AG-946 PHOSPHATE for Sickle cell disease

Inclusion criteria

• {"criterion_text":"- ≥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.\n- 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).\n- 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.\n- 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\n- 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.\n- 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\n- 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."}

Exclusion criteria

• {"criterion_text":"- 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.\n- 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.\n- 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.\n- >10 Sickle Cell Pain Crises (SCPC) in the 12 months before providing informed consent.\n- 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]).\n- 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.\n- 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\n- Receiving treatment with voxelotor, crizanlizumab, or L-glutamine within 90 days before randomization.\n- Platelet count \n- Receiving treatment with hematopoietic stimulating agents within 90 days before randomization.\n- Prior exposure to gene therapy or prior bone marrow or stem cell transplantation, including any conditioning regimen.\n- 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.\n- 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.\n- Pregnant or breastfeeding.\n- 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.\n- 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.\n- 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.\n- Nonfasting triglycerides >500 mg/dL (5 mmol/L).\n- Active uncontrolled infection requiring systemic antimicrobial therapy.\n- Positive test for hepatitis C virus (HCV) antibody (Ab) with evidence of active HCV infection, or positive test for hepatitis B surface antigen (HBsAg).\n- Positive test for HIV-1 Ab or HIV-2 Ab.\n- History of major surgery (including splenectomy) ≤16 weeks before providing informed consent and/or planning to undergo a major surgical procedure during the study."}

Primary endpoints

• {"endpoint_text":"- Hb response, defined as a ≥1.0 g/dL increase in average Hb concentration from Week 10 through Week 12 compared with baseline","definition_or_measurement_approach":"Defined as a ≥1.0 g/dL increase in average Hb concentration from Week 10 through Week 12 compared with baseline"}

Secondary endpoints

• {"endpoint_text":"- Type, frequency, severity, and relationship to study drug of adverse events (AEs) and serious (SAEs)","definition_or_measurement_approach":"Collection and reporting of AEs and SAEs; type, frequency, severity and investigator assessment of relationship to study drug"}
• {"endpoint_text":"- Average change from baseline in Hb concentration from Week 10 through Week 12","definition_or_measurement_approach":"Mean change in hemoglobin concentration from baseline averaged over Week 10 to Week 12"}
• {"endpoint_text":"- Average change from baseline in markers of hemolysis, including indirect bilirubin and lactate dehydrogenase (LDH), from Week 10 through Week 12","definition_or_measurement_approach":"Mean change from baseline in hemolysis markers (e.g., indirect bilirubin, LDH) averaged Week 10–Week 12"}
• {"endpoint_text":"- Average change from baseline in markers of erythropoiesis, including absolute reticulocyte count, percent reticulocytes, and erythropoietin, from Week 10 through Week 12","definition_or_measurement_approach":"Mean change from baseline in erythropoiesis markers (absolute reticulocyte count, percent reticulocytes, erythropoietin) averaged Week 10–Week 12"}
• {"endpoint_text":"- Average change from baseline in Patient Reported Outcomes Measurement Information System® (PROMIS) Fatigue 13a Short Form score from Week 10 through Week 12","definition_or_measurement_approach":"Mean change from baseline in PROMIS Fatigue 13a Short Form score averaged Week 10–Week 12"}
• {"endpoint_text":"- Average change from baseline in PROMIS Pain Intensity 1a score from Week 10 through Week 12","definition_or_measurement_approach":"Mean change from baseline in PROMIS Pain Intensity 1a score averaged Week 10–Week 12"}
• {"endpoint_text":"- Average change from baseline in Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) Pain Impact score from Week 10 through Week 12","definition_or_measurement_approach":"Mean change from baseline in ASCQ‑Me Pain Impact score averaged Week 10–Week 12"}
• {"endpoint_text":"- Plasma concentration and PK parameters of tebapivat during the Double-blind Period","definition_or_measurement_approach":"Plasma concentrations and derived PK parameters (e.g., Cmax, AUC) measured during the double-blind period"}
• {"endpoint_text":"- Whole blood concentrations and PD parameters, including 2,3-DPG and ATP, during the Doubleblind Period","definition_or_measurement_approach":"Whole blood levels and PD markers (including 2,3‑DPG and ATP) assessed during the double-blind period"}
• {"endpoint_text":"- Annualized rate of SCPCs through Week 12","definition_or_measurement_approach":"Annualized incidence rate of Sickle Cell Pain Crises through Week 12"}
• {"endpoint_text":"- Change from baseline in 6MWT at Week 12","definition_or_measurement_approach":"Change from baseline in 6-minute walk test distance at Week 12"}
• {"endpoint_text":"- Change from baseline in the 3 Cogstate cognition tests (Identification Test, One Back Test, and Groton Maze Learning Test) at Week 12","definition_or_measurement_approach":"Change from baseline in scores of the three specified Cogstate cognitive tests at Week 12"}
• {"endpoint_text":"- Change from baseline in 4 WPAI scores (absenteeism, presenteeism, work productivity loss, and activity impairment) at Week 12","definition_or_measurement_approach":"Change from baseline in WPAI domain scores at Week 12"}
• {"endpoint_text":"- Change from baseline in biomarkers related to inflammation, vascular biology, and the pathogenesis of SCD at Week 8","definition_or_measurement_approach":"Change from baseline in specified biomarkers related to inflammation and vascular biology at Week 8"}
• {"endpoint_text":"- Change from baseline in biomarkers related to iron metabolism at Week 10","definition_or_measurement_approach":"Change from baseline in iron metabolism biomarkers at Week 10"}
• {"endpoint_text":"- Exposure-response relationship between relevant PK parameters and endpoints that are indicators of clinical activity (changes in Hb hemolysis markers and PD markers [ATP and 2,3-DPG]) and safety (including platelet counts) during the Double-blind Period","definition_or_measurement_approach":"Assessment of exposure-response relationships between PK parameters and clinical/PD/safety endpoints during the double-blind period"}
• {"endpoint_text":"- Change from baseline during the Open-label Extension (OLE) Period in: - Hb concentration - Markers of erythropoiesis and hemolysis - Patient-reported outcomes (PROs) and performance outcomes (PerfOs) - Biomarkers","definition_or_measurement_approach":"Changes from baseline in specified efficacy, PD, PRO, PerfO and biomarker measures during the OLE period"}
• {"endpoint_text":"- AEs, SAEs, discontinuations due to AEs, and laboratory abnormalities during the OLE Period","definition_or_measurement_approach":"Safety reporting (AEs, SAEs, discontinuations for AEs, lab abnormalities) during the open-label extension"}

