Sickle Cell DiseaseEarly Phase 1NCT04000165
A Dose-Finding Study of AG-348 in Sickle Cell Disease
A Early Phase 1 study testing AG-348 in people with Sickle Cell Disease, run by National Institutes of Health Clinical Center (CC) at 1 site in United States.
Trial summary
Background: Sickle Cell Disease (SCD) is an inherited blood disorder. People with SCD have abnormal hemoglobin in their red blood cells. Researchers are investigating the safety and efficacy of an investigational medicine called AG-348 (mitapivat sulfate) to determine if it will help people with SCD. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Sickle Cell Disease
- What is being tested?
- AG-348
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 17 participants
- Where
- 1 siteUnited States
- Study dates
- 11 Jul 2019to 21 Jun 2021
- Phase
- Early Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- For enrollment, subjects must meet all of the following criteria during the screening period:
- 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 90 days prior to the first dose of study drug or absence of HbA on hemoglobin analysis (by high-performance liquid chromatography; HPLC)
- Have adequate organ function, as defined by:
Show all 15Show fewer
- Serum aspartate aminotransferase (AST) less than or equal to 2.5 (SqrRoot) Upper Limit of Normal (ULN) (unless the increased AST is assessed by the Investigator as due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase (ALT) less than or equal to 2.5 (SqrRoot) ULN (unless the increased ALT is assessed by the Investigator as due to hepatic iron deposition).
- Serum creatinine less than or equal to 1.25 (SqrRoot) ULN. If serum creatinine is >1.25 (SqrRoot) ULN, then glomerular filtration rate (based on creatinine) must be greater than or equal to 60 mL/min.
- Absolute neutrophil count greater than or equal to 1.0 (SqrRoot) 10^9/L.
- Hemoglobin greater than or equal to 7 g/dL
- Platelet count greater than or equal to 100 (SqrRoot) 10^9/L.
- Activated partial thromboplastin time and international normalized ratio less than or equal to 1.5 (SqrRoot) ULN, unless the subject is receiving therapeutic anticoagulants.
- For women of reproductive potential, have a negative serum or urine 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 12 months prior to signing informed consent and have an elevated follicle-stimulating hormone level indicative of menopause during the screening period).
- 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 for women and 90 days for men following the last dose of study treatment. An effective form of contraception is defined as hormonal oral contraceptives, injectables, patches, and barrier methods.
- Be willing to comply with all study procedures for the duration of the study.
Who cannot join
- Subjects who meet any of the following criteria during screening will not receive AG348 and will not be counted toward the final enrollment count for statistical purposes:
- Documented pyruvate kinase deficiency
- 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 6 months prior to signing informed consent) 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.
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- Heart-rate corrected QT interval-Fredericia's method (QTcF) >480 msec with the exception of subjects with right or left bundle branch block.
- 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.
- 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 HCV Ab, 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 greater than or equal to 3 in severity (per National Cancer Institute Common Terminology Criteria for Adverse Events) within 2 months prior to signing informed consent.
- 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.
- 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.
- Unstable extramedullary hematopoiesis that could pose a risk of imminent neurologic compromise.
- 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.
- Are currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo. Sickle cell anemia subjects on hydroxyurea or L-glutamine will also be considered, provided that they have been on an unchanged dose of hydroxyurea or L-Glutamine for three months prior to enrollment.
- Have exposure to any investigational drug, device, or invasive procedure within 3 months prior to the first dose of study treatment. All noninvestigational invasive procedures within 3 months of starting study treatment may be considered as a potential exclusion criteria per the PI s discretion.
- Have had any prior treatment with a pyruvate kinase activator.
- Have received crizanlizumab or voxelotor in the 12 weeks prior to signing consent
- Have a prior bone marrow or stem cell transplant.
- Are currently pregnant or breastfeeding.
- 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 the first dose of AG-348.
- 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 the first dose of study treatment.
