Trial Review

Technical difficulties have been reported by some users of the search function and is being investigated by technical staff. Thank you for your patience and apologies for any inconvenience caused.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT05490446




Registration number
NCT05490446
Ethics application status
Date submitted
26/07/2022
Date registered
5/08/2022
Date last updated
16/05/2024

Titles & IDs
Public title
A Study of AG-946 in Participants With Anemia Due to Lower-Risk Myelodysplastic Syndromes (LR-MDS)
Scientific title
A Phase 2a/2b, Open-label, Proof of Concept (Phase 2a) and Double-blind, Randomized, Placebo-Controlled (Phase 2b), Multicenter, Efficacy, and Safety Study of AG-946 in Participants With Anemia Due to Lower-Risk Myelodysplastic Syndromes
Secondary ID [1] 0 0
2022-500609-42-00
Secondary ID [2] 0 0
AG946-C-002
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Myelodysplastic Syndromes 0 0
Condition category
Condition code
Blood 0 0 0 0
Haematological diseases
Blood 0 0 0 0
Anaemia
Blood 0 0 0 0
Other blood disorders
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - AG-946
Treatment: Drugs - Placebo

Experimental: Core Period: Phase 2a - AG-946 5 mg - Participants will receive AG-946, 5 milligrams (mg) orally, once daily for up to 16 weeks. At the discretion of the investigator, participants who complete Core Period will be eligible to receive the same dose in Extension Period for up to 156 weeks.

Experimental: Double-blind Period: Phase 2b - AG-946 2 mg - Participants will receive AG-946, 2 mg orally, once daily for up to 24 weeks.

Experimental: Double-blind Period: Phase 2b - AG-946 3 mg - Participants will receive AG-946, 3 mg orally, once daily for up to 24 weeks.

Experimental: Double-blind Period: Phase 2b - AG-946 5 mg - Participants will receive AG-946, 5 mg orally, once daily for up to 24 weeks.

Placebo Comparator: Double-blind Period: Phase 2b - Matching-placebo - Participants will receive AG-946-matching placebo orally, once daily for up to 24 weeks.

Experimental: Extension Period: AG-946 2 mg - At the discretion of the investigator, participants who received placebo in the Double-blind Period will receive AG-946, 2 mg orally, once daily for up to 156 weeks.

Experimental: Extension Period: AG-946 3 mg - At the discretion of the investigator, participants who received placebo in the Double-blind Period will receive AG-946, 3 mg orally, once daily for up to 156 weeks.

Experimental: Extension Period: AG-946 5 mg - At the discretion of the investigator, participants who received placebo in the Double-blind Period will receive AG-946, 5 mg orally, once daily for up to 156 weeks.


