Mitapivat is a first-in-class oral activator of pyruvate kinase designed to improve red blood cell energy metabolism by increasing ATP production and reducing 2,3-DPG levels. Through this mechanism, the therapy aims to improve red blood cell health, reduce hemolysis, and decrease sickling.

The global Phase III RISE UP trial randomized 207 patients with SCD to receive mitapivat or placebo.

Safety Outcomes-

• SAEs were reported in 20.3% (n = 28) and 29.0% (n = 20) of patients receiving mitapivat and placebo, respectively; 0.7% (n = 1) and 0.0% (n = 0) were considered treatment-related by the investigators. 

• AEs led to treatment discontinuation in 4.3% of patients (n = 6) receiving mitapivat and 2.9% (n = 2) receiving placebo. 

KOL Insights-

“The RISE UP Phase III data presented today showcase the strong anti-hemolytic profile of mitapivat, with rapid and durable improvements in both hemoglobin and indirect bilirubin as well as a meaningful reduction in transfusion burden. Importantly, this anti-hemolytic effect translates to clear clinical benefits, including improvements for hemoglobin responders across measures of sickle cell pain crises, pain, sleep, and physical function compared with non-responders. Together, these data reinforce the potential for mitapivat to improve the relentless physical toll that comes with living with sickle cell disease.”– Expert Opinion

“Building on over a decade of clinical experience with mitapivat across several hemolytic anemias, these results reinforce both its consistent benefits and its well-established safety profile, which is supported by over 1,300 patient-years of data. Taken together, mitapivat represents a differentiated anti-hemolytic approach that can provide meaningful clinical benefits for patients with sickle cell disease – an underserved population in desperate need of innovative therapies.”– Expert Opinion

Conclusion-

SCD is a lifelong inherited hemoglobin disorder affecting an estimated 8–10 million people worldwide. Chronic hemolytic anemia is a hallmark of the disease and contributes substantially to organ dysfunction, hospitalization, reduced quality of life, and premature mortality. While recent therapeutic advances have improved disease management, there remains a significant need for convenient therapies that address the underlying pathophysiology of red blood cell dysfunction.

The Phase III RISE UP trial demonstrated that mitapivat significantly improved hemoglobin levels and markers of hemolysis, validating pyruvate kinase activation as a novel therapeutic strategy in SCD. Although the study narrowly missed statistical significance for reducing sickle cell pain crises, patients achieving hemoglobin responses experienced fewer crises, fewer hospitalizations, and clinically meaningful fatigue improvements. Combined with a favorable safety profile and oral administration, these findings support mitapivat as a potentially important disease-modifying treatment that could complement existing SCD therapies and broaden treatment options for patients living with chronic hemolytic anemia.