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
Official title: A Pilot Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Escalating Multiple Oral Doses of AG-348 in Subjects With Stable Sickle Cell Disease
Background:
Sickle Cell Disease (SCD) is an inherited blood disorder. People with SCD have abnormal hemoglobin in their red blood cells. Researchers are investigating the safety and efficacy of an investigational medicine called AG-348 (mitapivat sulfate) to determine if it will help people with SCD.
Read more
Objective:
To test the tolerability and safety of AG-348 in people with SCD.
Eligibility:
People ages 18 and older with SCD.
Design:
Participants will have 8 visits over approximately 14 weeks. At the first visit participants will be screened with a medical history, a physical exam, blood and urine testing, and an EKG. During the following 5 visits, participants will stay at the clinic for 1 night each. Participants will take study drug in increasing doses up to visit 6, after which the drug will be tapered off. All visits will include physical exam, blood, and urine tests. The last visit will occur 4 weeks after stopping the drug. Participants will provide DNA from the blood samples they provide. The DNA will be tested for an inherited gene that can cause differences in response to the study drug. Researchers may also test other genes to see if they can find any genes that interact with SCD.
Read the 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 micro-vasoocclusion induced by sickled red blood cells, is the most common acute complication and the leading cause of hospitalization. Management strategies for SCD have evolved very slowly, and treatment of acute pain is still limited to supportive therapy with opioid medication. Until recently in 2017, the only approved therapy for SCD was hydroxyurea (HU), indicated to reduce frequency of acute painful crises but not universally effective. In addition to HU, transfusions with normal red blood cells are widely used to treat severe sickle crises, but this strategy has limitations (not uniformly accessible, accompanied by risks of alloimmunization, hemolytic transfusion reactions and transfusional iron overload). The only curative treatment is bone marrow transplantation, but this option carries significant risks and is limited by the availability of histocompatible donors.
As the root cause of SCD is polymerization of deoxy-HbS, there is a strong rationale for exploring agents that could inhibit/ reduce the polymerization process itself. HbS polymerizes only when deoxygenated, its oxygenation is influenced by a few factors, one key factor being the 2,3- diphosphoglycerate (2,3-DPG) concentration in the red blood cell. 2,3-DPG decreases oxygen binding by preferentially binding to the low oxygen-affinity T conformation of HbS and also stabilizes the T form of hemoglobin S and HbS fiber. In addition, increased 2,3- DPG concentration decreases intracellular red cell pH further promoting HbS polymerization. 2,3-DPG is an intermediate substrate in the glycolytic pathway, the only source of ATP production in red blood cells. Pyruvate kinase (PK) is a key enzyme in the final step of glycolysis; PK converts phosphoenolpyruvate to pyruvate, creating 50% of the total red cell ATP that is essential for maintaining integrity of the red cell membrane. Reduced PK activity leads to accumulation of the upstream enzyme substrates, including 2,3- DPG, that favors polymerization of deoxy-HbS. In humans with SCD, and even in sickle carriers who are generally asymptomatic, reduced oxygen affinity will favor deoxygenation of HbS and its polymerization, and thus sickling. Indeed, the combination of PK deficiency and sickle cell trait causing an acute sickling syndrome has been previously reported in two cases.
Current approaches to reduce HbS polymerization include fetal hemoglobin induction via multiple strategies and drugs that targets HbS polymerization through increasing affinity of hemoglobin for oxygen (eg. Oxbryta (TM) / Voxelotor / GBT440).
Increasing red cell PK (PK-R) activity, leading to a decrease in intracellular 2,3-DPG concentration, presents a potentially attractive therapeutic target for thwarting HbS polymerization and acute sickle pain. AG-348 / mitapivat is a novel, orally bioavailable, small molecule allosteric activator of PK-R, that is currently in Phase II/III clinical trials in humans with PK deficiency (NCT02476916, NCT03548220 / AG348-C-006; NCT03559699 / AG348-C-007). Overview of the preclinical AG-348 data and other data support dose-dependent changes in blood glycolytic intermediates consistent with glycolytic pathway activation at all multiple ascending doses tested, supporting the potential role of AG-348 in the treatment of sickle cell disease. The overall objective of the present study is to determine the clinical safety and tolerability of AG-348 in subjects with SCD.
