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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04610866
Recruitment Status : Recruiting
First Posted : November 2, 2020
Last Update Posted : March 8, 2021
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Brief Summary:


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.


To test the long-term tolerability and safety of mitapivat (or AG-348) in people with SCD.


Adults age 18-70 with SCD who took part in and benefited from NIH study #19H0097.


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.

Condition or disease Intervention/treatment Phase
Sickle Cell Disease Hemolytic Anemia Drug: Mitapivat Phase 1 Phase 2

Detailed Description:

Sickle cell disease (SCD) is a multisystem disorder associated with episodes of acute clinical events and progressive organ damage. Episodic pain, triggered by microvascular vaso-occlusion induced by sickling of red blood cells (RBCs), is the most common acute complication and the leading cause of hospitalization. As the root cause of SCD is polymerization of deoxy-hemoglobin S (HbS), there is a strong rationale for exploring agents that could inhibit or reduce the polymerization process itself. HbS polymerization is influenced by a number of factors, including 2,3-diphosphoglycerate (2,3-DPG) concentration in the RBC. Increased 2,3-DPG levels in SCD decrease oxygen binding of hemoglobin and stabilizes the deoxygenated state, causing HbS to polymerize. In addition, increased 2,3-DPG concentration decreases intraerythrocyte pH, further promoting HbS polymerization. 2,3-DPG is an intermediate substrate in the glycolytic pathway, the only source of energy production in RBCs in the form of adenosine triphosphate (ATP). Pyruvate kinase (PK) is a key enzyme in the final step of glycolysis that is responsible for 50% of the total red cell ATP production. ATP is essential for maintaining integrity of the RBC membrane, and therefore reduced PK activity not only leads to the accumulation of upstream 2,3-DPG and HbS polymerization but also affects RBC membrane health. Therefore, increasing red cell PK (PKR) activity presents a new and potentially attractive therapeutic target for thwarting HbS polymerization, vaso-occlusion, and hemolysis in SCD.

Mitapivat (AG-348) is an orally bioavailable small molecule allosteric activator of PKR, currently being studied in Phase II/III clinical trials in humans with PK deficiency (NCT02476916, NCT03548220 / AG348-C-006; NCT03559699 / AG348-C-007), as well as in an ongoing Phase II clinical trial in humans with non-transfusion-dependent thalassemia (NCT03692052). The recently published results of mitapivat treatment in a large cohort of PK deficient subjects appear promising, with demonstrated durable improvement in anemia and reduction in hemolysis, as well as an acceptable safety profile. The preclinical and clinical mitapivat data support dose-dependent changes in blood glycolytic intermediates including 2,3-DPG, consistent with glycolytic pathway activation at multiple ascending doses tested, supporting the potential anti-sickling role of mitapivat in the treatment of SCD.

We (PI: Dr. S. L. Thein) initiated a Phase I study (NCT04000165) to assess clinical safety and tolerability of multiple escalating doses of mitapivat in subjects with SCD. To date, we have observed an acceptable safety profile for mitapivat at all doses, as well as preliminary evidence of efficacy, with increases in hemoglobin level and decreases in hemolytic markers observed in a majority of SCD subjects. Following on these preliminary results, the present study has been initiated to evaluate the safety, tolerability, and efficacy of long-term treatment with maintenance dosing of mitapivat in subjects with SCD.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Evaluation of the 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
Actual Study Start Date : December 9, 2020
Estimated Primary Completion Date : October 19, 2021
Estimated Study Completion Date : October 19, 2023

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: 1
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
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).

Primary Outcome Measures :
  1. Primary outcome measure: Long-term safety and tolerability of mitapivat in subjects with stable sickle cell disease [ Time Frame: 48 weeks ]
    Frequency and severity of AEs and changes in clinical and laboratory parameters over 48 weeks of maintenance therapy with mitapivat.

Secondary Outcome Measures :
  1. To evaluate the pharmacokinetic [ Time Frame: 24 and 48 weeks ]
    Change from baseline in pharmacokinetic and pharmacodynamic measures over time.

  2. 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. [ Time Frame: 24 and 48 weeks ]
    - Hemoglobin (Hb) response and changes in hemolytic markers at 24 and 48 weeks on mitapivat. Sustained Hb response from weeks 12-48. - Change from baseline in functional and cardiopulmonary status at 24 and 48 weeks on mitapivat. - Change from baseline in quality of life at 24 and 48 weeks on mitapivat

  3. To monitor SCD-related safety endpoints in SCD subjects maintained on mitapivat long-term. [ Time Frame: 24 and 48 weeks ]
    - Frequency of acute vaso- occlusive events (acute vaso-occlusive pain crisis, acute chest syndrome, hepatic sequestration, splenic sequestration, and priapism) at 24 and 48 weeks on mitapivat.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
  • Only subjects completing Study 19H0097 will be screened for eligibility. Eligibility criteria are identical with the exception of criteria 1.4, 2.2, and 2.3.p.

