A Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AG-946 in Healthy Volunteers and in Participants With Sickle Cell Disease

NCT04536792 | Completed Phase 1 FDA Drug

• 2 other identifiers: AG946-C-0012020-000691-38
• Study Type: interventional
• Target: 122
• Locations: 3 countries
• Sites: 10

Brief Summary

The purpose of the study is to assess the safety and tolerability of AG-946 in healthy volunteers after oral administration of single ascending doses (SAD) and multiple ascending doses (MAD) of AG-946 over 14 or up to 28 days of dosing, and to identify a range of doses that are safe and pharmacologically active in participants with sickle cell disease. The SAD and MAD parts of the study will be randomized and double-blinded, and will assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of AG-946 as well as the effect of food (SAD only) on the pharmacokinetics (PK) of AG-946. The sickle cell disease (SCD) part of the study will be non-randomized and open-label, and is designed to identify 1 or more safe and tolerable dose(s) of AG-946 with potential activity in the treatment of participants with sickle cell disease (SCD).

Conditions

Healthy Volunteers; Anemia, Sickle Cell

Keywords

Sickle Cell Disease; Healthy

Outcome Measures

Primary Outcomes (10)

• SAD and MAD: Number of Participants Who Experienced at Least One Adverse Event (AE), by Severity

  SAD: Up to Day 13; MAD: Up to Day 49

• SAD and MAD: Number of Participants Who Experienced at Least One AE Related to the Study Drug

  SAD: Up to Day 13; MAD: Up to Day 49

• SAD and MAD: Number of Participants Who Experienced at Least One Serious Adverse Event (SAE)

  SAD: Up to Day 13; MAD: Up to Day 49

• SAD and MAD: Number of Participants With Clinically Significant Laboratory Abnormalities, by Severity

  SAD: Up to Day 13; MAD: Up to Day 49

• SAD and MAD: Number of Participants With Clinically Significant Changes in Vital Signs and in Electrocardiogram (ECG) Parameters

  SAD: Up to Day 13; MAD: Up to Day 49

• SCD: Number of Participants Who Experienced at Least One AE, by Severity

  Up to Day 56

• SCD: Number of Participants Who Experienced at Least One AE Related to the Study Drug

  Up to Day 56

• SCD: Number of Participants Who Experienced at Least One SAE

  Up to Day 56

• SCD: Number of Participants With Clinically Significant Laboratory Abnormalities, by Severity

  Up to Day 56

• SCD: Number of Participants With Clinically Significant Changes in Vital Signs and in ECG Parameters

  Up to Day 56

Secondary Outcomes (17)

• Maximum Observed Concentration (Cmax) of AG-946

  SAD: Up to Day 8; MAD: Up to Day 49; SCD: Up to Day 56

• Time to Reach Maximum Observed Concentration (Tmax) of AG-946

  SAD: Up to Day 8; MAD: Up to Day 49; SCD: Up to Day 56

• Area Under the Plasma Concentration-Time Curve from Time Zero to Last Quantifiable Concentration (AUC0-t), Time Curve from Time Zero to Infinity (AUC0-∞), and Time Curve from Time Zero to Time tau Over the Dosing Interval (AUC0-τ) for AG-946

  SAD: Up to Day 8; MAD: Up to Day 49; SCD: Up to Day 56

• SAD: Apparent Clearance (CL/F) for AG-946

  SAD: Up to Day 8

• SAD: Apparent Volume of Distribution (Vd/F) for AG-946

  SAD: Up to Day 8

Study Arms (3)

Part 1: Single Ascending Dose (SAD) Phase

EXPERIMENTAL

Participants will receive a range of doses of AG-946 or placebo, orally, once on Day 1. AG-946 will be given under fasted or fed conditions.

Drug: AG-946; Drug: AG-946 Matched Placebo

Part 2: Multiple Ascending Dose (MAD) Phase

EXPERIMENTAL

Participants will receive a range of doses of AG-946 or placebo, orally, once daily (QD) for 14 days or using an alternative dosing regimen for up to 28 days under fasted conditions.

Drug: AG-946; Drug: AG-946 Matched Placebo

Part 3: Sickle Cell Disease (SCD) Phase

EXPERIMENTAL

Participants will receive a range of selected ascending doses of AG-946, orally, QD or using an alternative dosing regimen for 28 days.

Drug: AG-946

Interventions

AG-946 DRUG

AG-946, oral encapsulated coated-granules or tablets.

Part 1: Single Ascending Dose (SAD) Phase; Part 2: Multiple Ascending Dose (MAD) Phase; Part 3: Sickle Cell Disease (SCD) Phase

AG-946 Matched Placebo DRUG

AG-946 matched-placebo, oral encapsulated sugar spheres or tablets.

Part 1: Single Ascending Dose (SAD) Phase; Part 2: Multiple Ascending Dose (MAD) Phase

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• SAD and MAD
• Participant is a healthy male or a female of nonchildbearing potential aged 18 to 55 years inclusive at the time of consent;
• Participant is able to understand and provide informed consent before the conduct of any protocol-specific screening procedures;
• Participant is willing and able to complete all study assessments and procedures;
• Participant has a bodyweight ≥50 kilograms (kg) and body mass index ≥18.5 and ≤32 kilograms per square meter (kg/m\^2) at screening;
• Participant is in good general health with no clinically significant deviations from normal in screening medical history, physical examination, vital signs, or electrocardiogram (ECGs);
• Male participants must agree to be abstinent as part of their usual lifestyle or use contraception up to 90 days after last dose of study treatment;
• Participant is a non-smoker and has not used nicotine-containing products for at least 3 months prior to screening;
• Participant is willing to refrain from caffeine- or xanthene-containing products (eg, coffee, tea, cola, chocolate) for 48 hours before the first dose of study treatment through 7 days after the last dose of study treatment;
• Participant is willing to refrain from marijuana- or cannabinol-containing products for 7 days before admission through the final visit;
• Participant is willing to refrain from strenuous exercise starting 72 hours before admission through the final visit;
• Participant is willing to refrain from use of alcohol starting 7 days prior to admission through final visit;
• Participant agrees not to donate blood products for duration of study participation;
• Male participants must agree not to donate sperm for duration of study and for 90 days after the last dose.

You may not qualify if:

• SAD and MAD
• Participant has previously enrolled in this study or has received an investigational drug with 3 months or 5 half-lives of the drug, whichever is longer, before the first dose of study treatment;
• Participant has previously received AG-946, except for participants who are dosing in the fed portion of the food-effect group;
• Participant has a heart rate-corrected QT interval (QTc) interval using Fridericia correction method (QTcF) \>450 milliseconds (ms) at screening;
• Participant has used over-the-counter medication (excluding routine vitamins) within 7 days of the first dose of study treatment, unless agreed as not clinically relevant;
• Participant has used acetaminophen greater than 2 grams (g) in any 24-hour period up to 48 hours before the first dose of study treatment;
• Participants has clinically relevant screening laboratory tests results outside the normal range;
• Participant has a history of any relevant cardiovascular, renal, hepatic, chronic respiratory, or gastrointestinal disease; or hematologic, lymphatic, neurologic, endocrine, psychiatric, musculoskeletal, genitourinary, immunologic, dermatologic, or connective tissue disease or disorders;
• Participant has a history of serious mental illness, that includes, but is not limited to schizophrenia, bipolar disorder, or major depression;
• Participant has a history of any primary malignancy, except for basal cell or squamous cell carcinomas of the skin or cervical carcinoma in situ or other malignancies that have been curatively treated and with no evidence of disease for at least 5 years before screening;
• Participant has had surgery within 6 months before the first dose of study treatment;
• Participant has a preexisting condition that interferes with normal gastrointestinal anatomy or motility, and/or hepatic and/or renal function that could interfere with the absorption, metabolism, and/or excretion of the study treatment or has previously undergone cholecystectomy;
• Participant has systolic blood pressure (BP) ≥140 mm Hg or a diastolic BP of ≥90 mm Hg after 10 minutes rest at screening or before the first dosing of study treatment;
• Participant has medical or psychological condition deemed by the Investigator to be likely to interfere with the volunteer's ability to provide informed consent, cooperate, and/or participate in the study;
• Participant has a known allergy to any of the excipients or components of the study treatment;

Sponsors & Collaborators

• Agios Pharmaceuticals, Inc.: lead

Study Sites (10)

University of California San Diego

La Jolla, California, 92037, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Boston Medical Center

Boston, Massachusetts, 02118, United States

Location

New York Presbyterian Hospital - Weill Cornell Medicine

New York, New York, 10065, United States

Location

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15213, United States

Location

PPD Development, LP

Austin, Texas, 78744, United States

Location

Texas Oncology-Baylor Charles A. Sammons Cancer Center - USOR

Dallas, Texas, 75246, United States

Location

University of Texas Health Science Center of Houston

Houston, Texas, 77030, United States

Location

Rigshospitalet, Department of Hematology

Copenhagen, 2100, Denmark

Location

Hospital Universitario Vall d'Hebron - PPDS

Barcelona, 08035, Spain

Location

MeSH Terms

Conditions

Anemia, Sickle Cell

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 15, 2020
• First Posted: September 3, 2020
• Study Start: July 10, 2020
• Primary Completion: December 19, 2023
• Study Completion: December 19, 2023
• Last Updated: April 16, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1); ES (1); US (8)