What side effects are associated with this type of intervention?

Common treatments for Myelodysplastic Syndrome (MDS) include erythropoiesis-stimulating agents (ESAs) like epoetin alfa and darbepoetin alfa, which can cause hypertension, thromboembolic events, and, in some cases, an increased risk of leukemic transformation. Thrombopoietin mimetics, such as romiplostim, may transiently improve platelet counts but have been associated with increased blast cell counts and a potential risk of progression to acute myeloid leukemia (AML). Other side effects of MDS treatments can include cytopenias, fatigue, and injection site reactions. It is important to monitor patients closely for these adverse effects and adjust treatment as necessary.

What prior FDA approvals exist?

The FDA has approved several treatments for Myelodysplastic Syndrome (MDS) that aim to improve erythroid response. Erythropoiesis-stimulating agents (ESAs) like epoetin alfa and darbepoetin alfa are commonly used to manage anemia in MDS patients. These agents have shown efficacy in reducing the need for red blood cell transfusions and improving hemoglobin levels. Additionally, hypomethylating agents such as azacitidine and decitabine are approved for MDS and are used to improve blood counts and reduce transfusion needs. Thrombopoietin receptor agonists like eltrombopag and romiplostim have been studied for their potential to manage thrombocytopenia in MDS, although their use is more controversial due to concerns about progression to acute myeloid leukemia (AML).

What other types of research exist?

Promising novel alternatives to AG-946 for Myelodysplastic Syndrome (MDS) patients include: 1) Eltrombopag, a thrombopoietin-receptor agonist, which has shown potential in improving platelet counts and may have antileukemic effects when combined with azacitidine. 2) Venetoclax combined with hypomethylating agents (HMAs) like azacitidine or decitabine, which has demonstrated superior outcomes compared to HMAs alone. 3) Ivosidenib, an IDH1 inhibitor, combined with azacitidine, which has shown efficacy and tolerability in patients with IDH1-mutated AML and could be considered for MDS with similar mutations.

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AG-946 for Myelodysplastic Syndrome

Phase 2

Waitlist Available

Research Sponsored by Agios Pharmaceuticals, Inc.

Eligibility Criteria Checklist

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

Must have

If taking iron chelation therapy, the iron chelation therapy dose must have been stable and started ≥56 days before administration of the first dose of study drug

2 forms of contraception, 1 of which must be considered highly effective, from the time of providing informed consent, throughout the study, and for 28 days after the last dose of study drug for women and 90 days after the last dose of study drug for men. The second form of contraception can be an acceptable barrier method

Must not have

Platelet count <50,000/μL (50 × 109/L) assessed in the absence of platelet transfusions within 28 days before Screening

Currently receiving treatment with luspatercept, EPO, or G-CSF. Treatment with EPO or G-CSF must have been stopped for ≥28 days before administration of the first dose of study drug; treatment with luspatercept must have been stopped for ≥65 days before randomization

Timeline

Screening 3 weeks

Treatment Varies

Follow Up baseline, week 8 through week 16

Awards & highlights

Summary

This trial is testing a new drug called AG-946 to see if it can help people with a blood disorder called Low-Risk Myelodysplastic Syndromes (LR-MDS). The goal is to find out if the drug can improve the production of healthy red blood cells.

Who is the study for?

Adults with low-risk myelodysplastic syndromes (LR-MDS) and anemia can join this trial. They should have hemoglobin levels below 11.0 g/dL, a good performance status, and less than 5% bone marrow blasts. Participants must not be heavily dependent on blood transfusions and agree to use effective contraception if applicable.

What is being tested?

The study is testing AG-946 against a placebo in two phases to see if it helps improve anemia in LR-MDS patients. Phase 2a establishes the concept while Phase 2b compares AG-946's effectiveness at different doses versus placebo.

What are the potential side effects?

Specific side effects of AG-946 are not listed but may include typical reactions seen with other treatments for MDS such as fatigue, nausea, injection site reactions, or potential allergic responses to the drug's components.

Eligibility Criteria

Inclusion Criteria

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

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I have been on a stable dose of iron chelation therapy for at least 56 days.

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I am using two forms of birth control, one highly effective, during and after the study.

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My MDS is classified as lower-risk with a score ≤3.5 and less than 5% blasts.

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I have been on a stable dose of iron chelation therapy for at least 56 days.

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I can take care of myself and am up and about more than half of my waking hours.

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I have received fewer than 3 blood transfusions in the last 4 months and none in the last 2 months.