- Conditions
- Sickle Cell Disease
- Being tested
- AG-348
- Keywords
- HbS polymerization, pyruvate kinase, 2,3- diphosphoglycerate, ATP in red blood cells, acute sickle pain
- Medical subject headings
- Anemia, Sickle Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AG-348Drug
Also called Mitapivat
This is a nonrandomized, intra-patient dose escalating clinical study. AG-348 will be administered starting at 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
| Study group | Role | What they receive |
|---|---|---|
| AG-348 in participants with Sickle Cell Disease | Experimental | Intra-patient dose escalating study, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days. Receives: Drug: AG-348 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number Participants With Most Common Reported Drug Related Adverse Events
To assess the clinical safety and tolerability of multiple escalating doses of AG-348, an allosteric activator of the enzyme pyruvate kinase, in subjects with stable sickle cell disease (SCD). Safety and tolerability were assessed by frequency and severity of adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) 5.0.
Measured: 14 weeks
Number Participants With Serious Adverse Events That Were Possibly Drug-related Serious Adverse Events
To assess the clinical safety and tolerability of multiple escalating doses of AG-348, an allosteric activator of the enzyme pyruvate kinase, in subjects with stable sickle cell disease (SCD). Safety and tolerability were assessed by frequency and severity of adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) 5.0.
Measured: 14 weeks
Number Participants With Increase of ≥ 1 g/dL in Hemoglobin
To assess the clinical safety and tolerability of multiple escalating doses of AG-348, an allosteric activator of the enzyme pyruvate kinase, in subjects with stable sickle cell disease (SCD). Safety and tolerability were assessed by defined as a ≥ 1 g/dL increase in hemoglobin at any dose level compared to baseline.
Measured: 14 weeks
Secondary outcomes (12)
Change in Hemoglobin at Each Dose Level of AG-348
To assess change in hemoglobin in stable sickle cell disease participants at each dose level of AG-348
Measured: 14 weeks
Change in Lactic Acid Dehydrogenase (LDH) at Each Dose Level of AG-348
To assess change in lactic acid dehydrogenase (LDH) in stable sickle cell disease participants at each dose level of AG-348
Measured: 14 weeks
Change in Total Bilirubin at Each Dose Level of AG-348
To assess change in total bilirubin in stable sickle cell disease participants at each dose level of AG-348
Measured: 14 weeks
Change in Absolute Reticulocyte Count at Each Dose Level of AG-348
To assess change in absolute reticulocyte count in stable sickle cell disease participants at each dose level of AG-348
Measured: 14 weeks
Change in Aspartate Aminotransferase (AST) at Each Dose Level of AG-348
To assess change in aspartate aminotransferase (AST) in stable sickle cell disease participants at each dose level of AG-348
Measured: 14 weeks
Change in Mean Corpuscular Volume (MCV) at Each Dose Level of AG-348
To assess change in mean corpuscular volume (MCV) in stable sickle cell disease participants at each dose level of AG-348
Measured: 14 weeks
Change in Fetal Hemoglobin at Each Dose Level of AG-348
To assess the change in fetal hemoglobin (HbF) in stable sickle cell disease participants at each dose level of AG-348
Measured: 14 weeks
Percent Change From Baseline of 2,3-DPG at Each Dose Level of AG-348
To understand the mechanisms of action of AG- 348 on the glycolytic pathway in sickle cell disease through laboratory studies of specific pharmacodynamics of 2,3-DPG at each dose level of AG-348.
Measured: 14 weeks
Percent Change From Baseline of Adenosine Triphosphate (ATP) at Each Dose Level of AG-348
To understand the mechanisms of action of AG- 348 on the glycolytic pathway in sickle cell disease through laboratory studies of specific pharmacodynamics of adenosine triphosphate (ATP) at each dose level of AG-348.
