Evaluation of the safety, tolerability, pharmacokinetics, and pharmacodynamics of long-term mitapivat dosing in subjects with stable sickle cell disease

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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 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, the only approved therapy for SCD was hydroxyurea (HU), indicated to reduce frequency of acute painful crises but which is not universally effective. 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.2 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 RBC. Increased intracellular 2,3-DPG decreases oxygen binding and stabilizes the deoxygenated form (T form) of hemoglobin. 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 adenosine triphosphate (ATP) production in RBCs. 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 RBC membrane. Reduced PK activity leads to accumulation of the upstream enzyme substrates, including 2,3-DPG which favors polymerization as it stabilizes the deoxygenated form (T form) of hemoglobin. 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 (Hb F) induction via multiple strategies and drugs that targets HbS polymerization through increasing affinity of hemoglobin for oxygen (e.g. voxelotor). Increasing red cell PK (PKR) activity, leading to a decrease in intracellular 2,3-DPG concentration, presents a new and potentially attractive therapeutic target for thwarting HbS polymerization and acute sickle pain. 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 in PK deficient subjects appear promising, and the safety profile of the drug was acceptable. Overview of the preclinical mitapivat 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 mitapivat in the treatment of SCD. We completed our Phase I study (NCT04000165, Study 19-H-0097) to determine the clinical safety and tolerability of multiple escalating doses of mitapivat in subjects with SCD. We have observed an acceptable safety profile for mitapivat doses up to 50 mg twice daily (BID) for all subjects and 100 mg BID for ten subjects, with a range of adverse effects comparable to those observed in PKD patients. Furthermore, our Phase I study has provided preliminary evidence of efficacy for mitapivat in SCD, with increases in hemoglobin level and decreases in hemolytic markers observed in the majority of SCD subjects and subjective improvements in symptoms reported by some subjects. The objective of the present study is to evaluate the safety and tolerability of long-term treatment with a stable dose of mitapivat in subjects with SCD.