A Safety and Pharmacokinetic Study of AG-881 in Healthy Male Participants Following Administration of a Single Oral Dose of [14C] AG-881 and Concomitant Intravenous Microdose of [13C315N3] AG-881

A Phase I, Open-label Study to Evaluate the Absorption, Distribution, Metabolism, and Excretion, and to Assess the Absolute Bioavailability of AG-881 in Healthy Male Subjects Following Administration of a Single Oral Dose of [14C] AG-881 and Concomitant Intravenous Microdose of [13C315N3] AG-881

The purpose of this Phase I, open-label study is to evaluate the absorption, distribution, metabolism, excretion, absolute bioavailability, and to characterize the metabolites of AG-881 in healthy male participants following administration of a single oral dose of [14C] AG-881 and a concomitant intravenous microdose of [13C315N3] AG-881.

Study Overview

• Status: Completed
• Conditions: Healthy Male Participants
• Intervention / Treatment: Drug: AG-881; Drug: [13C315N3]AG-881

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53704
      • Covance Clinical Research Unit Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Able to comprehend and willing to sign an informed consent form (ICF) and to abide by the study restrictions, including confinement, as well as adhere to all study procedures;
• Males of any race, between 18 and 55 years of age, inclusive;
• Body mass index between 18.0 and 32.0 kilograms per meter squared (kg/m^2), inclusive, and a total body weight between 50 and 100 kg, inclusive;
• In good health, determined by no clinically significant findings from medical history, physical examination, 12-lead electrocardiogram (ECG), vital sign measurements, and clinical laboratory evaluations (congenital non-hemolytic hyperbilirubinemia [e.g., suspicion of Gilbert's syndrome based on total and direct bilirubin] is not acceptable) at Screening and/or Check-in (Day -1), as assessed by the Investigator (or designee);
• Alanine aminotransferase (ALT; at or within normal limits [WNL]), aspartate aminotransferase (AST; at or within normal limits), alkaline phosphatase (ALP; <1.5 × upper limit of normal [ULN]), bilirubin (at or below WNL). One repeat assessment allowed at each time point;
• Male participants will agree to use contraception;
• Agrees to abstain from any alcohol consumption, starting 48 hours before Check-in (Day -1) and continuing until Discharge;
• History of a minimum of one bowel movement per day;
• Adequate peripheral venous access.

Exclusion Criteria:

• Significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as determined by the Investigator (or designee);
• History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator (or designee);
• History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs (uncomplicated appendectomy and hernia repair will be allowed);
• Has undergone any major surgical procedure within the 3 months prior to Screening;
• History of alcoholism or drug/chemical abuse within 2 years prior to Check-in (Day -1);
• History of severe and/or uncontrolled ventricular arrhythmias or other factors that increase the risk of long QT syndrome, or use, or intend to use, medications that are known to prolong the QT interval or history of unexplained syncopal events or familial history of unexplained death in young person;
• After at least 5 minutes of rest in the supine position at Screening, has a systolic blood pressure reading of ≥140 millimeters of mercury (mmHg) OR a diastolic blood pressure reading of ≥90 mmHg;
• A heart rate-corrected QT interval by Fridericia's (QTcF) method of ≥450 milliseconds (ms);
• Alcohol consumption of >21 units per week. One unit of alcohol equals 12 ounces (360 millimeters [mL]) of beer, 1½ oz (45 mL) of liquor, or 5 oz (150 mL) of wine;
• Positive urine drug screen at Screening or positive alcohol breath test result or positive urine drug screen at Check-in (Day -1);
• Positive hepatitis panel and/or positive human immunodeficiency virus test;
• Participation in a clinical study involving administration of an investigational drug (new chemical entity) in the past 30 days or 5 half-lives (whichever is longer), prior to dosing;
• Use or intend to use any medications/products known to alter drug absorption, metabolism, or elimination processes, including St. John's wort, within 30 days prior to Check-in (Day -1), unless deemed acceptable by the Investigator (or designee);
• Use or intend to use any prescription medications/products within 14 days prior to Check-in (Day -1), unless deemed acceptable by the Investigator (or designee);
• Use or intend to use slow-release medications/products considered to still be active within 30 days prior to Check-in (Day -1), unless deemed acceptable by the Investigator (or designee);
• Use or intend to use any nonprescription medications/products including vitamins, minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior to Check-in (Day -1), unless deemed acceptable by the Investigator (or designee);
• Use of tobacco- or nicotine-containing products within 3 months prior to Check-in (Day -1), or positive cotinine at Screening or Check-in (Day -1);
• Receipt of blood products within 2 months prior to Check-in (Day -1);
• Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior to Screening, or platelets from 6 weeks prior to Screening;
• Have previously completed or withdrawn from this study or any other study investigating AG-881, and have previously received the investigational product;
• Participants with exposure to significant diagnostic or therapeutic radiation (e.g., serial X-ray, computed tomography scan, barium meal) or current employment in a job requiring radiation exposure monitoring within 12 months prior to Check-in (Day -1);
• Participants who have participated in a radiolabeled drug study where exposures are known to the Investigator within the previous 4 months prior to admission to the clinic for this study or participated in a radiolabeled drug study where exposures are not known to the Investigator within the previous 6 months prior to admission to the clinic for this study. The total 12-month exposure from this study and a maximum of 2 other previous radiolabeled studies within 4 to 12 months prior to this study will be within the Code of Federal Regulations (CFR) recommended levels considered safe, per United States (US) Title 21 CFR 361.1: less than 5,000 millirems (mrem) whole-body annual exposure with consideration given to the half-lives of the previous radiolabeled study drugs received;
• Is an employee of, or an immediate family member of an employee of, the study site or the Sponsor;
• Participants who, in the opinion of the Investigator (or designee), should not be part of this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AG881; On Day 1, after fasting for 10 hours participants, will receive an oral capsule of [14C]AG-881 followed 2 hours later by a single intravenous (IV) infusion of [13C315N3]AG-881.	Drug: AG-881; Single oral dose of approximately 50 mg AG-881 (free form) containing approximately 100 microcuries (μCi) of [14C]AG-881.; Drug: [13C315N3]AG-881; Single IV microdose of approximately 100 μg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Amount of AG-881 Excreted in Urine (Aeu)	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Cumulative Aeu (Cum Aeu) of AG-881	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Percentage of AG-881 excreted in Urine and Feces (feu and fef, Respectively)	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Cumulative Percentage of AG-881 Excreted in Urine (Cum feu)	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Cumulative Percentage of AG-881 Excreted in Feces (Cum fef)	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Renal Clearance (CLR) of AG-881	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Renal Clearance Expressed as a Percentage of Total Clearance (CLR/CL) of AG-881	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Percentage of Total Radioactivity in Total Excreta Calculated as Cumulative Percentage of AG-881 Excreted in Urine and Feces (Cum fe)	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Area Under the Concentration-time Curve from Time Zero to the Last Measurable Concentration (AUC0-last) of AG-881	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Area Under the Concentration-time Curve from Time Zero to 72 hours (AUC0-72) of AG-881	Up to 72 hours
Partial Area Under the Concentration-time Curve from Time Zero to Common Time Point (AUC0-t) of AG-881	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Area Under the Concentration-time Curve from Time Zero to Infinity (AUC0-∞) of AG-881 Calculated Using the Observed Value of the Last Quantifiable Concentration	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Maximum Observed Plasma Concentration (Cmax) of AG-881	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Time to Maximum Observed Plasma Concentration (Tmax) of AG-881	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Apparent Terminal Elimination Half-life (t½) of AG-881	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
AUC0-∞ or AUC0-t of AG-881 in Plasma/AUC0-∞ or AUC0-t of Total Radioactivity in Plasma (AUC Plasma AG-881/Total Radioactivity Ratio)	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
AUC0-∞ of Total Radioactivity in Whole Blood to AUC0-∞ of Total Radioactivity in Plasma (AUC Blood/Plasma Ratio), Calculated Using the Observed Value of the Last Quantifiable Concentration	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Total Clearance of AG-881 Following Intravenous (IV) Administration (CL)	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Apparent Clearance Following Oral Administration of AG-881 (CL/F)	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Volume of Distribution of AG-881 at Steady-state Following IV Administration (Vss)	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Apparent Volume of Distribution During the Terminal Phase Following Oral Administration of AG-881 (Vz/F)	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Absolute bioavailability (F) for AG-881 Calculated as the Ratio of Dose-normalized AUC0-∞ of Oral/Intravenous Dosing	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Metabolic Profiles of AG-881 in Plasma, Urine, and Feces, When Possible	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Structures of AG-881 Metabolites in Plasma, Urine, and, Where Possible, Feces	At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants with Adverse Events (AEs), Graded by Severity	AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03)	Up to approximately 12 weeks
Percentage of Participants with Laboratory Abnormalities	Laboratory assessments will include parameters assessing clinical chemistry, hematology, coagulation, urinalysis, and serology.	Up to approximately 8 weeks
Percentage of Participants with Abnormalities in 12-lead Electrocardiogram (ECG)		Up to approximately 8 weeks
Percentage of Participants with Abnormalities in Vital Signs Measurements	Vital signs will include supine blood pressure, supine pulse rate, and oral body temperature.	Up to approximately 8 weeks
Percentage of Participants with Abnormalities in Physical Examinations		Up to approximately 8 weeks

Collaborators and Investigators

• Sponsor: Agios Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): May 16, 2019
• Primary Completion (Actual): September 7, 2019
• Study Completion (Actual): September 7, 2019

Study Registration Dates

• First Submitted: May 21, 2019
• First Submitted That Met QC Criteria: May 21, 2019
• First Posted (Actual): May 23, 2019

Study Record Updates

• Last Update Posted (Actual): October 23, 2019
• Last Update Submitted That Met QC Criteria: October 22, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: Pharmacokinetic study; Safety and tolerability
• Other Study ID Numbers: AG881-C-005

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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