Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Long-term Mitapivat Dosing in Subjects With Stable Sickle Cell Disease: An Extension of a Phase I Pilot Study of Mitapivat

NCT04610866 | Active Not Recruiting Phase 1 FDA Drug

• 2 other identifiers: 10000049000049-H
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Sickle cell disease (SCD) is a disorder that causes episodes of acute pain and progressive organ damage. Ways to manage SCD have evolved slowly. Treatments do not always work. Researchers want to see if a drug called mitapivat can help people with SCD. Objective: To test the long-term tolerability and safety of mitapivat (or AG-348) in people with SCD. Eligibility: Adults age 18-70 with SCD who took part in and benefited from NIH study #19H0097. Design: Participants will be screened with a medical history and physical exam. They will give a blood sample. They will have an electrocardiogram to test heart function. Participants will repeat some of the screening tests during the study. Participants will complete 6-minute walk tests to measure mobility and function. They will have transthoracic echocardiograms to measure heart and lung function. They will have dual-energy X-ray absorptiometry scans to measure bone health. They will complete online questionnaires that measure their overall health and well-being. Participants will take the study drug in the form of a tablet twice a day. Participants will keep a study diary. They will record any symptoms they may have. Participation will last for about 54 weeks. After 48 weeks, participants can either keep taking the study drug for 48 more weeks or be tapered off of the study drug to complete the study. Those who are on the study for 1 year will have 10 study visits. Those who are on the study for 2 years will have 14 study visits.

Conditions

Sickle Cell Disease; Hemolytic Anemia

Keywords

HbS polymerization; pyruvate kinase; 2,3- diphosphoglycerate; ATP in red blood cells; Hemolytic Anemia

Outcome Measures

Primary Outcomes (1)

• Primary outcome measure: Long-term safety and tolerability of mitapivat in subjects with stable sickle cell disease

  Frequency and severity of AEs and changes in clinical and laboratory parameters over 48 weeks of maintenance therapy with mitapivat.

  48 weeks

Secondary Outcomes (3)

• To evaluate the pharmacokinetic

  24 and 48 weeks

• To evaluate hemoglobin (Hb) response, changes in hemolytic markers, functional status, cardiopulmonary function, and health-related quality of life in SCD subjects maintained on mitapivat long-term.

  24 and 48 weeks

• To monitor SCD-related safety endpoints in SCD subjects maintained on mitapivat long-term.

  24 and 48 weeks

Study Arms (1)

1

EXPERIMENTAL

Subjects will be treated with a maintenance dose of mitapivat previously assessed for safety and tolerability in the Phase I study for an initial 48 weeks and undergo safety monitoring, evaluation of pharmacokinetics and pharmacodynamics, and assessment of secondary laboratory and clinical endpoints at pre-specified intervals during the study period.

Drug: Mitapivat

Interventions

Mitapivat DRUG

Investigational drug mitapivat (also known as AG-348, AGI-1480 and AGX-0841) is an orally bioavailable, broad-spectrum allosteric activator of alleles of the RBC-specific form of pyruvate kinase (PKR), as well as liver-type pyruvate kinase (PKL) and muscle pyruvate kinase (PKM1 and PKM2).

1

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects completing Study 19H0097 will first be screened for eligibility. Eligibility criteria are identical with the exception of criteria 5.1.4, 5.2.2, and 5.2.3.p. If any of the 15 subjects completing the 19H0097 study are unable to participate in or complete the current extension study (defined as completing 24 weeks of treatment with study drug to allow for assessment of the primary endpoint), then additional new subjects naive to mitapivat treatment may be enrolled to replace them.
• Subjects will enroll onto the study and undergo screening. Subjects who do not meet any of the following criteria during screening will not receive the study intervention but will be counted toward study accrual. Screen failures may be rescreened at a later time.
• In order to be eligible to participate in this study, an individual must meet all of the following criteria:
• Have provided signed written informed consent prior to performing any study procedure, including screening procedures.
• Age between 18-70 years
• Unequivocal diagnosis of HbSS confirmed by hemoglobin electrophoresis performed on patients at least 90 days after a blood transfusion if previously transfused, or DNA genotyping
• No transfusion in the 12 weeks prior to signing consent, or absence of Hb A on hemoglobin analysis (by high-performance liquid chromatography; HPLC)
• Have adequate organ function, as defined by:
• Serum aspartate aminotransferase (AST) \<=2.5 x Upper Limit of Normal (ULN) (unless the increased AST is assessed by the Investigator as due to hemolysis) and alanine aminotransferase (ALT) \<=2.5 x ULN.
• Serum creatinine \<=1.25 x ULN. If serum creatinine is \>1.25 x ULN, then glomerular filtration rate (based on creatinine) must be \>=60 mL/min.
• Absolute neutrophil count \>=1.0 x 10\^9/L.
• Hemoglobin \>= 7 g/dL
• Platelet count \>=100 x 10\^9/L.
• Activated partial thromboplastin time and international normalized ratio \<=1.5 x ULN, unless the subject is receiving therapeutic anticoagulants.
• For women of reproductive potential, have a negative serum pregnancy test during the screening period. Women of reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion; or who have not been naturally postmenopausal (i.e., who have not menstruated at all for at least the preceding 1 year prior to signing informed consent unrelated to hormonal contraception).