Measured: 14 weeks
Percent Change From Baseline in Oxygen Binding p50 Value at Each Dose Level of AG-348
Measure percent change from baseline in oxygen binding p50 value at each dose level of AG-348
Measured: 14 weeks
Percent Change in Time (Mins) at Which 50% of Red Blood Cells Are Sickled (t50) Value at Each Dose Level of AG-348
Measure percent change in Time (mins) at which 50% of red blood cells are sickled (t50) Value at Each Dose Level of AG-348
Measured: 14 weeks
Percent Change of PK-R at Each Dose Level of AG-348
To understand the mechanisms of action of AG- 348 on the glycolytic pathway in sickle cell disease through laboratory studies of specific pharmacodynamics of PK-R at each dose level of AG-348.
Measured: 14 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jun 2019
- Study start11 Jul 2019
- Primary completion21 Jun 2021
- Study completion21 Jun 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Sickle Cell DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 17 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Institutes of Health Clinical Center (CC)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Swee Lay Thein, M.D., National Institutes of Health Clinical Center (CC)
- Investigators
- Swee Lay Thein, M.D., Principal investigator, National Heart, Lung, and Blood Institute (NHLBI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04000165
- Sponsor's protocol ID
- 190097
- Other IDs
- 19-H-0097
- Status last verified
- Jun 2022
- First submitted
- 22 Jun 2019
- Last updated
- 12 Jul 2022
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Deidentified individual participant results data will be made available 6 months after publication date for a period of 5 year by sending a request to sweelay.thein@nih.gov.
Publications
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.
PubMed 41809202Le K, Wang X, Chu J, Lundt M, Lee YY, Conrey A, Frey I, Giannini S, Kosinski PA, Hausman JM, Low PS, Jeffries N, Desai SA, Thein SL. Activating pyruvate kinase improves red blood cell integrity by reducing band 3 tyrosine phosphorylation. Blood Adv. 2024 Nov 12;8(21):5653-5662. doi: 10.1182/bloodadvances.2024013504.
PubMed 39265169Xu JZ, Conrey A, Frey I, Gwaabe E, Menapace LA, Tumburu L, Lundt M, Lequang T, Li Q, Glass K, Dunkelberger EB, Iyer V, Mangus H, Kung C, Dang L, Kosinski PA, Hawkins P, Jeffries N, Eaton WA, Lay Thein S. A phase 1 dose escalation study of the pyruvate kinase activator mitapivat (AG-348) in sickle cell disease. Blood. 2022 Nov 10;140(19):2053-2062. doi: 10.1182/blood.2022015403.
PubMed 35576529
Study at a glance
From the registry record, last updated by the sponsor on 12 Jul 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Escalating Multiple Oral Doses of AG-348 in Subjects With Stable Sickle Cell Disease
- ClinicalTrials.gov ID
- NCT04000165
- Acronym / sponsor ID
- 190097
- Conditions
- Sickle Cell Disease
- Keywords
- HbS polymerization, pyruvate kinase, 2,3- diphosphoglycerate, ATP in red blood cells, acute sickle pain
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 17 participants (actual)
- Lead sponsor
- National Institutes of Health Clinical Center (CC)US National Institutes of Health
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI), Agios Pharmaceuticals, Inc.
- Study start
- 11 Jul 2019 (actual)
- Primary completion
- 21 Jun 2021 (actual)
- Study completion
- 21 Jun 2021 (actual)
- First posted
- 27 Jun 2019 (actual)
- Results
- Posted 12 Jul 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background:
Sickle Cell Disease (SCD) is an inherited blood disorder. People with SCD have abnormal hemoglobin in their red blood cells. Researchers are investigating the safety and efficacy of an investigational medicine called AG-348 (mitapivat sulfate) to determine if it will help people with SCD.
Objective:
To test the tolerability and safety of AG-348 in people with SCD.
Eligibility:
People ages 18 and older with SCD.
Design:
Participants will have 8 visits over approximately 14 weeks. At the first visit participants will be screened with a medical history, a physical exam, blood and urine testing, and an EKG. During the following 5 visits, participants will stay at the clinic for 1 night each. Participants will take study drug in increasing doses up to visit 6, after which the drug will be tapered off. All visits will include physical exam, blood, and urine tests. The last visit will occur 4 weeks after stopping the drug. Participants will provide DNA from the blood samples they provide. The DNA will be tested for an inherited gene that can cause differences in response to the study drug. Researchers may also test other genes to see if they can find any genes that interact with SCD.
