Study to Investigate the Safety, Tolerability, and Pharmacokinetic Profile With Oral AB521 in Healthy Volunteers

Study Overview
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Brief Summary
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This study will evaluate the safety and tolerability, pharmacokinetic, and pharmacodynamic profile, and drug-drug interaction (DDI) of AB521 in healthy participants.

Official Title
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A First-in-human, Participant and Investigator-blinded, Randomized, Placebo-controlled, Single-and Multiple-Ascending Dose Study With Drug-Drug Interaction, to Investigate the Safety, Tolerability, and Pharmacokinetic Profile of AB521, in Healthy Volunteers

Conditions
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Healthy Participants

Intervention / Treatment
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* Drug: AB521
* Drug: Placebo
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants who are healthy volunteers (in the opinion of the investigator) as determined by pre-study medical history, physical examination, vital signs, and 12-lead electrocardiogram (ECG) All clinical laboratory tests of blood and urine must be within the normal range or show no clinically relevant excursions from the normal range as judged by Principal Investigator at screening and admission. Screening and randomization hemoglobin ≥for males and females is as follows: SAD: male and female hemoglobin level ≥ 12.5 grams/ deciliters (g/dL) (7.7 millimoles/liters [mmol/L]) MAD and DDI: male hemoglobin level ≥ 14.2 g/dL (8.8 mmol/L) and female hemoglobin level ≥ 12.5 g/dL (7.7 mmol/L). Participants should have adequate peripheral venous access. Body weight of 45 kilograms (kg) or greater and body mass index within the range of 18 to 32 kg/meters squared (m^2) (inclusive) Male participants must be vasectomized and have been vasectomized for at least 3 months prior to screening visit with confirmed history of azoospermia subsequent to the vasectomy procedure Contraceptive use should be consistent with local regulations Exclusion Criteria: Has any (acute or chronic [including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection]) medical or psychiatric condition that, in the opinion of the investigator, could jeopardize or would compromise the study participant's ability to participate in this study Has history or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrinological, hematological, cerebrovascular, neurological, or other major disorders capable of significantly altering the absorption, metabolism, or elimination of investigational drug; constituting a risk when taking the study intervention; or interfering with the interpretation of data in the opinion of the investigator Abnormal blood pressure (BP) or pulse measurements at the Screening Visit or Day -2/-1 (Admission) in a supine position after 5 minutes of rest as follows: mean systolic BP ≥139 millimeters of mercury (mm Hg) or mean diastolic BP ≥89 mm Hg; mean pulse < 40 beats per minute (bpm) or > 100 bpm. Liver enzyme test results: Alanine aminotransferase, aspartate aminotransferase, bilirubin, or alkaline phosphatase >1.0x the upper limit of normal Current or chronic history of liver disease or known hepatic or biliary abnormalities Has 12-lead electrocardiogram with changes considered to be clinically significant at the Screening Visit or day of admission

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAD-AB521 Dose 1<br>Participants will receive Dose 1 of AB521 orally with water under fasting conditions. | Drug: AB521<br>* Capsule<br>|
| Experimental: SAD-AB521 Dose 2<br>Participants will receive Dose 2 of AB521 orally with water under fasting conditions. | Drug: AB521<br>* Capsule<br>|
| Experimental: SAD-AB521 Dose 3<br>Participants will receive Dose 3 of AB521 orally with water under fasting conditions. | Drug: AB521<br>* Capsule<br>|
| Experimental: SAD-AB521 Dose 4<br>Participants will receive Dose 4 of AB521 orally with water under fasting conditions. | Drug: AB521<br>* Capsule<br>|
| Placebo Comparator: SAD-Placebo<br>Participants will receive matching placebo orally with water under fasting conditions. | Drug: Placebo<br>* Capsule<br>|
| Experimental: MAD-AB521 Dose 1<br>Participants will receive Dose 1 of AB521 orally with water under fasting conditions. | Drug: AB521<br>* Capsule<br>|
| Experimental: MAD-AB521 Dose 2<br>Participants will receive Dose 2 of AB521 orally with water under fasting conditions. | Drug: AB521<br>* Capsule<br>|
| Placebo Comparator: MAD-Placebo<br>Participants will receive matching placebo orally with water under fasting conditions. | Drug: Placebo<br>* Capsule<br>|
| Experimental: DDI-AB521 Dose + Midazolam<br>Participants will receive highest safe dose level of AB521 from MAD and midazolam orally with water under fasting conditions | Drug: AB521<br>* Capsule<br>Drug: Midazolam<br>* Syrup solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) |  | Up to 21.5 Weeks | 
| Number of Participants With Abnormal Changes From Baseline in Laboratory Parameter Values |  | Baseline; Up to 21.5 Weeks | 
| Number of Participants With Abnormal Changes from Baseline in Vital Sign Values |  | Baseline; Up to 21.5 Weeks | 
| Maximum Observed Plasma Concentration (Cmax) of AB521 |  | multiple timepoints up to approximately 21.5 Weeks | 
| Area Under the Plasma Concentration Time Curve From Hour 0 to the Last Sample With Measurable Plasma Concentrations (AUClast) of AB521 |  | multiple timepoints up to approximately 21.5 Weeks | 
| Time of Occurrence of Cmax (tmax) of AB521 |  | multiple timepoints up to approximately 21.5 Weeks | 
| Apparent Terminal Elimination Rate Constant (λz) of AB521 |  | multiple timepoints up to approximately 21.5 Weeks | 
| Terminal Half-Life (t1/2) of AB521 |  | multiple timepoints up to approximately 21.5 Weeks | 
| Area Under the Plasma Concentration Time Curve From Hour 0 to Infinity (AUCinf) of AB521 |  | multiple timepoints up to approximately 21.5 Weeks | 
| Apparent Volume of Distribution of AB521 |  | multiple timepoints up to approximately 21.5 Weeks | 
| Apparent Total Body Clearance of AB521 |  | multiple timepoints up to approximately 21.5 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of midazolam and 1 hydroxymidazolam |  | multiple timepoints up to approximately 21.5 Weeks | 
| Area Under the Plasma Concentration Time Curve From Hour 0 to the Last Sample With Measurable Plasma Concentrations (AUClast) of midazolam and 1 hydroxymidazolam |  | multiple timepoints up to approximately 21.5 Weeks | 
| Time of Occurrence of Cmax (tmax) of midazolam and 1 hydroxymidazolam |  | multiple timepoints up to approximately 21.5 Weeks | 
| Apparent Terminal Elimination Rate Constant (λz) of midazolam and 1 hydroxymidazolam |  | multiple timepoints up to approximately 21.5 Weeks | 
| Terminal Half-Life (t1/2) of midazolam and 1 hydroxymidazolam |  | multiple timepoints up to approximately 21.5 Weeks | 
| Area Under the Plasma Concentration Time Curve From Hour 0 to Infinity (AUCinf) of midazolam and 1 hydroxymidazolam |  | multiple timepoints up to approximately 21.5 Weeks | 
| Apparent Volume of Distribution of midazolam and 1 hydroxymidazolam |  | multiple timepoints up to approximately 21.5 Weeks | 
| Apparent Total Body Clearance of midazolam and 1 hydroxymidazolam |  | multiple timepoints up to approximately 21.5 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AB521, HIF-2α, hypoxia-inducible factor 2 alpha, Single ascending dose (SAD), Multiple ascending dose (MAD), Drug-drug interaction (DDI)