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

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ClinicalTrials.gov Identifier: NCT04536792
Recruitment Status : Recruiting
First Posted : September 3, 2020
Last Update Posted : April 21, 2021
Sponsor:
Information provided by (Responsible Party):
Agios Pharmaceuticals, Inc.

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 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).

Condition or disease Intervention/treatment Phase
Healthy Volunteers Anemia, Sickle Cell Drug: AG-946 Drug: AG-946 Matched Placebo Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 1 Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AG-946 in Healthy Volunteers and in Subjects With Sickle Cell Disease
Actual Study Start Date : July 10, 2020
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Part 1: Single Ascending Dose (SAD) Phase
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
AG-946, oral encapsulated coated-granules or tablets.

Drug: AG-946 Matched Placebo
AG-946 matched-placebo, oral encapsulated sugar spheres or tablets.

Experimental: Part 2: Multiple Ascending Dose (MAD) Phase
Participants will receive a range of doses of AG-946 or placebo, orally, once daily (QD) for 14 days.
Drug: AG-946
AG-946, oral encapsulated coated-granules or tablets.

Drug: AG-946 Matched Placebo
AG-946 matched-placebo, oral encapsulated sugar spheres or tablets.

Experimental: Part 3: Sickle Cell Disease (SCD) Phase
Participants will receive a range of selected ascending doses of AG-946, orally, QD for 28 days.
Drug: AG-946
AG-946, oral encapsulated coated-granules or tablets.




Primary Outcome Measures :
  1. SAD and MAD: Number of Participants Who Experienced at Least One Adverse Event (AE), by Severity [ Time Frame: SAD: Up to Day 13; MAD: Up to Day 26 ]
  2. SAD and MAD: Number of Participants With Clinically Significant Laboratory Abnormalities, by Severity [ Time Frame: SAD: Up to Day 13; MAD: Up to Day 26 ]
  3. SAD and MAD: Number of Participants With Clinically Significant Changes in Vital Signs and in Electrocardiogram (ECG) Parameters [ Time Frame: SAD: Up to Day 13; MAD: Up to Day 26 ]
  4. SCD: Number of Participants Who Experienced at Least One AE, by Severity [ Time Frame: Up to Day 56 ]
  5. SCD: Number of Participants With Clinically Significant Laboratory Abnormalities, by Severity [ Time Frame: Up to Day 56 ]
  6. SCD: Number of Participants With Clinically Significant Changes in Vital Signs and in ECG Parameters [ Time Frame: Up to Day 56 ]

Secondary Outcome Measures :
  1. Maximum Observed Concentration (Cmax) of AG-946 [ Time Frame: SAD: Up to Day 8; MAD: Up to Day 21; SCD: Up to Day 16 ]
    Cmax will be determined under fasted and fed conditions in SAD and under fasted conditions only in MAD and SCD.

  2. Time to Reach Maximum Observed Concentration (Tmax) of AG-946 [ Time Frame: SAD: Up to Day 8; MAD: Up to Day 21; SCD: Up to Day 16 ]
    Tmax will be determined under fasted and fed conditions in SAD and under fasted conditions only in MAD and SCD.

  3. 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 [ Time Frame: SAD: Up to Day 8; MAD: Up to Day 21; SCD: Up to Day 16 ]
    AUC0-t, AUC0-∞, and AUC0-τ will be determined under fasted and fed conditions in SAD and under fasted conditions only in MAD and SCD.

  4. Apparent Clearance (CL/F) for AG-946 [ Time Frame: SAD: Up to Day 8; MAD: Up to Day 21; SCD: Up to Day 16 ]
    CL/F will be determined under fasted and fed conditions in SAD and under fasted conditions only in MAD and SCD.

  5. Apparent Volume of Distribution (Vd/F) for AG-946 [ Time Frame: SAD: Up to Day 8; MAD: Up to Day 21; SCD: Up to Day 16 ]
    V/F will be determined under fasted and fed conditions in SAD and under fasted conditions only in MAD and SCD.