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 micro-vasoocclusion induced by sickled red blood cells, is the most common acute complication and the leading cause of hospitalization. Management strategies for SCD have evolved very slowly, and treatment of acute pain is still limited to supportive therapy with opioid medication. Until recently in 2017, the only approved therapy for SCD was hydroxyurea (HU), indicated to reduce frequency of acute painful crises but not universally effective. In addition to HU, transfusions with normal red blood cells are widely used to treat severe sickle crises, but this strategy has limitations (not uniformly accessible, accompanied by risks of alloimmunization, hemolytic transfusion reactions and transfusional iron overload). The only curative treatment is bone marrow transplantation, but this option carries significant risks and is limited by the availability of histocompatible donors.
As the root cause of SCD is polymerization of deoxy-HbS, there is a strong rationale for exploring agents that could inhibit/ reduce the polymerization process itself. HbS polymerizes only when deoxygenated, its oxygenation is influenced by a few factors, one key factor being the 2,3- diphosphoglycerate (2,3-DPG) concentration in the red blood cell. 2,3-DPG decreases oxygen binding by preferentially binding to the low oxygen-affinity T conformation of HbS and also stabilizes the T form of hemoglobin S and HbS fiber. In addition, increased 2,3- DPG concentration decreases intracellular red cell pH further promoting HbS polymerization. 2,3-DPG is an intermediate substrate in the glycolytic pathway, the only source of ATP production in red blood cells. Pyruvate kinase (PK) is a key enzyme in the final step of glycolysis; PK converts phosphoenolpyruvate to pyruvate, creating 50% of the total red cell ATP that is essential for maintaining integrity of the red cell membrane. Reduced PK activity leads to accumulation of the upstream enzyme substrates, including 2,3- DPG, that favors polymerization of deoxy-HbS. In humans with SCD, and even in sickle carriers who are generally asymptomatic, reduced oxygen affinity will favor deoxygenation of HbS and its polymerization, and thus sickling. Indeed, the combination of PK deficiency and sickle cell trait causing an acute sickling syndrome has been previously reported in two cases.
Current approaches to reduce HbS polymerization include fetal hemoglobin induction via multiple strategies and drugs that targets HbS polymerization through increasing affinity of hemoglobin for oxygen (eg. Oxbryta (TM) / Voxelotor / GBT440).
Increasing red cell PK (PK-R) activity, leading to a decrease in intracellular 2,3-DPG concentration, presents a potentially attractive therapeutic target for thwarting HbS polymerization and acute sickle pain. AG-348 / mitapivat is a novel, orally bioavailable, small molecule allosteric activator of PK-R, that is currently in Phase II/III clinical trials in humans with PK deficiency (NCT02476916, NCT03548220 / AG348-C-006; NCT03559699 / AG348-C-007). Overview of the preclinical AG-348 data and other data support dose-dependent changes in blood glycolytic intermediates consistent with glycolytic pathway activation at all multiple ascending doses tested, supporting the potential role of AG-348 in the treatment of sickle cell disease. The overall objective of the present study is to determine the clinical safety and tolerability of AG-348 in subjects with SCD.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| AG-348 in participants with Sickle Cell Disease | Experimental | Drug: AG-348Intra-patient dose escalating study, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (15 listed)
- For enrollment, subjects must meet all of the following criteria during the screening period:
- 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 90 days prior to the first dose of study drug or absence of HbA on hemoglobin analysis (by high-performance liquid chromatography; HPLC)
Key exclusion criteria (27 listed)
- Subjects who meet any of the following criteria during screening will not receive AG348 and will not be counted toward the final enrollment count for statistical purposes:
- Documented pyruvate kinase deficiency
- 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:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AG-348Also: MitapivatThis is a nonrandomized, intra-patient dose escalating clinical study. AG-348 will be administered starting at 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days. | Drug | AG-348 in participants with Sickle Cell Disease |
Primary outcome
Number Participants With Most Common Reported Drug Related Adverse Events
Time frame: 14 weeks
To assess the clinical safety and tolerability of multiple escalating doses of AG-348, an allosteric activator of the enzyme pyruvate kinase, in subjects with stable sickle cell disease (SCD). Safety and tolerability were assessed by frequency and severity of adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) 5.0.