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My MDS is classified as lower-risk with a score of ≤3.5 and less than 5% blasts.

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I am 18 years old or older.

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My MDS is classified as lower-risk with a score ≤3.5 and less than 5% blasts.

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I can take care of myself and am up and about more than half of my waking hours.

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I am able to care for myself and perform daily activities.

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I am 18 years old or older.

Exclusion Criteria

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

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My platelet count is below 50,000 without recent transfusions.

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I stopped taking EPO or G-CSF at least 28 days ago, or luspatercept at least 65 days ago.

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My kidney function is reduced, with an eGFR below 45 mL/min.

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I have stopped taking EPO or G-CSF for at least 28 days, or luspatercept for at least 65 days, before starting the study drug.

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My kidney function is reduced, with an eGFR below 45 mL/min.

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My MDS developed after treatment for another disease.

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I haven't had serious heart or lung problems in the last 6 months.

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I am allergic to AG-946 or its ingredients.

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I have been diagnosed with acute myeloid leukemia.

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I have fully recovered from any major surgery I had in the last 12 weeks.

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I have an active hepatitis C infection or tested positive for hepatitis B.

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I am allergic to AG-946 or its ingredients.

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I have fully recovered from any major surgery I had in the last 12 weeks.

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My platelet count is 75,000 or less without recent transfusions.

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I haven't stopped P-gp inhibitors for the required time before starting the study drug.

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I have a history of acute myeloid leukemia (AML).

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ baseline, week 8 through week 16

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~baseline, week 8 through week 16

This trial's timeline: 3 weeks for screening, Varies for treatment, and baseline, week 8 through week 16 for reporting.

Treatment Details

Study Objectives

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

Primary study objectives

Phase 2a: Proportion of Participants With Hemoglobin (Hb) Response

Phase 2a: Proportion of Participants With Transfusion Independence During the Core Period

Phase 2b: Proportion of Participants With Transfusion Independence

Secondary study objectives

Phase 2a: Proportion of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Leading to Discontinuation During the Core Period

Phase 2a: Proportion of Participants With Hb 1.0+ Response

Phase 2b: Duration of Transfusion Independence (TI)

+1 more

Trial Design

4Treatment groups

Experimental Treatment

Group I: Core Period: Phase 2b - Tebapivat Dose Level 3Experimental Treatment1 Intervention

Participants will receive Dose level 3 of tebapivat, orally, once daily for up to 24 weeks. At the discretion of the investigator, participants who complete the Core Period will be eligible to receive the same dose in Extension Period for up to 156 weeks.

Group II: Core Period: Phase 2b - Tebapivat Dose Level 2Experimental Treatment1 Intervention

Participants will receive Dose level 2 of tebapivat, orally, once daily for up to 24 weeks. At the discretion of the investigator, participants who complete the Core Period will be eligible to receive the same dose in Extension Period for up to 156 weeks.

Group III: Core Period: Phase 2b - Tebapivat Dose Level 1Experimental Treatment1 Intervention

Participants will receive Dose level 1 of tebapivat, orally, once daily for up to 24 weeks. At the discretion of the investigator, participants who complete the Core Period will be eligible to receive the same dose in Extension Period for up to 156 weeks.

Group IV: Core Period: Phase 2a - TebapivatExperimental Treatment1 Intervention

Participants will receive tebapivat orally, once daily for up to 16 weeks. At the discretion of the investigator, participants who complete the Core Period will be eligible to receive the same dose in Extension Period for up to 156 weeks.

0 / 28Eligibility 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 for Myelodysplastic Syndrome (MDS) include erythropoiesis-stimulating agents (ESAs) like epoetin alfa and darbepoetin alfa, which boost red blood cell production by stimulating the bone marrow. Thrombopoietin mimetics, such as romiplostim, increase platelet counts but carry a risk of leukemic transformation. DNA methyltransferase inhibitors like azacitidine and decitabine work by reactivating silenced genes that control cell growth and differentiation, thereby reducing the proliferation of abnormal cells. These treatments are crucial for MDS patients as they address the hematologic deficiencies characteristic of the disease, improving quality of life and potentially delaying progression to acute myeloid leukemia (AML).

Mutations in myelodysplastic syndromes: Core abnormalities and CHIPping away at the edges.Lenalidomide as a disease-modifying agent in patients with del(5q) myelodysplastic syndromes: linking mechanism of action to clinical outcomes.Combination therapy with DNA methyltransferase inhibitors in hematologic malignancies.