Methods

• K1_Recruitment Arrangements_public (document listed in CTIS documents) - recruitment arrangement material (details not extractable from provided text)
• Reloadable ScoutPass Mailer (document: L2_Other participant information materials_Reloadable ScoutPass Mailer_redacted) - named recruitment material (content not extractable)
• ScoutClinical Study Brochure (document: L2_Other participant information materials_ScoutClinical Study Brochure_redacted) - named recruitment brochure (content not extractable)
• ScoutClinical_Email communication (document: L2_Other participant information materials_ScoutClinical_Email communication_redacted) - named email communication material
• GP Letter (document: L2_Other participant information materials_GP Letter_public) - general practitioner letter template

France

Earliest CTIS Part Ii Submission Date

09-07-2025

Latest Decision Or Authorization Date

15-07-2025

Processing Time Days

6

Number Of Sites

4

Number Of Participants

4

Netherlands

Earliest CTIS Part Ii Submission Date

08-07-2025

Latest Decision Or Authorization Date

14-07-2025

Processing Time Days

6

Number Of Sites

3

Number Of Participants

5

Ireland

Earliest CTIS Part Ii Submission Date

17-06-2025

Latest Decision Or Authorization Date

18-07-2025

Processing Time Days

31

Number Of Sites

1

Number Of Participants

2

Belgium

Earliest CTIS Part Ii Submission Date

23-06-2025

Latest Decision Or Authorization Date

23-04-2026

Processing Time Days

305

Number Of Sites

1

Number Of Participants

9

Primary sponsor

Full Name

Agios Pharmaceuticals Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

PPD Development LP

Responsibilities

Safety management (listed duty)

Name

Icon Clinical Research Limited

Name

Iqvia Biotech Limited

Responsibilities

Translation services and other vendor/CRO support

Third parties

• {"country":"United States","full_name":"PPD Development LP","duties_or_roles":"Safety management","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Scout Clinical","duties_or_roles":"Patient Reimbursement","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"Suvoda LLC","duties_or_roles":"","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Deltamed Solutions Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"PPD Development LP","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Definitive Media Corp.","duties_or_roles":"ePRO","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Australia","full_name":"Cogstate Limited","duties_or_roles":"ePRO/questionnaires","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Veeva Systems Inc.","duties_or_roles":"Trial Master File (TMF) services","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Preventiongenetics LLC","duties_or_roles":"Genetic Testing","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United Kingdom","full_name":"Biotec Services International Limited","duties_or_roles":"IP labeling","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Iqvia Biotech Limited","duties_or_roles":"IQVIA Translation Services and other support (multiple duties listed)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"","organisation_type":"Non-Pharmaceutical company"}