18.0 to 30.0 kg/m2, inclusive, at screening Body weight between 55 kg and 105 kg, inclusive, at screening Women must not be breastfeeding Exclusion Criteria (Healthy Patients): Previous participation in the current study Participation in a drug study or exposure to any investigational drug or placebo within 2 months prior to (the first) drug administration in the current study Employees of PRA or the Sponsor and their relatives Any significant acute or chronic medical condition that presents a potential risk to the subject and/or that may compromise the objectives of the study, including active, or history of, liver disease, or intestinal disorder including irritable bowel syndrome Current or recent (within 3 months of study treatment administration) gastrointestinal disease that could affect pharmacokinetics; history of cholecystectomy is not allowed Inclusion Criteria (Psoriasis Patients): Males and females, ages 18 to 70 years, inclusive, at screening BMI of 18.0 to 35.0 kg/m2, inclusive, at screening Body weight between 55 kg and 120 kg, inclusive, at screening Diagnosed with stable chronic plaque psoriasis, for at least 6 months prior to screening and be candidates for either photo-therapy or systemic treatment Moderate-to-severe intensity of psoriasis as defined by: Affected body surface area (BSA) of ≥10% Psoriasis Area and Severity Index (PASI) ≥12 Physician Global Assessment (PGA; 6-point scale) ≥3 Exclusion Criteria (Psoriasis Patients): Previous participation in the current study Participation in a drug study or exposure to any investigational drug or placebo within 2 months prior to (the first) drug administration in the current study Employees of PRA or the Sponsor and their relatives Any significant acute or chronic medical condition that presents a potential risk to the subject and/or that may compromise the objectives of the study, including active, or history of, liver disease, or intestinal disorder including irritable bowel syndrome Current or recent (within 3 months of study treatment administration) gastrointestinal disease that could affect pharmacokinetics; history of cholecystectomy is not allowed Other protocol defined inclusion/exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A Single Ascending Dose (SAD) in Healthy Patients<br>Healthy patient will receive single escalating oral doses of BMS-986251 or placebo | Drug: BMS-986251<br>* Escalating oral dose<br>Other: Placebo<br>* Escalating oral dose<br>|
| Experimental: Part B Multiple Ascending Dose (MAD) in Healthy Patients<br>Healthy patients will receive daily escalating oral doses of BMS-986251 or placebo | Drug: BMS-986251<br>* Escalating oral dose<br>Other: Placebo<br>* Escalating oral dose<br>|
| Experimental: Part C Multiple Dosing in Psoriasis Patients<br>Psoriasis patients will receive daily escalating oral doses of BMS-986251 or placebo | Drug: BMS-986251<br>* Escalating oral dose<br>Other: Placebo<br>* Escalating oral dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants That Experienced the Following: Serious Adverse Events (SAEs), Death or an Adverse Event (AE) Leading to Study Discontinuation | An adverse event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with the treatment. A Serious Adverse Event is defined as any untoward medical occurrence that, at any dose results in death or is life-threatening or requires inpatient hospitalization | AEs: Day 1 to Day 11 (Part A), Day 1 to Day 24 (Part B); SAEs: Day -21 to within 30 days of discontinuation of dosing (Part A), Day -21 to within 30 days of discontinuation of dosing (Part B) | 
| Number of Participants With Potentially Clinically Significant Changes in Vital Signs | Vital signs (Systolic and diastolic blood pressure and pulse) were recorded after the participant had been resting for at least 5 minutes in the supine position. | Part A: Days 1, 2, 3, 4, 5, 6, 7, 9 and 11; Part B: Days 1, 2-13, 15, 16, 18, 20, 24 | 
| Number of Participants With Potentially Clinically Significant Changes in Electrocardiogram (ECG) Parameters | The following ECG parameters were recorded: heart rate, PR-interval, QRS-duration, QT-interval, QTcinterval, (Fridericia's) and the interpretation of the ECG profile by the Investigator | Part A: Days 1, 2, 3,5, 7 and 11; Part B: Days 1, 2, 4, 6, 8, 10, and 12,24 | 
| Number of Participants With Potentially Clinically Significant Changes in Clinical Laboratory Parameters | Hematology: Hemoglobin, Hematocrit, Total leukocyte count, including differential Platelet count, Red blood cell count, Reticulocyte count; Chemistry: Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Total bilirubin, Direct bilirubin, Alkaline phosphatase, Lactate dehydrogenase , (LDH), Creatinine, Urea, Uric acid, Fasting glucose, High sensitivity C-reactive protein (hs-CRP), Total protein, Albumin Sodium, Potassium, Chloride, Calcium Inorganic phosphate, Magnesium, Creatine kinase, Creatinine clearance (CLcr)- screening only, Cholesterol Triglycerides, High-density lipoprotein (HDL), Low-density lipoprotein (LDL), Urinalysis: Protein, Glucose, Blood Leukocyte esterase, Specific gravity, pH,Microscopic examination of the sediment if blood, protein or leukocytes esterase are positive on the dipstick; Other Analyses: Urine test for alcohol, Urine test for drugs of abuse, Pregnancy test | Part A: Days 2, 4, 7 and 11; Part B: Days 3, 7, 10, 14, 16, 24 | 
