Efficacy and Safety Evaluation of Mitapivat in Non–Transfusion-Dependent Alpha- or Beta-Thalassemia: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Study

Trial ID: 2024-512745-16-00
Protocol: AG348-C-017
Sponsor: Agios Pharmaceuticals Inc.

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Diseases & Conditions

Thalassaemia

Objectives

The primary objective of this Phase 3, double-blind, randomized, placebo-controlled, multicenter study is to compare the effect of **mitapivat** versus placebo on anemia in subjects with non–transfusion-dependent alpha- or beta-thalassemia (NTDT). This objective is clinically relevant as it aims to address the management of anemia in NTDT, a condition where patients experience chronic anemia without the need for regular blood transfusions, potentially improving their quality of life and reducing disease-related complications.

Participants

The clinical trial involves a total of **86 participants** diagnosed with **non–transfusion-dependent alpha- or beta-thalassemia**. The study population includes both male and female subjects, aged **18 years and older**, who are considered part of a vulnerable population due to their medical condition. Participants were selected based on specific criteria, including a documented diagnosis of thalassemia and a hemoglobin concentration of **≤10.0 g/dL**. The trial population is non-transfusion dependent, defined as having received **≤5 red blood cell units** in the 24 weeks prior to randomization and no transfusions within 8 weeks before providing informed consent. Lifestyle considerations include the requirement for women of childbearing potential to use effective contraception throughout the study. The selection process ensures that participants are willing to comply with all study procedures and have provided written informed consent. The trial aims to compare the effect of mitapivat versus placebo on anemia in these subjects.

Plans and Procedures

The clinical trial is a **Phase 3**, double-blind, randomized, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of **mitapivat** in subjects with non-transfusion-dependent alpha or beta thalassemia. The primary objective is to compare the effect of mitapivat versus placebo on anemia in these subjects. The trial is expected to run from February 2022 to May 2029, with participant involvement lasting approximately 24 weeks. The study will include a screening visit, multiple follow-up visits, and an end-of-study visit. During the screening visit, eligibility will be confirmed based on criteria such as age, documented diagnosis of thalassemia, hemoglobin concentration, and transfusion history. Participants will be randomized to receive either mitapivat or a placebo, both administered orally in tablet form.

Follow-up visits will occur at regular intervals to monitor hemoglobin levels and assess any adverse events. The primary endpoint is a hemoglobin response, defined as a ≥1.0 g/dL increase in average hemoglobin concentration from Week 12 through Week 24 compared with baseline. The end-of-study visit will involve a final assessment of the participant's health status and the collection of any remaining data. Participants may be withdrawn from the study early if they experience significant adverse effects, fail to comply with study procedures, or withdraw consent. The trial aims to provide valuable insights into the potential benefits of mitapivat for individuals with non-transfusion-dependent thalassemia.

Treatment

The clinical trial involves the administration of **Mitapivat**, an investigational medicinal product, in the form of a **tablet**. Mitapivat is chemically synthesized and is identified by the sponsor product code AG-348. The active substance, Mitapivat, is also known by its chemical name, N-(4-((4-(cyclopropylmethyl)-1-piperazinyl)carbonyl)phenyl)-8-quinolinesulfonamide. The pharmaceutical form of Mitapivat is a tablet, and it is administered orally. The dosing schedule and frequency of administration are determined by the study protocol, with a maximum treatment period of 1111 days. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.

The study also includes a **placebo** group, where participants receive a placebo designed to match the Mitapivat tablet in appearance. The placebo is administered orally, following the same dosing schedule as the active treatment group. The placebo serves as a comparator to evaluate the efficacy and safety of Mitapivat in subjects with non-transfusion-dependent alpha or beta thalassemia. The placebo does not contain any active pharmaceutical ingredients and is used to maintain the double-blind nature of the study. Compliance with placebo administration is similarly monitored to ensure the integrity of the trial results.

Efficacy

The efficacy of Mitapivat in subjects with non–transfusion-dependent alpha or beta thalassemia will be assessed in a Phase 3, double-blind, randomized, placebo-controlled, multicenter study. The primary endpoint for evaluating efficacy is the **Hemoglobin (Hb) response**, defined as a ≥1.0 g/dL increase in average Hb concentration from Week 12 through Week 24 compared with baseline. This endpoint will be measured using validated laboratory tests to ensure accuracy and reliability of the data collected. The schedule for measuring Hb concentration involves multiple timepoints, specifically from Week 12 through Week 24, to capture the change in Hb levels over time. The data collected will be analyzed to determine the efficacy of Mitapivat in improving anemia in the target population. The study aims to provide robust evidence on the therapeutic benefits of Mitapivat compared to placebo in managing non–transfusion-dependent thalassemia.

