What side effects are associated with this type of intervention?

Common side effects observed in clinical trials involving investigational drugs like AG-946 typically include mild to moderate adverse events such as headache, nausea, dizziness, and gastrointestinal discomfort. These side effects are generally transient and resolve without intervention. In some cases, more specific side effects related to the pharmacological action of the drug may occur, but these are usually identified and monitored closely during the trial. Overall, the safety profile of investigational drugs in healthy volunteers is carefully evaluated to ensure tolerability before proceeding to patient populations.

What prior FDA approvals exist?

Prior FDA approvals for treatments often involve initial studies in healthy subjects to assess safety, tolerability, pharmacokinetics, and pharmacodynamics. These studies are essential for drugs targeting chronic conditions, such as sickle cell disease, to ensure a comprehensive understanding of the drug's effects before administering it to patients. Examples include hydroxyurea, which has been extensively studied for its safety and efficacy in both healthy volunteers and sickle cell disease patients.

What other types of research exist?

Promising novel alternatives to AG-946 for healthy subjects considering treatment in 2024 include: 1) Hydroxyurea, which has a long history of efficacy in reducing vaso-occlusive pain and other complications in SCD patients. 2) L-glutamine (Endari), which has shown a significant reduction in pain crises events in clinical trials. 3) IDH inhibitors, which can be used for at least two years if the patient has a continued response and tolerates the agent. These alternatives have demonstrated safety, tolerability, and efficacy in clinical settings.

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AG-946 for Sickle Cell Anemia

Phase 1

Recruiting

Research Sponsored by Agios Pharmaceuticals, Inc.

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Participant is a healthy male or a female of nonchildbearing potential aged 18 to 55 years inclusive at the time of consent;

Participant has a bodyweight ≥50 kilograms (kg) and body mass index ≥18.5 and ≤32 kilograms per square meter (kg/m^2) at screening;

Must not have

Used acetaminophen greater than 2 g in any 24-hour period up to 48 hours before first dose

Had surgery within 6 months before first dose

Timeline

Screening 3 weeks

Treatment Varies

Follow Up sad: up to day 13; mad: up to day 49; scd: up to day 56

Summary

This trial tests a new oral drug, AG-946, for safety and effectiveness. It involves healthy volunteers and people with sickle cell disease. Researchers will measure how the body processes the drug and its effects.

Who is the study for?

This trial is for healthy adults aged 18-55 and those with sickle cell disease (SCD) aged 18-70. Participants must be non-smokers, in good health, understand the study, and agree to use contraception. Those with SCD should have stable medication doses and adequate organ function. Exclusions include recent surgery, certain medical conditions or drug use that could affect results.

What is being tested?

AG-946 is being tested for safety and effectiveness in both healthy volunteers through single/multiple dose trials and participants with SCD in an open-label part of the study. The trial will explore how AG-946 behaves inside the body (pharmacokinetics) and its impact on the disease (pharmacodynamics).

What are the potential side effects?

While specific side effects are not listed here, common ones may include digestive issues, headaches, fatigue or allergic reactions. Side effects can vary based on individual responses to AG-946.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am a healthy adult between 18 and 55 years old and cannot become pregnant.

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I weigh at least 50 kg and my BMI is between 18.5 and 32.

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I am in good health with normal medical exams and tests.

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I agree to either abstain from sex or use contraception for 90 days after my last treatment dose.

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I am between 18 and 55 years old and cannot have children.

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I understand the study and can give my consent.

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I weigh at least 50 kg and my BMI is between 18.5 and 32.

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I agree not to donate sperm during and for 3 months after the study.

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I have been diagnosed with sickle cell anemia.

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I must take at least 0.8 mg of folic acid daily for the study.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have taken more than 2 grams of acetaminophen in a day within the last 2 days.

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I had surgery less than 6 months ago.

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I have no conditions affecting my stomach, liver, kidneys, or had my gallbladder removed that could affect medication absorption or removal.

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I haven't donated blood, lost more than 500 mL of blood, or received a blood transfusion in the last 3 months.

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I haven't taken prescription drugs within 2 weeks or 5 half-lives before starting.

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I have difficulty communicating with my doctor.

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I have a known G6PD deficiency.

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I am a candidate for a bone marrow transplant that could potentially cure my SCD, but participating in this study would delay or stop me from receiving it.

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I have a confirmed diagnosis of pyruvate kinase deficiency.

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I've had over 6 pain crises due to sickle cell disease that needed hospital care in the last year.

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I regularly get or got a blood transfusion in the last 3 months.

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I am currently on treatment to improve oxygen delivery by my red blood cells.

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I have not had major surgery in the last 6 months.

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I have had a bone marrow or stem cell transplant.

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I haven't taken strong P-gp inhibitors recently.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ sad: up to day 13; mad: up to day 49; scd: up to day 56

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~sad: up to day 13; mad: up to day 49; scd: up to day 56

This trial's timeline: 3 weeks for screening, Varies for treatment, and sad: up to day 13; mad: up to day 49; scd: up to day 56 for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

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

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

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

+7 more

Secondary study objectives

Area Under the Effect Curve (AUEC) from Time zero to t for 2,3-DPG and ATP

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

Changes in the Concentration of 2,3-diphosphoglycerate (2,3-DPG) and Adenosine Triphosphate (ATP) in Whole Blood

+14 more

Trial Design

3Treatment groups

Experimental Treatment

Group I: Part 3: Sickle Cell Disease (SCD) PhaseExperimental Treatment1 Intervention

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

Group II: Part 2: Multiple Ascending Dose (MAD) PhaseExperimental Treatment2 Interventions

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.

Group III: Part 1: Single Ascending Dose (SAD) PhaseExperimental Treatment2 Interventions

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.

0 / 25Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments in healthy subjects often involve drugs that modulate metabolic pathways, enzyme activity, or receptor interactions to understand their pharmacokinetics and pharmacodynamics. For example, AG-946 is being studied to assess its safety and tolerability, which involves understanding how the drug is absorbed, distributed, metabolized, and excreted in the body. This is crucial for determining the appropriate dosage and identifying any potential side effects, ensuring that the drug is safe and effective before being administered to patients with specific conditions like sickle cell disease.

Primary prevention of stroke in children with sickle cell anemia in sub-Saharan Africa: rationale and design of phase III randomized clinical trial.Antibiotics for treating acute chest syndrome in people with sickle cell disease.Fluid replacement therapy for acute episodes of pain in people with sickle cell disease.