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:

  • 1.1 Have provided signed written informed consent prior to performing any study procedure, including screening procedures.
  • 1.2 Age between 18-70 years
  • 1.3 Have previously been enrolled in Study 19H0097 with study drug mitapivat, completed at least 3 dose escalation levels, and demonstrated clinical benefit from mitapivat treatment as determined by the PI
  • 1.4 No transfusion in the 12 weeks prior to signing consent, or absence of Hb A on hemoglobin analysis (by high-performance liquid chromatography; HPLC)
  • 1.5 Have adequate organ function, as defined by:

    • a. 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.
    • b. 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.
    • c. Absolute neutrophil count >=1.0 x 10^9power/L.
    • d. Hemoglobin >= 7 g/dL
    • e. Platelet count >=100 x 10^9/L.
    • f. Activated partial thromboplastin time and international normalized ratio <=1.5 x ULN, unless the subject is receiving therapeutic anticoagulants.
  • 1.6 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 and have an elevated follicle-stimulating hormone level indicative of menopause during the screening period).
  • 1.7 For women of reproductive potential as well as men and their partners who are women of reproductive potential, be abstinent as part of their usual lifestyle, or agree to use 2 effective forms of contraception from the time of giving informed consent, during the study, and for 28 days (both men and women) following the last dose of study treatment. An effective form of contraception is defined as hormonal oral contraceptives, injectables, patches, intrauterine or subdermal contraceptive implants, and barrier methods.
  • 1.8 Be willing to comply with all study procedures for the duration of the study.


  • 2.1 Documented pyruvate kinase deficiency
  • 2.2 Screening hemoglobin level of >= 11 g/dL
  • 2.3 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:

    • a. Poorly controlled hypertension (defined as systolic blood pressure [BP] >150 mmHg or diastolic BP >90 mmHg) refractory to medical management.
    • b. 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.
    • c. Cardiac dysrhythmias judged as clinically significant by the Investigator.
    • d. Heart-rate corrected QT interval-Fredericia's method (QTcF) >480 msec with the exception of subjects with right or left bundle branch block.
    • e. Clinically symptomatic cholelithiasis or cholecystitis. Prior cholecystectomy is not exclusionary. Subjects with symptomatic cholelithiasis or cholecystitis may be rescreened once the disorder has been treated and clinical symptoms have resolved.
    • f. History of drug-induced cholestatic hepatitis.
    • g. 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.
    • h. 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.
    • i. 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.
    • j. Positive test for human immunodeficiency virus 1 or 2 Ab.
    • k. 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.
    • l. Diabetes mellitus judged to be under poor control by the Investigator or requiring >3 antidiabetic agents, including insulin (all insulins are considered 1 agent); use of insulin per se is not exclusionary.
    • m. 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.
    • n. 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.
    • o. Are currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo. SCD subjects on hydroxyurea or L-glutamine will also be considered, provided that they have been on an unchanged dose of hydroxyurea or LGlutamine for 12 weeks prior to signing consent. Use of the newer SCD therapies voxelotor or crizanlizumab will not be permitted on this study, and subjects who have received voxelotor or crizanlizumab in the 12 weeks prior to signing consent will be excluded.
    • p. Have exposure to any investigational drug (other than the current drug, mitapivat), device, or invasive procedure within 12 weeks prior to signing consent. All non-investigational invasive procedures within 12 weeks of signing consent may be considered as a potential exclusion criteria per the PI s discretion.
    • q. Have had a prior bone marrow or stem cell transplant.
    • r. Are currently pregnant or breastfeeding.
    • s. Are currently receiving medications that are strong inhibitors of cytochrome P450 (CYP)3A4 or strong inducers of CYP3A4 that have not been stopped for a duration of at least 5 days or a timeframe equivalent to 5 half-lives (whichever is longer) prior to signing consent.
    • t. Are currently receiving hematopoietic stimulating agents (e.g., erythropoietins, granulocyte colony stimulating factors, thrombopoietins) that have not been stopped for a duration of at least 28 days prior to signing consent.
    • u. Have a history of allergy to sulfonamides if characterized by acute hemolytic anemia, drug-induced liver injury, anaphylaxis, rash of erythema multiforme type or Stevens-Johnson syndrome, cholestatic hepatitis, or other serious clinical manifestations.
    • v. Have a history of allergy to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, and mannitol).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04610866

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Contact: Ingrid C Frey (301) 402-6674

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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010   
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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Principal Investigator: Julia Z Xu, M.D. National Heart, Lung, and Blood Institute (NHLBI)
Additional Information:
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Responsible Party: National Heart, Lung, and Blood Institute (NHLBI) Identifier: NCT04610866    
Other Study ID Numbers: 10000049
First Posted: November 2, 2020    Key Record Dates
Last Update Posted: March 8, 2021
Last Verified: March 4, 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ):
HbS polymerization
pyruvate kinase
2,3- diphosphoglycerate
ATP in red blood cells
Hemolytic Anemia
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Anemia, Hemolytic
Hematologic Diseases
Anemia, Hemolytic, Congenital
Genetic Diseases, Inborn
Pathologic Processes