Number Participants With Serious Adverse Events That Were Possibly Drug-related Serious Adverse Events
Time frame: 14 weeks
To assess the clinical safety and tolerability of multiple escalating doses of AG-348, an allosteric activator of the enzyme pyruvate kinase, in subjects with stable sickle cell disease (SCD). Safety and tolerability were assessed by frequency and severity of adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) 5.0.
Number Participants With Increase of ≥ 1 g/dL in Hemoglobin
Time frame: 14 weeks
To assess the clinical safety and tolerability of multiple escalating doses of AG-348, an allosteric activator of the enzyme pyruvate kinase, in subjects with stable sickle cell disease (SCD). Safety and tolerability were assessed by defined as a ≥ 1 g/dL increase in hemoglobin at any dose level compared to baseline.
12 secondary outcomes
Change in Hemoglobin at Each Dose Level of AG-348
Time frame: 14 weeks
Change in Lactic Acid Dehydrogenase (LDH) at Each Dose Level of AG-348
Time frame: 14 weeks
Change in Total Bilirubin at Each Dose Level of AG-348
Time frame: 14 weeks
Change in Absolute Reticulocyte Count at Each Dose Level of AG-348
Time frame: 14 weeks
Change in Aspartate Aminotransferase (AST) at Each Dose Level of AG-348
Time frame: 14 weeks
Change in Mean Corpuscular Volume (MCV) at Each Dose Level of AG-348
Time frame: 14 weeks
Change in Fetal Hemoglobin at Each Dose Level of AG-348
Time frame: 14 weeks
Percent Change From Baseline of 2,3-DPG at Each Dose Level of AG-348
Time frame: 14 weeks
Percent Change From Baseline of Adenosine Triphosphate (ATP) at Each Dose Level of AG-348
Time frame: 14 weeks
Percent Change From Baseline in Oxygen Binding p50 Value at Each Dose Level of AG-348
Time frame: 14 weeks
Percent Change in Time (Mins) at Which 50% of Red Blood Cells Are Sickled (t50) Value at Each Dose Level of AG-348
Time frame: 14 weeks
Percent Change of PK-R at Each Dose Level of AG-348
Time frame: 14 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Jul 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 41809202Conrey 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.
- Derived from this study: PubMed 39265169Le K, Wang X, Chu J, Lundt M, Lee YY, Conrey A, Frey I, Giannini S, Kosinski PA, Hausman JM, Low PS, Jeffries N, Desai SA, Thein SL. Activating pyruvate kinase improves red blood cell integrity by reducing band 3 tyrosine phosphorylation. Blood Adv. 2024 Nov 12;8(21):5653-5662. doi: 10.1182/bloodadvances.2024013504.
- Derived from this study: PubMed 35576529Xu JZ, Conrey A, Frey I, Gwaabe E, Menapace LA, Tumburu L, Lundt M, Lequang T, Li Q, Glass K, Dunkelberger EB, Iyer V, Mangus H, Kung C, Dang L, Kosinski PA, Hawkins P, Jeffries N, Eaton WA, Lay Thein S. A phase 1 dose escalation study of the pyruvate kinase activator mitapivat (AG-348) in sickle cell disease. Blood. 2022 Nov 10;140(19):2053-2062. doi: 10.1182/blood.2022015403.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. Deidentified individual participant results data will be made available 6 months after publication date for a period of 5 year by sending a request to sweelay.thein@nih.gov.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Swee Lay Thein, M.D. principal investigator
National Heart, Lung, and Blood Institute (NHLBI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing AG-348 in people with Sickle Cell Disease, run by National Institutes of Health Clinical Center (CC) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Jul 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 12 Jul 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number Participants With Most Common Reported Drug Related Adverse Events (time frame: 14 weeks). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04000165, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Jul 2022.