You may not qualify if:

• Documented pyruvate kinase deficiency
• Screening hemoglobin level of \>= 11 g/dL
• Have a significant medical condition that confers an unacceptable risk to participating in the study, and/or that could confound the interpretation of the study data. Such significant medical conditions include, but are not limited to the following:
• Poorly controlled hypertension (defined as systolic blood pressure \[BP\] \>150 mmHg or diastolic BP \>90 mmHg) refractory to medical management.
• History of recent (within 24 weeks prior to signing consent) decompensated congestive heart failure; myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism.
• Cardiac dysrhythmias judged as clinically significant by the Investigator.
• Heart-rate corrected QT interval-Fredericia's method (QTcF) \>480 msec with the exception of subjects with right or left bundle branch block.
• History of drug-induced cholestatic hepatitis.
• Iron overload sufficiently severe to result in a clinical diagnosis by the Investigator of cardiac (e.g., clinically significant impaired left ventricular ejection fraction), hepatic (e.g., fibrosis, cirrhosis), or pancreatic (e.g., diabetes) dysfunction.
• Have a diagnosis of any other congenital or acquired blood disorder, or any other hemolytic process as defined by a positive direct antiglobulin test (DAT), except mild allo-immunization as a consequence of transfusion therapy.
• Positive test for hepatitis B surface antigen or hepatitis C virus (HCV) antibody (Ab) with signs of active hepatitis B or C virus infection. If the subject is positive for HCVAb, a reverse transcriptase-polymerase chain reaction test will be conducted. Subjects with hepatitis C may be rescreened after receiving appropriate hepatitis C treatment.
• Positive test for human immunodeficiency virus 1 or 2 Ab.
• Active infection requiring any use of systemic antimicrobial agents (parenteral or oral) or Grade \>=3 in severity (per National Cancer Institute Common Terminology Criteria for Adverse Events) within 8 weeks prior to signing consent.
• History of any primary malignancy, with the exception of: curatively treated nonmelanomatous skin cancer; curatively treated cervical or breast carcinoma in situ; or other primary tumor treated with curative intent, no known active disease present, and no treatment administered during the last 3 years.
• Current or recent history of psychiatric disorder that, in the opinion of the Investigator or Medical Monitor, could compromise the ability of the subject to cooperate with study visits and procedures.

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (2)

• Conrey A, Asomaning N, Frey I, Charles RP, Lovins D, Xu JZ, Mendez-Marti S, Le K, Kruah B, Li Q, Dunkelberger E, Cellmer T, Yates A, Wind-Rotolo M, Huston C, Jeffries N, Eaton WA, Thein SL. Long-term mitapivat treatment is safe and efficacious in patients with sickle cell disease. Blood Red Cells Iron. 2025 Sep;1(2):100014. doi: 10.1016/j.brci.2025.100014. Epub 2025 Sep 11.

  PMID: 41809202 DERIVED

• D'Alessandro A, Le K, Lundt M, Li Q, Dunkelberger EB, Cellmer T, Worth AJ, Patil S, Huston C, Grier A, Dzieciatkowska M, Stephenson D, Eaton WA, Thein SL. Functional and multi-omics signatures of mitapivat efficacy upon activation of pyruvate kinase in red blood cells from patients with sickle cell disease. Haematologica. 2024 Aug 1;109(8):2639-2652. doi: 10.3324/haematol.2023.284831.

  PMID: 38450513 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Anemia, Sickle Cell; Anemia, Hemolytic

Interventions

mitapivat

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Swee Lay Thein, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 30, 2020
• First Posted: November 2, 2020
• Study Start: December 9, 2020
• Primary Completion (Estimated): February 28, 2028
• Study Completion (Estimated): February 28, 2028
• Last Updated: May 5, 2026

Record last verified: 2026-04-20

Locations

US (1)