Study to Investigate the Safety, Tolerability, and Pharmacokinetic Profile With Oral AB521 in Healthy Volunteers (ARC-14)

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

This study will evaluate the safety and tolerability, pharmacokinetic, and pharmacodynamic profile, and drug-drug interaction (DDI) of casdatifan in healthy participants.

Study Overview

• Status: Completed
• Conditions: Healthy Participants
• Intervention / Treatment: Drug: Placebo; Drug: Midazolam; Drug: casdatifan

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands
    • Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

9

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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 casdatifan	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 casdatifan	multiple timepoints up to approximately 21.5 Weeks
Time of Occurrence of Cmax (tmax) of casdatifan	multiple timepoints up to approximately 21.5 Weeks
Apparent Terminal Elimination Rate Constant (λz) of casdatifan	multiple timepoints up to approximately 21.5 Weeks
Terminal Half-Life (t1/2) of casdatifan	multiple timepoints up to approximately 21.5 Weeks
Area Under the Plasma Concentration Time Curve From Hour 0 to Infinity (AUCinf) of casdatifan	multiple timepoints up to approximately 21.5 Weeks
Apparent Volume of Distribution of casdatifan	multiple timepoints up to approximately 21.5 Weeks
Apparent Total Body Clearance of casdatifan	multiple timepoints up to approximately 21.5 Weeks

Secondary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Arcus Biosciences, Inc.
• Investigators: Study Director: Medical Director, Arcus Biosciences, Inc.

Publications and helpful links

Helpful Links

• ARC-14 - Public website

Study record dates

Study Major Dates

• Study Start (Actual): November 9, 2021
• Primary Completion (Actual): February 17, 2023
• Study Completion (Actual): February 17, 2023

Study Registration Dates

• First Submitted: November 2, 2021
• First Submitted That Met QC Criteria: November 2, 2021
• First Posted (Actual): November 11, 2021

Study Record Updates

• Last Update Posted (Actual): October 17, 2024
• Last Update Submitted That Met QC Criteria: October 16, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: AB521; HIF-2α; hypoxia-inducible factor 2 alpha; Single ascending dose (SAD); Multiple ascending dose (MAD); Drug-drug interaction (DDI); casdatifan
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: ARC-14; 2021-003856-17 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Arcus will provide access to individual de-identified participant data and related study documents (e.g., protocol, Statistical Analysis Plan [SAP], Clinical Study Report [CSR]) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions.

For more information, please visit our website.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No