Oral PK Activator Shows Sustained Safety, Efficacy in SCD

The oral pyruvate kinase (PK) activator mitapivat continues to demonstrate safety and efficacy in patients with sickle cell disease (SCD), according to a phase II, open-label study published in Blood Advances.

Myrthe van Dijk, of the University Medical Center Utrecht, and colleagues reported results from a one-year, fixed-dose extension period of the ESTIMATE study. An eight-week, dose-finding portion of the study previously found that mitapivat was well tolerated and efficacious in patients with SCD.

Safety was evaluated by frequency and severity of adverse events (AEs), while efficacy was evaluated by hemoglobin (Hb) and antisickling responses.

Nine of 10 patients continued into the fixed-dose extension period. Mitapivat led to sustained improvement in Hb level, accompanied by decreases in markers of hemolysis.

When combining the dose-finding period with the fixed-dose extension period, the rate of vaso-occlusive events decreased from a historic baseline of 1.33 ± 1.32 to 0.64 ± 0.87 (P=.0489). The adenosine triphosphate-to-2,3-diphosphoglycerate ratio and Hb-oxygen affinity increased, and red blood cell sickling decreased.

All patients experienced treatment-emergent AEs (TEAEs), most commonly transaminase increase and headache. No grade ≥3 TEAEs were reported.

“In conclusion, we established longer-term proof of concept for PK activation as a potential therapeutic option in SCD,” wrote Dr. van Dijk and colleagues. “Treatment with mitapivat demonstrated durable beneficial mechanistic effects and a favorable safety profile at doses up to 100 mg twice daily for more than one year in SCD.”

Reference

van Dijk MJ, Rab MAE, van Oirschot BA, et al. One-year safety and efficacy of mitapivat in sickle cell disease: follow-up results of a phase 2, open-label study. Blood Adv. 2023;7(24):7539-7550. doi:10.1182/bloodadvances.2023011477