Long-term mitapivat treatment is safe and efficacious in patients with sickle cell disease Open Access

• Median of 2.53-year follow-up of mitapivat showed favorable safety and tolerability in patients with sickle cell disease (SCD).

• Sustained improvements in hemoglobin, hemolytic markers and sickling kinetics support mitapivat as a disease-modifying treatment in SCD.

In a Phase 1 open-label study (NCT04000165), mitapivat, a pyruvate kinase (PK) activator that is FDA-approved for treating anemia of PK deficiency, showed promise as a disease-modifying therapy for sickle cell disease (SCD). We now report updated findings from a Phase 1/2 study with a median follow-up of 132 weeks (2.53 years), involving 15 patients—13 from the initial study and two new to mitapivat. Patients with HbSS over 18 years started mitapivat 50 mg twice daily for four weeks followed by a dose escalation to 100 mg twice daily for another 20 weeks to complete a 24-week core period. Nine patients continued treatment for over 120 weeks, resulting in 1884 patient-weeks of exposure to mitapivat. Common treatment-emergent adverse events (TEAEs) included vaso-occlusive crises (VOCs), decreased hormone levels, arthralgia, cough, and COVID-19 infections. Changes in laboratory values were not clinically significant. Serious TEAEs were mainly VOCs in 10 patients and lung infections in 3; all VOCs were linked to known triggers. No TEAEs led to discontinuation of mitapivat. Ninety-three percent (14/15) of the patients had at least a 1 g/dL increase in hemoglobin at some point within the 24-week core period, with a mean increase of 1.38 g/dL (SD 0.88). Improvements in hemoglobin, hemolytic markers, oxygen affinity, sickling kinetics, and ATP/2,3-DPG ratio were sustained during the extension period. These findings suggest that long-term mitapivat is safe and effective for SCD patients, warranting further investigation in the ongoing Phase 3 study (RISE UP, NCT05031780). This trial is registered at ClinicalTrials.gov under NCT04610866.