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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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 h...

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.

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