Efficacy and Safety Evaluation of Tebapivat in Sickle Cell Disease: A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Dose-Finding Study

Trial ID: 2024-519746-70-01
Protocol: AG946-C-003
Sponsor: Agios Pharmaceuticals Inc.

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Diseases & Conditions

Sickle cell disease

Objectives

The primary objective of this study is to compare the effect of **tebapivat** versus placebo on anemia and to detect a dose response for hemoglobin (Hb) response in participants with **Sickle Cell Disease** (SCD). This is clinically relevant as it aims to address the chronic anemia associated with SCD, potentially improving patient outcomes by identifying an effective dose of tebapivat that enhances hemoglobin levels.

Secondary objectives include:

Evaluating the safety of tebapivat.
Assessing the effect of tebapivat versus placebo on additional measures of anemia, markers of hemolysis, markers of erythropoiesis, and patient-reported outcomes such as fatigue and pain.
Evaluating the pharmacokinetics (PK) and pharmacodynamics (PD) of tebapivat.
Exploring the effect of tebapivat versus placebo on sickle cell pain crises (SCPCs), the 6-minute walk test (6MWT), cognition, and work productivity and activity impairment.
Investigating the effect of tebapivat on biomarkers related to inflammation, vascular biology, the pathogenesis of SCD, and iron metabolism.
Exploring the long-term effects of tebapivat on efficacy and safety.

Participants

The clinical trial involves a total of **36 participants** diagnosed with **Sickle Cell Disease**. The study population includes both male and female subjects, with an age range starting from 16 years, and for participants in France, from 18 years. Participants were selected based on specific criteria, including a documented diagnosis of Sickle Cell Disease and a hemoglobin level between 5.5 and 10.5 g/dL. The trial does not include a vulnerable population. Participants are required to have stable health conditions, particularly if they are on hydroxyurea, which must be stable for at least 90 days prior to randomization. Lifestyle considerations include the requirement for women of childbearing potential and men with partners who are women of childbearing potential to adhere to effective contraceptive measures throughout the study duration and for 28 days after the last dose of the study drug. The selection process ensures that participants are willing to comply with all study procedures and have provided informed consent or assent, with additional consent from a legally acceptable representative for those under the age of legal adulthood.

Plans and Procedures

The clinical trial is a **Phase 2**, double-blind, randomized, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of tebapivat in participants with **sickle cell disease**. The primary objective is to compare the effect of tebapivat versus placebo on anemia and to detect a dose response for hemoglobin (Hb) response. The trial is expected to commence recruitment on July 1, 2025, and conclude by September 30, 2027. Participants will be randomly assigned to receive either the investigational drug AG-946 or a placebo, both administered as oral coated tablets. The maximum treatment period is 64 weeks.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will confirm eligibility based on criteria such as age, documented diagnosis of sickle cell disease, and stable hemoglobin levels. Participants must provide informed consent and, if applicable, assent from a legally acceptable representative. Follow-up visits will occur regularly to assess primary and secondary endpoints, including Hb response, adverse events, and changes in various biomarkers. The end-of-study visit will finalize data collection and assess the overall health status of participants.

Participant involvement is anticipated to last the entire duration of the trial, contingent upon adherence to study protocols. Conditions that may lead to early termination include non-compliance with study procedures, withdrawal of consent, or adverse events that compromise participant safety. The trial will rigorously monitor safety and efficacy through predefined endpoints, such as a ≥1.0 g/dL increase in average Hb concentration from Week 10 through Week 12 compared with baseline, and secondary endpoints including changes in markers of hemolysis and erythropoiesis, patient-reported outcomes, and pharmacokinetic parameters of tebapivat.

Treatment

The clinical trial involves the administration of **AG-946**, an investigational medication, which is formulated as a **coated tablet**. The active substance in AG-946 is **AG-946 phosphate**, a chemical compound developed by Agios Pharmaceuticals. The medication is designed as an allosteric activator of pyruvate kinase isoforms. AG-946 is administered orally, with a maximum daily dose of 5.0 mg and a total maximum dose of 2245 mg over a treatment period of 64 days. An alternative dosing regimen involves a maximum daily dose of 2.5 mg, with a total maximum dose of 1122.5 mg over the same treatment period. Participant compliance with the dosing schedule is monitored throughout the study.

The trial also includes a **placebo** group, where participants receive a placebo formulated as an oral tablet. The placebo is designed to match the appearance and administration route of the AG-946 tablets, ensuring the study remains double-blind. The placebo serves as a control to evaluate the efficacy and safety of AG-946 in participants with sickle cell disease. The administration of the placebo follows the same oral route and dosing schedule as the experimental medication, ensuring consistency across the study arms.

Efficacy

The efficacy of tebapivat in participants with **Sickle Cell Disease** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the hemoglobin (Hb) response, defined as a ≥1.0 g/dL increase in average Hb concentration from Week 10 through Week 12 compared with baseline. Secondary endpoints include the type, frequency, severity, and relationship to the study drug of adverse events (AEs) and serious adverse events (SAEs), as well as the average change from baseline in Hb concentration from Week 10 through Week 12.