Treatment: Drugs: AG-946
AG-946 Tablet

Treatment: Drugs: Placebo
Matching-placebo Tablet
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Phase 2a: Number of Participants With Hemoglobin (Hb) Response
Timepoint [1] 0 0
Baseline, Week 8 through Week 16
Primary outcome [2] 0 0
Phase 2a: Number of Participants With Transfusion Independence During the Core Period
Timepoint [2] 0 0
Up to 16 weeks
Primary outcome [3] 0 0
Phase 2b: Number of Participants With Modified Hematologic Improvement-erythroid (mHI-E) Response
Timepoint [3] 0 0
Up to 24 weeks
Secondary outcome [1] 0 0
Phase 2a: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Leading to Discontinuation During the Core Period
Timepoint [1] 0 0
Up to 16 weeks
Secondary outcome [2] 0 0
Phase 2a: Number of Participants With Laboratory Abnormalities During the Core Period
Timepoint [2] 0 0
Up to 16 weeks
Secondary outcome [3] 0 0
Phase 2a: Number of Participants With Hb 1.0+ Response
Timepoint [3] 0 0
Baseline, Week 8 through Week 16
Secondary outcome [4] 0 0
Phase 2a: Change From Baseline in Hb Concentration During the Core Period
Timepoint [4] 0 0
Baseline up to 16 weeks
Secondary outcome [5] 0 0
Phase 2a: Number of Participants With =1.5-g/dL increase From Baseline in the Hb Concentration at =2 Consecutive Time Points From Week 8 through Week 16
Timepoint [5] 0 0
Baseline, Week 8 through Week 16
Secondary outcome [6] 0 0
Phase 2a: Change from Baseline in Total Transfused Red Blood Cell (RBC) Units During the Core Period
Timepoint [6] 0 0
Baseline up to 16 weeks
Secondary outcome [7] 0 0
Phase 2a: Number of Participants With =50% Reduction in Total Transfused RBC Units for =8 Consecutive Weeks During the Core Period Compared With Baseline
Timepoint [7] 0 0
Baseline up to 16 weeks
Secondary outcome [8] 0 0
Phase 2a: Plasma Concentration of AG-946 During the Core Period
Timepoint [8] 0 0
Day 1 and Week 8 (=60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (=60 minutes predose)
Secondary outcome [9] 0 0
Phase 2a: Maximum (Peak) Concentration (Cmax) of AG-946 During the Core Period
Timepoint [9] 0 0
Day 1 and Week 8 (=60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (=60 minutes predose)
Secondary outcome [10] 0 0
Phase 2a: Time to Cmax (tmax) of AG-946 During the Core Period
Timepoint [10] 0 0
Day 1 and Week 8 (=60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (=60 minutes predose)
Secondary outcome [11] 0 0
Phase 2a: Area Under the Concentration-time Curve From 0 to t Hours (AUC0-t) of AG-946 During the Core Period
Timepoint [11] 0 0
Day 1 and Week 8 (=60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (=60 minutes predose)
Secondary outcome [12] 0 0
Phase 2a: Area Under the Concentration-time Curve From 0 to the End of the Dosing Interval (AUC0-t) of AG-946 During the Core Period
Timepoint [12] 0 0
Day 1 and Week 8 (=60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (=60 minutes predose)
Secondary outcome [13] 0 0
Phase 2a: Apparent Terminal Elimination Half-life (t½) of AG-946 During the Core Period
Timepoint [13] 0 0
Day 1 and Week 8 (=60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (=60 minutes predose)
Secondary outcome [14] 0 0
Phase 2a: Whole Blood Concentrations of 2,3-diphosphoglycerate (2,3-DPG) During the Core Period
Timepoint [14] 0 0
Day 1 and Week 8 (=60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (=60 minutes predose)
Secondary outcome [15] 0 0
Phase 2a: Whole Blood Concentrations of Adenosine Triphosphate (ATP) During the Core Period
Timepoint [15] 0 0
Day 1 and Week 8 (=60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (=60 minutes predose)
Secondary outcome [16] 0 0
Phase 2b: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Leading to Discontinuation During the Double-blind Period
Timepoint [16] 0 0
Up to 24 weeks
Secondary outcome [17] 0 0
Phase 2b: Change From Baseline in Hb Concentration During the Double-Blind Period
Timepoint [17] 0 0
Baseline up to 24 weeks
Secondary outcome [18] 0 0
Phase 2b: Change From Baseline in Total Transfused RBC Units From Week 8 Through Week 24
Timepoint [18] 0 0
Baseline, Week 8 through Week 24
Secondary outcome [19] 0 0
Phase 2b: Number of Participants With Transfusion Independence during the Double-blind Period
Timepoint [19] 0 0
Baseline up to 24 weeks
Secondary outcome [20] 0 0
Phase 2b: Time to First mHI-E Response During the Double-blind Period
Timepoint [20] 0 0
Baseline up to 24 weeks
Secondary outcome [21] 0 0
Phase 2b: Maximum Duration of mHI-E Response for Participants Who Achieved an mHI-E Response During the Double-blind Period
Timepoint [21] 0 0
Baseline up to 24 weeks
Secondary outcome [22] 0 0
Phase 2b: Plasma Concentration of AG-946 During the Double-blind Period
Timepoint [22] 0 0
Day 1 and Week 8 (=60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (=60 minutes predose)
Secondary outcome [23] 0 0
Phase 2b: Maximum (Peak) Concentration (Cmax) of AG-946 During the Double-blind Period
Timepoint [23] 0 0
Day 1 and Week 8 (=60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (=60 minutes predose)
Secondary outcome [24] 0 0
Phase 2b: Time to Cmax (tmax) of AG-946 During the Double-blind Period
Timepoint [24] 0 0
Day 1 and Week 8 (=60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (=60 minutes predose)
Secondary outcome [25] 0 0
Phase 2b: Area Under the Concentration-time Curve From 0 to t Hours (AUC0-t) of AG-946 During the Double-blind Period
Timepoint [25] 0 0
Day 1 and Week 8 (=60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (=60 minutes predose)
Secondary outcome [26] 0 0
Phase 2b: Area Under the Concentration-time Curve From 0 to the End of the Dosing Interval (AUC0-t) of AG-946 During the Double-blind Period
Timepoint [26] 0 0
Day 1 and Week 8 (=60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (=60 minutes predose)
Secondary outcome [27] 0 0
Phase 2b: Apparent Terminal Elimination Half-life (t½) of AG-946 During the Double-blind Period
Timepoint [27] 0 0
Day 1 and Week 8 (=60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (=60 minutes predose)
Secondary outcome [28] 0 0
Phase 2b: Whole Blood Concentrations of 2,3-diphosphoglycerate (2,3-DPG) During the Double-blind Period
Timepoint [28] 0 0
Day 1 and Week 8 (=60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (=60 minutes predose)
Secondary outcome [29] 0 0
Phase 2b: Whole Blood Concentrations of Adenosine Triphosphate (ATP) During the Double-blind Period
Timepoint [29] 0 0
Day 1 and Week 8 (=60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (=60 minutes predose)
Secondary outcome [30] 0 0
Phase 2b: Correlation Between AG-946 Plasma Concentration/exposure and Percentage of Participants With mHI-E Response During the Double-blind Period, as Assessed by Regression Analysis
Timepoint [30] 0 0
Baseline up to 24 weeks
Secondary outcome [31] 0 0
Phase 2b: Correlation Between AG-946 Plasma Concentration/exposure and Change From Baseline in Hb Concentration During the Double-blind Period, as Assessed by Regression Analysis
Timepoint [31] 0 0
Baseline up to 24 weeks
Secondary outcome [32] 0 0
Phase 2b: Correlation Between AG-946 Plasma Concentration/exposure and Percentage of Participants Having AEs of Clinical Interest During the Double-blind Period, as Assessed by Regression Analysis
Timepoint [32] 0 0
Baseline up to 24 weeks

