Efficacy and safety of Mitapivat in sickle cell disease: a systematic review.

Background: Sickle cell disease (SCD) is a chronic hemoglobinopathy marked by hemolytic anemia, VOEs, and multiorgan complications. Mitapivat, an oral Pyruvate Kinase (PK) activator, has emerged as a potential disease-modifying therapy. This systematic review assessed the efficacy and safety of Mitapivat in individuals with SCD.

Methods: A systematic literature search was conducted from different search engines from inception. The review followed PRISMA 2020 guidelines, and the protocol was registered in PROSPERO [CRD420251000061]. RCTs and NRSIs evaluating Mitapivat monotherapy were included. ROB was assessed. A narrative synthesis was undertaken due to heterogeneity.

Results: One RCT and two NRSIs involving 156 participants were included. Reduced annualized Vaso-occlusive episodes (VOE) rates compared to placebo by 51.6% (50 mg) and 70.0% (100 mg). Statistically significant hemoglobin response was observed in 46.2%-56% of participants. Increased markers of hemolysis and reduced transfusion requirements in Mitapivat groups were reported. However, SAEs were low, in 8%-19% of Mitapivat recipients.

Conclusions: Preliminary evidence suggests Mitapivat demonstrates potential to reduce VOEs, improve hemoglobin levels, and decrease hemolysis with an acceptable safety profile. However, small sample sizes, lack of functional outcomes, and limited follow-up warrant cautious interpretation. Further large-scale RCTs are needed to validate these findings and establish a long-term benefit-risk balance.