Design of mitapivat extension study in SCD. This is a nonrandomized, open-label study, which included 15 patients with HbSS: 13 patients participated and completed the previous phase 1 dose-escalation study, and 2 patients were mitapivat naïve. After screening, all patients started mitapivat at 50 mg twice daily, escalating after 4 weeks to 100 mg twice daily, unless there was a rapid Hb increase of ≥2 g/dL), the maximum Hb level of 12.5 g/dL had been reached, or not tolerated. After completion of the 24-week core period, patients had an option to continue on mitapivat treatment in the extension period for up to 6 years. Study visits were conducted every 2 weeks (×2), 4 weeks (×2), and then every 12 weeks for the first 2 years, and will continue every 24 weeks for the remaining 4 years. The primary end point was long-term safety and tolerability, in conjunction with changes in clinical laboratory values. Secondary end points included assessment of Hb response and changes in hemolytic markers and how well the Hb response was sustained; pharmacokinetic and pharmacodynamic parameters; p50, a measure of oxygen affinity; and t50, a measure of HbS polymerization kinetics.