Eligibility
Key inclusion criteria
Phase 2a

- At least 18 years of age at the time of providing informed consent;

- Documented diagnosis of myelodysplastic syndromes (MDS) according to World Health
Organization (WHO) classification (Arber et al, 2016), that meets Revised
International Prognostic Scoring System (IPSS-R) classification of lower-risk disease
(risk score: =3.5) and <5% blasts as determined by the participant's bone marrow
biopsy/aspirate during the Screening Period;

- Nontransfused or with low transfusion burden (LTB), based on transfusion history from
the participant's medical record, according to revised International Working Group
(IWG) 2018 criteria:

- Nontransfused (NTD): <3 red blood cell (RBC) units in the 16-week period before
administration of the first dose of study drug and no transfusions in the 8-week
period before administration of the first dose of study drug, or

- LTB: 3 to 7 RBC units in the 16-week period before administration of the first
dose of study drug and <4 RBC units in the 8-week period before administration of
the first dose of study drug;

- An hemoglobin (Hb) concentration <11.0 grams per deciliter (g/dL) during the 4-week
Screening Period;

- Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2;

- 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;

- Women of childbearing potential (WOCBP) must be abstinent of sexual activities that
may result in pregnancy as part of their usual lifestyle or agree to use a highly
effective method of contraception from the time of providing informed consent,
throughout the study, and for 28 days after the last dose of study drug; if the highly
effective method of contraception is hormonal contraception, then an acceptable
barrier method must also be used. Men with partners who are WOCBP must be abstinent of
sexual activities that may result in pregnancy as part of their usual lifestyle or
agree to use a condom from the time of providing informed consent throughout the study
and for 28 days after the last dose of study drug;

- Written informed consent from the participant before any study-related procedures are
conducted and willing to comply with all study procedures for the duration of the
study.

Phase 2b

- At least 18 years of age at the time of providing informed consent;

- Documented diagnosis of MDS according to WHO classification (Arber et al, 2016), that
meets IPSS-R classification of lower-risk disease (risk score: =3.5) and <5% blasts as
determined by the participant's bone marrow biopsy/aspirate during the Screening
Period;

- Nontransfused, with LTB, or with high transfusion burden (HTB), based on transfusion
history from the participant's medical record, according to revised IWG 2018 criteria:

- NTD: <3 RBC units in the 16-week period before randomization and no transfusions
in the 8-week period before randomization, or

- LTB: 3 to 7 RBC units in the 16-week period before randomization and <4 RBC units
in the 8-week period before randomization, or

- HTB: =8 RBC units in the 16-week period before randomization and =4 RBC units in
the 8-week period before randomization;