  6. SAD: Total Amount of Drug Excreted in Urine from Time 0 to Time T (Aet) and from Time t1 to Time t2 (Aet1-t2) for AG-946 Under Fasted Conditions [ Time Frame: Up to Day 3 ]
  7. SAD: Percentage Dose of Drug Excreted in Urine from Time 0 to Time t (fet) and from Time t1 to Time t2 (fet1-t2) for AG-946 Under Fasted Conditions [ Time Frame: Up to Day 3 ]
  8. SAD: Renal Clearance (CLr) for AG-946 Under Fasted Conditions [ Time Frame: Up to Day 3 ]
  9. Changes in the Concentration of 2,3-diphosphoglycerate (2,3-DPG) and Adenosine Triphosphate (ATP) in Whole Blood [ Time Frame: SAD: Up to Day 8; MAD: Up to Day 21; SCD: Up to Day 16 ]
  10. Area Under the Effect Curve (AUEC) from Time zero to t for 2,3-DPG and ATP [ Time Frame: SAD: Up to Day 8; MAD: Up to Day 21; SCD: Up to Day 16 ]
  11. SAD: Relative Bioavailability Comparing Fasted to Fed Conditions Determined from the PK Parameters of AG-946 [ Time Frame: SAD: Up to Day 8 ]
  12. SCD: Number of Participants with Clinically Significant Changes in Hematological Parameters [ Time Frame: Up to Day 56 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

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.

Exclusion Criteria:

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;
  • 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 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 had surgery within 6 months before the first dose 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;
  • Participant tests positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody (Ab), or human immunodeficiency virus (HIV) infection -1 or -2 Ab;
  • Participant has donated blood, had blood loss of more than 500 milliliters (mL), or has received transfusion of blood or plasma within 3 months before screening;
  • Participant has a history of illicit drug abuse or alcoholism within the last 1 year before screening;
  • Participant has consumed more than 21 units of alcohol a week within the last 1 year before screening;
  • Participant has used prescription drugs within 2 weeks or 5 half-lives (whichever is longer) before the first dose of study treatment;
  • Participant has a positive screen for drugs of abuse or urinary cotinine >200 nanograms per milliliter (ng/mL) at screening or admission; or a positive screen for alcohol (via urine analysis) at admission;
  • Participant has used St. John's wort within 28 days before the first dose of study treatment;
  • Participant is unwilling to forgo consumption of Seville oranges, grapefruit or grapefruit juice, grapefruit hybrids, pumeloes, or exotic citrus fruits from 1 day before the first dose of study treatment through the final visit;
  • Participant cannot communicate reliably with the Investigator;
  • Participant cannot or is unlikely to cooperate with the requirements of the study;
  • Participant has any conditions that, in the judgment of the Investigator, would make the volunteer unsuitable for enrollment or could interfere with the volunteer's participation in, or completion of, the study.

Inclusion Criteria:

SCD

  • Participant is a male or female aged 18 to 70 years inclusive at the time of consent;
  • Participant has documented sickle cell anemia;
  • Provided informed consent before the conduct of any protocol-specific screening procedures;
  • If the participant is taking hydroxyurea (HU), L-glutamine, and/or crizanlizumab, the dose(s) must have been stable for at least 3 months before the first dose of AG-946;
  • Participant must start or continue to take folic acid in the equivalent of at least 0.8 milligrams per day (mg/day) orally for the duration of the study, unless the Investigator considers dietary folic acid intake to be adequate;
  • Participant has adequate organ function;
  • Female participants who are of childbearing potential, must have negative pregnancy test during screening;
  • Female participants who are of childbearing potential and male participants who have partners who are females of childbearing potential, must agree to be abstinent as part of their usual lifestyle or agree to use contraception from the time of providing informed consent to 28 days for women and 90 days for men after the last dose of AG-946;
  • Participant must be willing to comply with all study procedures for the duration of the study.

