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.
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 Type
INTERVENTIONAL
Allocation
NA
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
17
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.
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
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.
Time frame: 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.
Time frame: 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.
Time frame: 14 weeks
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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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
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
Measure 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
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.
Time frame: 14 weeks
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