Investigating the Mechanistic Effects of Mitapivat in Subjects With Sickle Cell Disease

Overview

Background: Sickle cell disease (SCD) is an inherited blood disorder. The disease affects the ability of red blood cells to carry oxygen; this in turn can injure organs including the heart, lungs, and kidneys. SCD can lead to serious illness and death. Treatments such as bone marrow transplants and gene therapies can cure SCD, but they are not widely available. Current drug treatments for SCD are not always effective. This natural history study will examine how a study drug (mitapivat) affects red blood cells in people with SCD. Objective: To learn how mitapivat affects red blood cells in people with SCD. Eligibility: People with SCD who are enrolled in the parent study, NIH protocol IRB001565-H. Design: Procedures for this study will be done during visits already scheduled for the parent study. Participants will have additional blood drawn during study visits. The additional amount will be about 3.5 teaspoons. Participants will undergo a test called near infrared spectroscopy (NIRS) up to 9 times. Probes will be placed on their skin. A blood pressure cuff will be placed on their arm. The cuff will be filled with air for up to 5 minutes and then released. Participants may be asked to breathe at a certain rate or to hold their breath during these measurements. NIRS measures oxygen levels, blood flow, and the makeup of skin and muscle. Researchers will draw additional information for this study from participants medical records.

Study Description: Subjects actively enrolled protocol AG348-C-020 (NIH protocol IRB001565-H), an industry-sponsored phase 2/3 study investigating the efficacy of mitapivat in treating sickle cell disease (SCD), will be invited to participate in this protocol simultaneously to further investigate the mechanistic effects of mitapivat. Subjects will be asked for a blood sample at study visits and undergo near infrared spectroscopy (NIRS) testing to investigate the mechanisms of action of mitapivat in subjects with SCD. Objectives: To evaluate the mechanisms of action of mitapivat in subjects with SCD. Endpoints: PRIMARY ENDPOINT DURING BLINDED PERIOD: The percentage change in the oxygen affinity measure p50 (defined as the partial pressure of oxygen at which Hb is 50% saturated with oxygen) between baseline and the average value at 12, 24 and 52 weeks. This change will be compared between the placebo and mitapivat arms. PRIMARY ENDPOINTS DURING OPEN LABEL EXTENSION (OLE): * Evaluate the effect of mitapivat by comparing inter-patient and intra-patient changes between year one and year two. * Evaluate the effects of long term use of mitapivat in patients who were randomized onto mitapivat during the first year of the study. * Evaluate the intra-patient changes for patients who were randomized onto the placebo during the first year of the study and transition to mitapivat during year two. SECONDARY ENDPOINTS DURING BLINDED PERIOD: * The p50 changes will also be assessed at the individual time points of 12, 24, and 52 weeks. * Percentage of sickled cells and time to 50% sickling (t50) under normal and hypoxic ex vivo conditions at regular time intervals on mitapivat and percentage change from baseline to the individual time points at 12, 24, and 52 weeks. This change will be compared between the placebo and mitapivat arms. * Percentage change in intracellular reactive oxidative species (ROS) in red blood cells (RBCs) using a ROS sensitive fluorescent probe and mass spectrometry- based proteomics of RBC lysates between baseline and the individual time points at 12, 24, and 52 weeks. This change will be compared between the placebo and mitapivat arms. * The percentage change in phosphatidylserine (PS) externalization using annexin V labeling (marker of red cell survival) by flow cytometry between baseline and the individual time points at 12, 24, and 52 weeks. This change will be compared between the placebo and mitapivat arms. * Percentage change in muscle physiology, tissue oxygenation and blood flow using NIRS methodologies between baseline the individual time points at 12, 24, and 52 weeks. This change will be compared between the placebo and mitapivat arms. * RBC deformability and sickling using osmotic and oxygen gradient ektacytometry TERTIARY/EXPLORATORY ENDPOINTS DURING BLINDED PERIOD: * Evaluate effect of mitapivat on RBC metabolomics and proteomics between baseline and various follow-up periods. This change will be compared between the placebo and mitapivat arms. * Measurement of glycated Hb S level as a surrogate measure for red cell half-life between baseline and various follow-up periods. This change will be compared between the placebo and mitapivat arms. * Evaluate effect of mitapivat on RBC band 3 tyrosine phosphorylation between baseline and various follow-up periods. This change will be compared between the placebo and mitapivat arms. * Correlation between potential exploratory biomarkers and clinical laboratory parameters. * Evaluate change in cerebral hemodynamic measurements through magnetic resonance imaging (MRI) for cerebral blood flow, oxygen extraction fraction, and cerebral metabolic rate of oxygen consumption from baseline, at 12 and 52 weeks. This change will be compared between the placebo and mitapivat arms.