Exclusion Criteria:

SCD

  • Participant is a candidate for potentially curative treatment with bone marrow transplantation, and for whom participation in this study would delay or preclude such definitive treatment;
  • Participant has documented history of pyruvate kinase deficiency (PKD) or red blood cell-specific form of pyruvate kinase (PKLR) mutation;
  • Participant has had more than 6 vaso-occlusive crisis (VOCs) within the past 12 months that required a hospital, emergency room, or clinic visit;
  • Participant is receiving regularly scheduled red blood cell (RBC) transfusion therapy, and/or has received a transfusion within the past 3 months before the first dose of AG-946;
  • Participant is currently receiving treatment with voxelotor or any other agent intended to increase hemoglobin (Hb)-oxygen affinity;
  • Participant has a significant medical condition that confers an unacceptable risk to participating in the study, and/or that could confound the interpretation of the study data as follows:

    1. Poorly controlled hypertension (defined as systolic BP >150 millimeters of mercury (mm Hg) or diastolic BP >90 mm Hg) refractory to medical management
    2. Any history of congestive heart failure; myocardial infarction; unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; or recent venous thrombosis or pulmonary or arterial embolism
    3. Cardiac dysrhythmias judged as clinically significant by the Investigator
    4. QTcF >450 milliseconds (ms), unless related to right or left bundle branch block
    5. Clinically symptomatic cholelithiasis or cholecystitis
    6. History of drug-induced cholestatic hepatitis
    7. Iron overload sufficiently severe to result in a clinical diagnosis by the Investigator of cardiac, hepatic, or pancreatic dysfunction
    8. Have a diagnosis of any other congenital or acquired blood disorder, or any other hemolytic process as defined by a positive direct antiglobulin test, except for mild alloimmunization as a consequence of transfusion therapy
    9. Positive test for HBsAg, or positive test for HCV Ab with evidence of active virus infection
    10. Positive test for HIV-1 or -2 Ab
    11. Active infection requiring the use of parenteral antimicrobial agents or Grade ≥3 in severity
    12. Diabetes mellitus judged to be under poor control by the Investigator or requiring >2 antidiabetic agents, including insulin
    13. History of any primary malignancy, except for curatively treated nonmelanoma skin cancer, cervical or breast carcinoma in situ, prostate cancer, or other primary tumor treated with curative intent, no known active disease present, and no treatment administered during the last 3 years before Screening
    14. Unstable extramedullary hematopoiesis that could pose a risk of imminent neurologic compromise
    15. Current or recent history of a psychiatric disorder
  • Participant is currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo;
  • Participant has had exposure to any investigational drug within 3 months or 5 half-lives of the drug, whichever is longer, before the first dose of AG-946;
  • Participant has had exposure to any investigational device or invasive procedure within 3 months before the first dose of AG-946;
  • Participant has a history of major surgery within 6 months of providing informed consent;
  • Participant has had a prior bone marrow or stem cell transplant;
  • Participant is currently pregnant or breastfeeding;
  • Participant has used St. John's wort within 28 days before the first dose of AG-946;
  • Participant has received medications that are strong inhibitors of permeability-glycoprotein (P-gp) within 5 days or a time frame equivalent to 5 half-lives (whichever is longer) before the first dose of AG-946;
  • Participant has received hematopoietic stimulating agents within 28 days before the first dose of AG-946;
  • Participant is unwilling to forgo consumption of red wine, Seville oranges, grapefruit or grapefruit juice, grapefruit hybrids, pumeloes, or exotic citrus fruits from 1 day before the first dose of AG-946 until completion of the 28-day follow-up period;
  • Participant has a known allergy to any of the excipients found in AG-946.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04536792


Contacts
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Contact: Agios Medical Affairs 833-228-8474 medinfo@agios.com

Locations
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United States, Texas
PPD Development, LP Recruiting
Austin, Texas, United States, 78744
Contact: Rebecca Wood         
Sponsors and Collaborators
Agios Pharmaceuticals, Inc.
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Responsible Party: Agios Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT04536792    
Other Study ID Numbers: AG946-C-001
First Posted: September 3, 2020    Key Record Dates
Last Update Posted: April 21, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Agios Pharmaceuticals, Inc.:
Sickle Cell Disease
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn