Observational Study Investigating the Mechanistic Effects of Mitapivat in Subjects with Sickle Cell Disease

National Heart, Lung, And Blood Institute

Investigators

Abstract

Sickle Cell Disease (SCD) is a multisystem disorder associated with episodes of acute clinical events, chronic hemolytic anemia and progressive organ damage. Episodic pain, triggered by microvascular vaso-occlusion 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 the FDA approval of L-glutamine (Endari) in 2017 and the more recent approvals of crizanlizumab (Adakveo) and voxelotor (Oxbryta) in 2019, hydroxyurea (HU) was the only therapy available for SCD, indicated to reduce frequency of acute painful crises but which is not universally effective. A Phase I open label multiple dose ascending study (Protocol 19-H-0097; NCT04000165) conducted at our institution provided preliminary evidence of the efficacy and safety of Mitapivat in SCD, with increases in hemoglobin levels and decreased hemolytic parameters (Xu Julia Z 2021). The data are consistent with glycolytic pathway activation at multiple ascending doses tested, supporting the potential anti-sickling role of mitapivat in the treatment of SCD. A subsequent extension study (Protocol 000049; NCT04610866) was initiated at our institution to assess the long-term safety and tolerability of Mitapivat in the SCD population; preliminary findings are consistent with trends observed in the Phase I study. This study will be conducted in subjects enrolled on the AG348-C-020 protocol (NIH Protocol IRB001565) to evaluate the mechanisms of action of mitapivat in subjects with SCD. The exploratory studies include testing red cell sickling, determination of reactive oxygen species (ROS), determination of phosphatidyl-serine (PS) externalization by flow cytometry, changes in RBC metabolomics and proteomics, RBC band 3 tyrosine phosphorylation, glycated HbS, muscle physiology, tissue oxygenation and blood flow using near infrared spectroscopy (NIRS) technologies and brain magnetic resonance imaging for assessment of cerebral hemodynamics, in response to mitapivat. The AG348-020 study will allow us to increase sample size of the exploratory data collected in the NIH extension study (Protocol 000049) as well as include additional studies based on preliminary observations. The companion study will also increase rigor of the results as it is randomized, double-blind and placebo controlled. The PI and her study team will be blinded to the study arm and sample analyses will occur at the end of the study. This study is no longer accruing and currently has 6 subjects enrolled.