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

Trial ID: 2024-512747-23-00
Protocol: AG348-C-018
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 transfusion burden in subjects with transfusion-dependent alpha- or beta-thalassemia (TDT). This objective is clinically relevant as it aims to assess the potential of mitapivat to reduce the need for blood transfusions, which are a critical component of managing TDT and can significantly impact patient quality of life and long-term health outcomes.

Participants

The clinical trial involves a total of **76 participants** diagnosed with **Transfusion-Dependent Alpha- or Beta-Thalassemia**. The study population includes both male and female subjects, aged **18 years and older**, who are transfusion-dependent, receiving between 6 to 20 red blood cell units within a 24-week period prior to randomization. Participants were selected based on documented diagnoses of thalassemia, confirmed through DNA analysis, and must have a stable dose of hydroxyurea if applicable. The trial includes individuals who are part of a vulnerable population, and women of childbearing potential are required to adhere to specific contraceptive measures. The selection criteria ensure that participants are willing to comply with all study procedures and have provided written informed consent. The trial aims to evaluate the effect of mitapivat compared to placebo on the transfusion burden in this specific patient group.

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 transfusion-dependent alpha- or beta-thalassemia. The primary objective is to compare the effect of mitapivat versus placebo on transfusion burden in these subjects. The trial is expected to run from November 30, 2021, to October 20, 2029, with participants involved for a duration that includes multiple study visits.

Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, documented diagnosis of thalassemia, and transfusion dependency. The trial will include follow-up visits to monitor the participants' response to the treatment and any adverse effects. The end-of-study visit will conclude the participant's involvement, assessing the overall impact of the treatment.

The expected length of participant involvement is determined by the study's design, with the primary endpoint being a transfusion reduction response, defined as a ≥50% reduction in transfused red blood cell units with a reduction of ≥2 units in any consecutive 12-week period through Week 48 compared with baseline. Conditions that may lead to early termination from the study include non-compliance with study procedures or the occurrence of significant adverse events. Participants are required to comply with all study procedures for the duration of the trial, including maintaining stable doses of any concurrent medications such as hydroxyurea, if applicable.

Treatment

The clinical trial involves the administration of **Mitapivat**, an investigational medication, in the form of a **tablet**. Mitapivat is chemically synthesized and is identified by the sponsor product code AG-348. The active substance, also known as N-(4-((4-(cyclopropylmethyl)-1-piperazinyl)carbonyl)phenyl)-8-quinolinesulfonamide, is provided by Agios Pharmaceuticals. The medication is administered orally. The specific dosage and frequency of administration are not detailed in the provided data. The maximum treatment period is indicated as 9999 days, although the exact dosing schedule is not specified. Participant compliance with the medication regimen will be monitored throughout the study.

The study also includes a **placebo** control, referred to as "Placebo for Mitapivat." The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know who is receiving the active medication versus the placebo. The pharmaceutical form and route of administration for the placebo are not specified in the data. The placebo serves as a comparator treatment to evaluate the efficacy and safety of Mitapivat in subjects with transfusion-dependent alpha or beta thalassemia. The trial aims to assess the impact of Mitapivat on transfusion burden in these subjects.

Efficacy

The efficacy of Mitapivat in the clinical trial will be assessed primarily through the **Transfusion Reduction Response (TRR)**. This endpoint is defined as a ≥50% reduction in transfused red blood cell (RBC) units, with a reduction of ≥2 units of transfused RBCs in any consecutive 12-week period through Week 48 compared with baseline. The trial is a Phase 3, double-blind, randomized, placebo-controlled, multicenter study aimed at evaluating the efficacy and safety of Mitapivat in subjects with transfusion-dependent alpha or beta thalassemia. The main objective is to compare the effect of Mitapivat versus placebo on transfusion burden in these subjects. The study will involve the administration of Mitapivat in tablet form, with the active substance being of chemical origin. The trial is not categorized as low intervention and is designed to provide robust data on the efficacy of Mitapivat in reducing transfusion requirements in the target population.

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 DNA analysis from the subject’s medical record. If this information is not available from the subject’s medical record, DNA analysis can be performed by a local laboratory during the Screening Period. If a local laboratory is unable to perform the test, results from the comprehensive α- and β-globin genotyping performed by the study central laboratory can be used.
Transfusion dependent, defined as 6 to 20 RBC units transfused and a ≤6-week transfusion-free period during the 24-week period before randomization.
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 induce 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 ≥36 weeks before randomization.
Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered ≥36 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) ≤6 months 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 treatment, 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 ≥12 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	30 Nov 2021	34
Denmark	Not Recruiting	30 Nov 2021	8
France	Not Recruiting	30 Nov 2021	15
Germany	Not Recruiting	30 Nov 2021	9
Greece	Not Recruiting	30 Nov 2021	19
Italy	Not Recruiting	30 Nov 2021	14
The Netherlands	Not Recruiting	30 Nov 2021	—
Spain	Not Recruiting	30 Nov 2021	17
Netherlands	—	—	12