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
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|ClinicalTrials.gov Identifier: NCT04610866|
Recruitment Status : Recruiting
First Posted : November 2, 2020
Last Update Posted : March 8, 2021
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|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||15 participants|
|Intervention Model:||Sequential Assignment|
|Masking:||None (Open Label)|
|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|
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.
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 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.
- To evaluate the pharmacokinetic [ Time Frame: 24 and 48 weeks ]Change from baseline in pharmacokinetic and pharmacodynamic measures over time.
- 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
- 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.
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 ClinicalTrials.gov identifier (NCT number): NCT04610866
|Contact: Ingrid C Frey||(301) firstname.lastname@example.org|
|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 email@example.com|
|Principal Investigator:||Julia Z Xu, M.D.||National Heart, Lung, and Blood Institute (NHLBI)|