3-part Study to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of EXS21546

Study Overview
=================
Brief Summary
-----------------
A 3-part Study to Assess Safety, Tolerability, PK and PD of Single (Part 1) and Multiple (Part 2) Ascending Doses of EXS21546, and to Evaluate the Relative Bioavailability of a Solid Dose Formulation Compared to a Powder for Oral Suspension (Part 3), in Healthy Male Subjects.

Detailed Description
-----------------
Part 1 is a randomised, double-blind, placebo-controlled, SAD study with a food effect assessment. Part 2 is a randomised, double-blind, placebo controlled, MAD study over 14 days. In order to explore the potential CYP3A4 inducer effect, midazolam will also be administered in one cohort. Part 3 is a 3-period, open label, randomised, sequential study. Each subject will receive solid dose formulation and powder for oral suspension in a randomised manner.

Official Title
-----------------
3-part Study to Assess Safety, Tolerability, PK and PD of Single and Multiple Ascending Doses of EXS21546, and to Evaluate the Relative Bioavailability of 2 Formulations, in Healthy Male Subjects

Conditions
-----------------
Oncology

Intervention / Treatment
-----------------
* Drug: EXS21546 Powder for Oral Suspension
* Drug: EXS21546 Granule in Capsule
* Other: Midazolam
* Other: Food Effect
* Other: Placebo Powder for Oral Suspension


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: BMI 18.0 to 30.0 kg/m2 Weight ≥60 kg Must adhere to contraception requirements Exclusion Criteria: Subjects who have received any IMP in a clinical research study within the 90 days prior to Day 1 Subjects who have previously been administered IMP in this study. Evidence of current SARS-CoV-2 infection History of any drug or alcohol abuse in the past 2 years Regular alcohol consumption in males >21 units per week A confirmed positive alcohol breath test at screening or admission Current smokers and those who have smoked within the last 12 months. A confirmed breath carbon monoxide reading of greater than 10 ppm at screening or admission Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months Subjects with pregnant or lactating partners Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) antibody results Regimen L only: History of sleep apnea Subjects with a history of cholecystectomy or gall stones Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active Donation of blood or plasma within the previous 3 months or loss of greater than 400 mL of blood

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EXS21546 Powder for Oral Suspension<br>EXS21546 Powder for Oral Suspension | Drug: EXS21546 Powder for Oral Suspension<br>* EXS21546 Powder for Oral Suspension<br>Other: Midazolam<br>* Interaction<br>Other: Food Effect<br>* Fed/Fasted<br>|
| Placebo Comparator: Placebo<br>Placebo Powder for Oral Suspension | Other: Midazolam<br>* Interaction<br>Other: Food Effect<br>* Fed/Fasted<br>Other: Placebo Powder for Oral Suspension<br>* Placebo Powder for Oral Suspension<br>|
| Experimental: EXS21546 Granule in Capsule<br>EXS21546 Granule in Capsule | Drug: EXS21546 Granule in Capsule<br>* EXS21546 Granule in Capsule<br>Other: Food Effect<br>* Fed/Fasted<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment emergent Adverse Events | Number of participants with treatment emergent Adverse Events | 1 month | 
| EXS21546 and Metabolite Area under the plasma concentration versus time curve (AUC) | EXS21546 and Metabolite Area under the plasma concentration versus time curve (AUC) | 17 days | 
| EXS21546 and Metabolite Peak Plasma Concentration (Cmax) | EXS21546 and Metabolite Peak Plasma Concentration (Cmax) | 17 days |