- An Hb concentration <11.0 g/dL during the 4-week Screening Period;

- Up to 2 prior therapies including erythropoiesis-stimulating agents (ESAs) (eg,
erythropoietin [EPO], EPO + granulocyte colony-stimulating factor [G-CSF]) and/or
luspatercept;

- ECOG Performance Status score of 0, 1, or 2;

- If taking iron chelation therapy, the iron chelation therapy dose must have been
stable and started =56 days before randomization;

- WOCBP must be abstinent of sexual activities that may result in pregnancy as part of
their usual lifestyle or agree to use a highly effective, from the time of providing
informed consent throughout the study and for 28 days after the last dose of study
drug; if the highly effective method of contraception is hormonal contraception, then
an acceptable barrier method must be used. Men with partners who are WOCBP must be
abstinent of sexual activities that may result in pregnancy as part of their usual
lifestyle or agree to use a condom from the time of providing informed consent
throughout the study and for 28 days after the last dose of study drug;

- Written informed consent from the participant before any study-related procedures are
conducted and willing to comply with all study procedures for the duration of the
study.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Phase 2a

- Known history of acute myeloid leukemia (AML);

- Secondary MDS, defined as MDS that is known to have arisen as a result of chemical
injury or treatment with chemotherapy and/or radiation for other diseases;

- Prior exposure to a pyruvate kinase activator and/or disease-modifying agents for
underlying MDS:

- Immunomodulatory drugs (IMiDs) such as lenalidomide; at the Investigator's
discretion and in consultation with the Medical Monitor, participants who
received =1 week of treatment with IMiDs may not be excluded, provided their last
dose was =8 weeks before administration of the first dose of study drug

- Hypomethylating agents (HMAs); at the Investigator's discretion and in
consultation with the Medical Monitor, participants who received =2 doses of HMAs
may not be excluded, provided that their last dose was =8 weeks before
administration of the first dose of study drug

- Isocitrate dehydrogenase (IDH) inhibitors

- Immunosuppressive therapy (IST)

- Allogeneic or autologous stem cell transplant;

- Currently receiving treatment with ESAs±G-CSF and/or luspatercept. Treatment with
ESAs±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
administration of the first dose of study drug;

- History of active and/or uncontrolled cardiac or pulmonary disease within 6 months
before providing informed consent, including but not limited to:

- New York Heart Association Class III or IV heart failure or clinically
significant dysrhythmia

- Myocardial infarction, unstable angina pectoris, or unstable hypertension; high
risk thrombosis; hemorrhagic, embolic, or thrombotic stroke; deep venous
thrombosis; or pulmonary or arterial embolism

- Heart rate-corrected QT interval using Fridericia's method of =470 milliseconds
for female participants and =450 milliseconds for male participants, except for
right or left bundle branch block

- Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sided
heart failure, and radiographic pulmonary fibrosis >50%

- Severe pulmonary hypertension as defined by severe symptoms associated with
hypoxia, right-sided heart failure, and oxygen indicated;

- History of hepatobiliary disorders, as defined by:

- Serum aspartate aminotransferase (AST) >2.5 × upper limit of normal (ULN) (unless
due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase
(ALT) >2.5 × ULN (unless due to hepatic iron deposition)

- Serum bilirubin >ULN, if the elevation is associated with clinically symptomatic
choledocholithiasis, cholecystitis, biliary obstruction, or hepatocellular
disease;

- Renal dysfunction, as defined by an estimated glomerular filtration rate (eGFR) <45
milliliters per minute (mL/min)/1.73 m^2;

- Active infection requiring systemic antimicrobial therapy at the time of providing
informed consent. If antimicrobial therapy is required during the Screening Period,
screening procedures should not be performed while antimicrobial therapy is being
administered, and the last dose of antimicrobial therapy must be administered =7 days
before administration of the first dose of study drug;

- Major surgery within 12 weeks before administration of the first dose of study drug.
Participants must have completely recovered from any previous surgery before
administration of the first dose of study drug;

- For any malignancy except MDS: History of malignancy (active or treated) =5 years
before providing informed consent for nonmelanomatous skin cancer in situ, cervical
carcinoma in situ, or breast carcinoma in situ;

- Positive test for hepatitis C virus (HCV) antibody (Ab) with evidence of active HCV
infection, or positive test for hepatitis B surface antigen (HBsAg);

- Positive test for HIV-1 Ab or HIV-2 Ab;

