A Phase 2/3, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Mitapivat in Subjects With Sickle Cell Disease

National Heart, Lung, And Blood Institute

Investigators

Abstract

In patients with SCD, PKR is thought to play a critical role because of increased energy demands, increased cellular oxidative stress, or because of the abnormal accumulation of upstream glycolytic metabolites (ie, 2,3-DPG). Therefore, pyruvate kinase activation may modulate the pathophysiology of SCD in several ways. In SCD, mutation of the globin gene(s) results in expression of a protein that, when conjugated to heme as Hb, is characterized by instability and a strong tendency to polymerize (HbS). There is a strong rationale for exploring agents that could inhibit or reduce the polymerization process itself. HbS polymerizes when deoxygenated, and its oxygenation is influenced by several factors, one key factor being the 2,3-DPG concentration in the RBC. 2,3-DPG is a key allosteric modulator of the binding of oxygen to Hb, stabilizing the deoxygenated form. Red blood cell 2,3-DPG concentrations are elevated in patients with SCD, thus favoring the deoxygenated state of HbS and promoting its polymerization and the consequent sickling of the RBC. PKR activation with mitapivat has been shown in both nonclinical models and in humans to decrease 2,3-DPG levels as well as increase levels of ATP. Reducing the concentration of 2,3-DPG via PKR activation should increase the percentage of oxygen-bound HbS and thereby reduce sickling and hemolysis. An additional effect of decreasing the concentration of 2,3-DPG is an increase in intracellular pH, which increases the solubility of deoxygenated HbS, further reducing the likelihood of sickling. In addition, increased ATP concentrations resulting from PKR activation should also ameliorate RBC sickling and hemolysis by improving cellular hydration and supporting RBC membrane integrity. Preliminary data from the ongoing NIH IST in subjects with SCD show that mitapivat can increase Hb concentration and ATP. In addition, mitapivat has been shown to decrease 2,3-DPG and reduce HbS polymerization which can potentially reduce VOCs in patients with SCD. These data support the hypothesis that activation of PKR by mitapivat may provide potential clinical benefits for subjects with SCD, and warrant further investigation of the safety and efficacy of mitapivat in this proposed Phase 2/3 study in subjects with SCD. In summary, as an allosteric activator of PKR, mitapivat decreases erythrocyte 2,3-DPG and increases ATP. Preliminary data indicate that through this mechanism of action, mitapivat may reduce HbS polymerization, sickling, and hemolysis. Therefore, mitapivat is a therapeutic candidate for the treatment of adult patients with SCD with the potential to provide clinical benefit by both improvement of anemia and reduction in sickle cell pain crises (SCPCs). The double-blind design of the Phase 3 portion minimizes assessment bias and the use of placebo as a comparator allows an objective evaluation of the efficacy and safety of mitapivat. Although new treatment options have emerged for the treatment of SCD in recent years, these agents are not approved in all regions and thus are not appropriate to serve as comparators in this global study. Additionally, none of these therapies have been shown to improve both hemolytic anemia and VOCs, the 2 primary objectives of the Phase 3 portion of the study. Therefore, it is appropriate to use a placebo control, rather than an active comparator, to evaluate the efficacy of mitapivat. The randomization ratios selected ensures that subjects have a greater likelihood of being randomized to receive mitapivat than placebo, and the Open-label Extension Period provides an opportunity for subjects who were randomized to placebo to receive mitapivat.