| Maximum Observed Plasma Concentration (Cmax) | PK parameters were derived from BMS-986251 concentration versus time data measured at the time points specified | Part A: Days 1, 2, 3, 4, 5, 6, 7, 9, 11; Part B : Day 1 and 14 | 
| Time of Maximum Observed Plasma Concentration (Tmax) | PK parameters were derived from BMS-986251 concentration versus time data measured at the time points specified | Part A: Days 1, 2, 3, 4, 5, 6, 7, 9, 11; Part B : Day 1 and 14 | 
| Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-t)] | PK parameters were derived from BMS-986251 concentration versus time data measured at the time points specified | Part A: Days 1, 2, 3, 4, 5, 6, 7, 9, 11; Part B : Day 1 and 14 | 
| Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(0-inf)] (Part A) | PK parameters were derived from BMS-986251 concentration versus time data measured at the time points specified | Part A: Days 1, 2, 3, 4, 5, 6, 7, 9, 11 | 
| Terminal Elimination Half-life, Calculated as 0.693/Kel [t(1/2)] | PK parameters were derived from BMS-986251 concentration versus time data measured at the time points specified | Part A: Days 1, 2, 3, 4, 5, 6, 7, 9, 11; Part B : Day 14 | 
| Apparent (Oral) Clearance (CL/F) Calculated as Dose/[AUC(0-inf)] for Single Dose | PK parameters were derived from BMS-986251 concentration versus time data measured at the time points specified | Part A: Day 1, Part B: Day 14 | 
| Apparent Volume of Distribution at Terminal Phase [V(z)/F] | PK parameters were derived from BMS-986251 concentration versus time data measured at the time points specified | Part A: Days 1, 2, 3, 4, 5, 6, 7, 9, 11; Part B : Day 14 | 
| Cumulative Urinary Excretion (of the Unchanged Drug) [Ae(t)] | Summary of BMS-986251 Excretion Parameters in Urine. PK parameters were derived from BMS-986251 concentration versus time data measured at the time points specified | Part A: Days 1, 2, 3, 4, 5, 6, 7 ; Part B : Day 14 | 
| Amount Excreted Unchanged in Urine (% of Dose) [Fe(Urine)%] | Summary of BMS-986251 Excretion Parameters in Urine. PK parameters were derived from BMS-986251 concentration versus time data measured at the time points specified | Part A: Days 1, 2, 3, 4, 5, 6, 7 ; Part B : Day 14 | 
| Renal Clearance [CL(R)] | Summary of BMS-986251 Excretion Parameters in Urine. PK parameters were derived from BMS-986251 concentration versus time data measured at the time points specified | Part A: Days 1, 2, 3, 4, 5, 6, 7 ; Part B : Day 14 | 
| Area Under the Concentration-time Curve Over 24 Hours (One Dosing Interval) [AUC(0-24)] (Part B) | PK parameters were derived from BMS-986251 concentration versus time data measured at the time points specified | Part B : Days 1 and Day 14 | 
| Ratio of AUC(0-24) Following Last Dose to AUC(0-24) Following First Dose [AR[AUC(0-24)]] (Part B) | PK parameters were derived from BMS-986251 concentration versus time data measured at the time points specified | Part B : Day 14 | 
| Ratio of Cmax Following Last Dose to Cmax Following First Dose [AR(Cmax)] (Part B) | PK parameters were derived from BMS-986251 concentration versus time data measured at the time points specified | Part B : Day 14 | 
| Pre-dose Plasma Concentration (Cpre) (Part B) | PK parameters were derived from BMS-986251 concentration versus time data measured at the time points specified | Part B : Days 2-14 | 
| Inhibition at Time t [I(t)] (Part B) | Summary of IL-17 Inhibition in Whole Blood Pharmacodynamic (PD) Parameters | Part B : Days 16, 20, and 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Inhibition [I(Max)] | Summary of IL-17 Inhibition in Whole Blood Pharmacodynamic (PD) Parameters | Part A: Days 1, 2, 3, 5, 7, 11 ; Part B : Day 1, 2, 16, 20, 24 | 
| Time of Maximum Observed Inhibition [t(Imax)] | Summary of IL-17 Inhibition in Whole Blood Pharmacodynamic (PD) Parameters | Part A: Days 1, 2, 3, 5, 7, 11 ; Part B : Day 1, 2, 16, 20, 24 | 
| Time of Inhibition Above 50% [t(I>50%)] | Summary of IL-17 Inhibition in Whole Blood Pharmacodynamic (PD) Parameters | Part A: Days 1, 2, 3, 5, 7, 11 ; Part B : Day 1, 2, 16, 20, 24 | 
| Time of Inhibition Above 90% [t(I>90%)] | Summary of IL-17 Inhibition in Whole Blood Pharmacodynamic (PD) Parameters | Part A: Days 1, 2, 3, 5, 7, 11 ; Part B : Day 1, 2, 16, 20, 24 | 
| Pre-dose Inhibition [I(Pre)] (Part B) | Summary of IL-17 Inhibition in Whole Blood Pharmacodynamic (PD) Parameters | Part B : Days 2, 4, 7, and 14 |