Additional secondary endpoints involve the average change from baseline in markers of hemolysis, such as indirect bilirubin and lactate dehydrogenase (LDH), and markers of erythropoiesis, including absolute reticulocyte count, percent reticulocytes, and erythropoietin, from Week 10 through Week 12. Patient-reported outcomes will be measured using the Patient Reported Outcomes Measurement Information System® (PROMIS) Fatigue 13a Short Form score and PROMIS Pain Intensity 1a score, as well as the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) Pain Impact score, all from Week 10 through Week 12.

Pharmacokinetic (PK) and pharmacodynamic (PD) parameters of tebapivat will be evaluated during the Double-blind Period, including plasma concentration and whole blood concentrations of 2,3-DPG and ATP. The annualized rate of sickle cell pain crises (SCPCs) through Week 12, changes from baseline in the 6-minute walk test (6MWT) at Week 12, and changes in cognitive function as assessed by the Cogstate cognition tests at Week 12 will also be analyzed. Furthermore, changes in work productivity and activity impairment, as well as biomarkers related to inflammation, vascular biology, and iron metabolism, will be assessed at specified timepoints.

Inclusion and Exclusion Criteria

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Inclusion Criteria

≥16 years of age at the time of providing informed assent/consent. For France ≥18 years of age at the time of providing informed consent.
Documented diagnosis of SCD (HbSS, HbSC [combined heterozygosity for hemoglobins S and C], HbS/β0-thalassemia, HbS/β+-thalassemia, or other sickle cell syndrome variants).
Hemoglobin ≥5.5 and ≤10.5 g/dL. Hemoglobin concentration must be based on an average of at least 2 Hb concentration measurements (separated by ≥7 days) collected during the Screening Period.
If taking hydroxyurea, the hydroxyurea dose must be stable for at least 90 days before randomization. Discontinuation of hydroxyurea requires a 90-day washout before providing informed consent
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 (see Appendix 1 for the definition of WOCBP and acceptable contraception methods). 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 assent/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
For participants under 18 years of age or under the age at which a participant is considered legally an adult per local regulations: Legally acceptable representative/parent(s) or legal guardian provides supplementary informed consent on behalf of the participant in addition to the participant’s assent. After the participant reaches the age of legal consent, if the participant is still in the clinical study, notification will be required, and a new consent form may need to be signed by participant.

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Exclusion Criteria

Receiving regularly scheduled RBC transfusion therapy (also termed chronic, prophylactic, or preventative transfusion); episodic transfusion in response to worsened anemia or VOC is permitted. Additionally, a participant who requires episodic transfusion(s) may not have received a transfusion(s) within 60 days before providing informed consent or during the Screening Period.
History of active and uncontrolled cardiac or pulmonary disease within 6 months before randomization, 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 of ≥470 milliseconds for female participants and ≥450 milliseconds for male participants, 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 as defined by: a. Serum aspartate aminotransferase >2.5×upper limit of normal (ULN) (unless due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase >2.5×ULN (unless due to hepatic iron deposition) b. 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 <30 mL/min/1.73 m2 by the Chronic Kidney Disease Epidemiology Collaboration creatinine equation.
Nonfasting triglycerides >500 mg/dL (5 mmol/L).
Active uncontrolled infection requiring systemic antimicrobial therapy.
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.
History of major surgery (including splenectomy) ≤16 weeks before providing informed consent and/or planning to undergo a major surgical procedure during the study.
Current enrollment or past participation (within 4 weeks or a timeframe equivalent to 5 half-lives of the investigational study drug before administration of the first dose of study drug, whichever is longer) in any other clinical study involving an investigational treatment or device.
Receiving inhibitors of P-glycoprotein (P-gp) that have not been stopped for ≥5 days or a timeframe equivalent to 5 half-lives (whichever is longer) before administration of the first dose of study drug.
>10 Sickle Cell Pain Crises (SCPC) in the 12 months before providing informed consent.
Known allergy to tebapivat or its excipients (silicified microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, and the Opadry® II Blue film coat [polyvinyl alcohol, titanium dioxide, macrogol/polyethylene glycol, talc, FD&C blue #2/indigo carmine aluminum lake/E132]).
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.
Hospitalized for an SCPC and/or other vaso-occlusive event within 14 days before providing informed consent or within 14 days before randomization. If an SCPC occurs during the Screening Period, the Screening Period may be extended with Medical Monitor approval. A hospitalization is defined as an in-patient admission to a hospital that may or may not be preceded by an emergency room or outpatient clinic visit. A visit to an emergency room that does not result in an in-patient admission does not meet the definition of hospitalization
Receiving treatment with voxelotor, crizanlizumab, or L-glutamine within 90 days before randomization.
Platelet count
Receiving treatment with hematopoietic stimulating agents within 90 days before randomization.
Prior exposure to gene therapy or prior bone marrow or stem cell transplantation, including any conditioning regimen.
History of any malignancy, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ. Participants must not have active disease or have received anticancer treatment ≤5 years before providing informed consent.
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: a. Participants deprived of liberty by court or administrative decision (eg, participants accommodated in an institution by order of an authority or court) b. Participants undergoing psychiatric care without their consent c. Participants admitted to a health or social establishment for purposes other than research d. Adult participants subject to a legal protection measure (guardian, curatorship, legal protection) e. Participants unable to express their consent.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	01 Jul 2025	9
France	Not Recruiting	01 Jul 2025	4
Ireland	Not Recruiting	01 Jul 2025	2
The Netherlands	Not Recruiting	01 Jul 2025	—
Netherlands	—	—	5