- Absolute neutrophil count (ANC) <500/microliter (µL) (0.5 × 109/L);

- Platelet count =75,000/µL during Screening (75 × 109/L) platelet transfusions within
28 days before Screening or during Screening;

- Nonfasting triglyceride concentration >500 mg/dL;

- Receiving inhibitors of P-glycoprotein (P-gp) that have not been stopped for =5 days
or a time frame equivalent to 5 half-lives (whichever is longer) before administration
of the first dose of study drug;

- Current enrollment or past participation (within 4 weeks or a time frame equivalent to
5 half-lives of the investigational study drug before administration of the first dose
of study drug or, whichever is longer) in any other clinical study involving an
investigational treatment or device;

- Known allergy to AG-946 or its excipients;

- Pregnant or breastfeeding;

- Any medical, hematologic, psychological, or behavioral condition(s) or prior or
current therapy that, in the opinion of the Investigator, may confer an unacceptable
risk to participating in the study and/or could confound the interpretation of the
study data. Also excluded are:

- Participants who are institutionalized by regulatory or court order;

- Participants with any condition(s) that could create undue influence (including
but not limited to incarceration, involuntary psychiatric confinement, and
financial or familial affiliation with the Investigator or Sponsor).

Phase 2b

- Known history of AML;

- Secondary MDS, defined as MDS that is known to have arisen as a result of chemical
injury or treatment with chemotherapy and/or radiation for other diseases;

- Prior exposure to a pyruvate kinase activator, including exposure to AG-946 in the
Phase 2a part of this study, and/or disease-modifying agents for underlying MDS:

- IMiDs such as lenalidomide; at the Investigator's discretion and in consultation
with the Medical Monitor, participants who received =1 week of treatment with
IMiDs may not be excluded, provided their last dose was =8 weeks before
randomization

- HMAs; at the Investigator's discretion and in consultation with the Medical
Monitor, participants who received =2 doses of HMAs may not be excluded, provided
that their last dose was =8 weeks before randomization

- IDH inhibitors

- IST

- Allogeneic or autologous stem cell transplant;

- Currently receiving treatment with ESAs±G-CSF and/or luspatercept. Treatment with
ESAs±G-CSF must have been stopped for =28 days before randomization; treatment with
luspatercept must have been stopped for =65 days before randomization;

- History of active and/or uncontrolled cardiac or pulmonary disease within 6 months
before providing informed consent, including but not limited to:

- New York Heart Association Class III or IV heart failure or clinically
significant dysrhythmia

- Myocardial infarction, unstable angina pectoris, or unstable hypertension; high
risk thrombosis; hemorrhagic, embolic, or thrombotic stroke; deep venous
thrombosis; or pulmonary or arterial embolism

- Heart rate-corrected QT interval using Fridericia's method of =470 milliseconds
for female participants and =450 milliseconds for male participants, except for
right or left bundle branch block

- Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sided
heart failure, and radiographic pulmonary fibrosis >50%

- Severe pulmonary hypertension as defined by severe symptoms associated with
hypoxia, right-sided heart failure, and oxygen indicated;

- History of hepatobiliary disorders, as defined by:

- Serum AST >2.5 × ULN (unless due to hemolysis and/or hepatic iron deposition) and
ALT >2.5 × ULN (unless due to hepatic iron deposition)

- Serum bilirubin >ULN, if the elevation is associated with clinically symptomatic
choledocholithiasis, cholecystitis, biliary obstruction, or hepatocellular
disease;

- Renal dysfunction, as defined by an eGFR <45 mL/min/1.73 m^2;

- Active infection requiring systemic antimicrobial therapy at the time of providing
informed consent. If antimicrobial therapy is required during the Screening Period,
screening procedures should not be performed while antimicrobial therapy is being
administered, and the last dose of antimicrobial therapy must be administered =7 days
before randomization;

- Major surgery within 12 weeks before randomization. Participants must have completely
recovered from any previous surgery before randomization;

- For any malignancy except MDS: History of malignancy (active or treated) =5 years
before providing informed consent, except for nonmelanomatous skin cancer in situ,
cervical carcinoma in situ, or breast carcinoma in situ.;

- Positive test for HCV Ab with evidence of active HCV infection, or positive test for
HBsAg;

- Positive test for HIV-1 Ab or HIV-2 Ab;

- ANC <500/µL (0.5 × 109/L);

- Platelet count <50,000/µL (50 × 109/L) during Screening; platelet transfusions within
28 days before Screening or during Screening;