Inclusion and Exclusion Criteria

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Inclusion Criteria

≥18 years of age at the time of providing informed consent.
Documented diagnosis of thalassemia (β-thalassemia with or without α-globin gene mutations, HbE/β-thalassemia, or α-thalassemia/HbH disease) based on Hb electrophoresis, Hb high-performance liquid chromatography, and/or DNA analysis from the subject’s medical record. If this information is not available from the subject’s medical record, the test(s) can be performed by a local laboratory during the Screening Period. If a local laboratory is unable to perform the test(s), results from the comprehensive α- and β-globin genotyping performed by the study central laboratory can be used.
Hb concentration ≤10.0 g/dL (100.0 g/L), based on an average of at least 2 Hb concentration measurements (separated by ≥7 days) collected during the Screening Period.
Non–transfusion dependent, defined as: ≤5 red blood cell (RBC) units during the 24-week period before randomization and no RBC transfusions ≤8 weeks before providing informed consent and no RBC transfusions during the Screening Period.
If taking hydroxyurea, the hydroxyurea dose must be stable for ≥16 weeks before randomization.
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 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. The second form of contraception can be an acceptable barrier method.
Written informed consent before any study-related procedures are conducted and willing to comply with all study procedures for the duration of the study.

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Exclusion Criteria

Pregnant, breastfeeding, or parturient.
Documented history of homozygous or heterozygous HbS or HbC.
Prior exposure to gene therapy or prior bone marrow or stem cell transplantation.
Currently receiving treatment with luspatercept; the last dose must have been administered ≥18 weeks before randomization.
Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered ≥18 weeks before randomization.
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.
History of active and/or uncontrolled cardiac or pulmonary disease ≤6 months before providing informed consent, including but not limited to: a. New York Heart Association Class III or IV heart failure or clinically significant dysrhythmia b. Myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism c. Heart rate–corrected QT interval using Fridericia’s method ≥450 milliseconds (males) or ≥470 milliseconds (females), except for right or left bundle branch block d. Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sided heart failure, and radiographic pulmonary fibrosis >50% e. Severe pulmonary hypertension as defined by severe symptoms associated with hypoxia, right-sided heart failure, and oxygen indicated
Hepatobiliary disorders, including but not limited to: a. Liver disease with histopathological evidence of cirrhosis or severe fibrosis b. Clinically symptomatic cholelithiasis or cholecystitis (prior cholecystectomy is not exclusionary) c. History of drug-induced cholestatic hepatitis d. Aspartate aminotransferase >2.5 × upper limit of normal (ULN); unless due to hemolysis and hepatic iron deposition) and alanine aminotransferase >2.5 × ULN (unless due to hepatic iron deposition).
Estimated glomerular filtration rate <45 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration creatinine equation.
Nonfasting triglycerides >440 mg/dL (5 mmol/L).
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.
Positive test for hepatitis C virus (HCV) antibody (Ab) with evidence of active HCV infection, or positive test for hepatitis B surface antigen.
Positive test for HIV-1 Ab or HIV-2 Ab.
History of major surgery (including splenectomy) ≤16 weeks before providing informed consent and/or a major surgical procedure planned during the study.
Current enrollment or past participation (≤12 weeks before administration of the first dose of study drug or a time frame equivalent to 5 half-lives of the investigational study drug, whichever is longer) in any other clinical study involving an investigational treatment or device.
Receiving strong cytochrome P450 (CYP)3A4/5 inhibitors that have not been stopped for ≥5 days or a time frame equivalent to 5 half-lives (whichever is longer), or strong CYP3A4 inducers that have not been stopped for ≥4 weeks or a time frame equivalent to 5 half-lives (whichever is longer), before randomization.
Receiving anabolic steroids, that have not been stopped for at least 4 weeks before randomization. Testosterone replacement therapy to treat hypogonadism is allowed; the testosterone dose and preparation must be stable for ≥10 weeks before randomization.
Known allergy, or other contraindication, to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, magnesium stearate, and Opadry® II Blue [hypromellose, titanium dioxide, lactose monohydrate, triacetin, and FD&C Blue #2]).
Any medical, hematological, 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: • Subjects who are institutionalized by regulatory or court order • Subjects 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).

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Bulgaria	Not Recruiting	02 Feb 2022	3
Denmark	Not Recruiting	02 Feb 2022	6
France	Not Recruiting	02 Feb 2022	6
Greece	Not Recruiting	02 Feb 2022	23
Italy	Not Recruiting	02 Feb 2022	29
The Netherlands	Not Recruiting	02 Feb 2022	—
Spain	Not Recruiting	02 Feb 2022	15
Netherlands	—	—	4