- Nonfasting triglyceride concentration >500 mg/dL;

- Receiving inhibitors of P-gp that have not been stopped for =5 days or a time frame
equivalent to 5 half-lives (whichever is longer) before randomization;

- Current enrollment or past participation (within 4 weeks or a time frame equivalent to
5 half-lives of the investigational study drug before randomization or, whichever is
longer) in any other clinical study involving an investigational treatment or device;

- Known allergy to AG-946 or its excipients, including placebo;

- Pregnant or breastfeeding;

- Any medical, hematologic, psychological, or behavioral condition(s) or prior or
current therapy that, in the opinion of the Investigator, may confer an unacceptable
risk to participating in the study and/or could confound the interpretation of the
study data. Also excluded are:

- Participants who are institutionalized by regulatory or court order

- Participants with any condition(s) that could create undue influence (including
but not limited to incarceration, involuntary psychiatric confinement, and
financial or familial affiliation with the Investigator or Sponsor).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Other
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
7/11/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/11/2028
Actual
Sample size
Target
116
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Monash Health, Monash Medical Centre - Clayton
Recruitment postcode(s) [1] 0 0
3168 - Clayton
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Florida
Country [3] 0 0
United States of America
State/province [3] 0 0
Illinois
Country [4] 0 0
United States of America
State/province [4] 0 0
Missouri
Country [5] 0 0
United States of America
State/province [5] 0 0
New York
Country [6] 0 0
United States of America
State/province [6] 0 0
North Carolina
Country [7] 0 0
Austria
State/province [7] 0 0
Oberösterreich
Country [8] 0 0
Czechia
State/province [8] 0 0
Ostrava
Country [9] 0 0
France
State/province [9] 0 0
Bouches-du-Rhône
Country [10] 0 0
France
State/province [10] 0 0
Maine-et-Loire
Country [11] 0 0
France
State/province [11] 0 0
Lille
Country [12] 0 0
France
State/province [12] 0 0
Paris
Country [13] 0 0
Germany
State/province [13] 0 0
Niedersachsen
Country [14] 0 0
Germany
State/province [14] 0 0
Nordrhein-Westfalen
Country [15] 0 0
Germany
State/province [15] 0 0
Sachsen
Country [16] 0 0
Greece
State/province [16] 0 0
Alexandroupolis
Country [17] 0 0
Greece
State/province [17] 0 0
Athens
Country [18] 0 0
Greece
State/province [18] 0 0
Patras
Country [19] 0 0
Greece
State/province [19] 0 0
Thessaloniki
Country [20] 0 0
Israel
State/province [20] 0 0
Jerusalem
Country [21] 0 0
Israel
State/province [21] 0 0
Tel Aviv
Country [22] 0 0
Italy
State/province [22] 0 0
Lombardia
Country [23] 0 0
Italy
State/province [23] 0 0
Piemonte
Country [24] 0 0
Italy
State/province [24] 0 0
Roma
Country [25] 0 0
Korea, Republic of
State/province [25] 0 0
Daegu
Country [26] 0 0
Korea, Republic of
State/province [26] 0 0
Seoul
Country [27] 0 0
Poland
State/province [27] 0 0
Mazowieckie
Country [28] 0 0
Poland
State/province [28] 0 0
Slaskie
Country [29] 0 0
Poland
State/province [29] 0 0
Warminsko-mazurskie
Country [30] 0 0
Spain
State/province [30] 0 0
Cordoba
Country [31] 0 0
Spain
State/province [31] 0 0
Madrid
Country [32] 0 0
Spain
State/province [32] 0 0
Salamanca
Country [33] 0 0
Spain
State/province [33] 0 0
Sevilla
Country [34] 0 0
United Kingdom
State/province [34] 0 0
Aberdeen City
Country [35] 0 0
United Kingdom
State/province [35] 0 0
Edinburgh
Country [36] 0 0
United Kingdom
State/province [36] 0 0
London
Country [37] 0 0
United Kingdom
State/province [37] 0 0
Oxford

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Agios Pharmaceuticals, Inc.
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This purpose of this study is to establish proof of concept of AG-946 in participants with
LR-MDS in Phase 2a and to compare the effect of AG-946 versus placebo and to detect a dose
response for erythroid response in participants with LR-MDS in Phase 2b.
Trial website
https://clinicaltrials.gov/ct2/show/NCT05490446
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Medical Affairs
Address 0 0
Agios Pharmaceuticals, Inc.
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries