Mitapivat Maintains Safety, Tolerability Over 2 Years in Sickle Cell Disease

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Extension analysis from a phase 1 trial show the investigative oral mitapivat was not associated with any discontinuations nor deaths over 2 years.

Long-term use of mitapivat, an investigational oral pyruvate kinase (PK) activator, is associated with generally safe and tolerable outcomes in patients with sickle cell disease, according to findings from a phase 1 extension trial.1

In new data presented at the American Society of Hematology (ASH) 2023 Annual Meeting in San Diego this weekend, investigators from the National Institutes of Health (NIH) reported early-stage data supporting the safety and tolerability of mitapivat as a potential disease-modifying therapy for the treatment of sickle cell disease. The ASH 2023 data were further complemented by phase 2 RISE UP findings suggesting up to half of patients with sickle cell disease administered either 50 mg or 100 mg mitapivat achieved a hemoglobin response, versus just 3% of patients receiving placebo.2

Presented by Swee Lay Thein, MBBS, DSc, FRCP, of the Sickle Cell Branch of the National Heart, Lung & Blood Institute (NHLBI), investigators followed up their proof-of-concept, phase 1 trial that which demonstrated mitapivat’s acceptable safety and tolerability profile at multiple ascending doses, as well as its activating pharmacokinetics, with an extension assessment that observed the would-be agent as a long-term maintenance therapy for patients with sickle cell disease.1

Their analysis included 15 adult patients aged ≥18 years old with confirmed sickle cell disease per Hemoglobin S (HbSS) and baseline hemoglobin 7.1 – 10.5 g/dL. Patients had no recent blood transfusions, erythropoietin therapy, nor changes in sickle cell disease-specific therapy including hydroxyurea and L-glutamine. All but 2 of the patients had previously participated in the phase 1 trial and were therefore exposed to mitapivat previously.

Investigators initiated patients at 50 mg twice-daily mitapivate before escalating them to 100 mg doses after 4 weeks—unless a rapid increase (per ≥2 g/dL) in hemoglobin was observed or a maximum hemoglobin level of 12.5 g/dL was achieved. Dose reductions were additionally given for any safety or tolerability purposes during the extension trial.

Following the 24-week dosing period, patients were allowed to either continue mitapivat in the extension period for ≤6 years, with study visits conducted every 2, 4 then 12 weeks for the first 2 years, followed by 6 months for the remaining 4 years. The data presented at ASH 2023 are from the ongoing extension period and pertain to ≤2 years od mitapivat exposure in the patient population. Any and all vaso-occlusive crises (VOCs) were considered adverse events if they occurred while during the study period leading up to March 23, 2023.

Mean patient age was 39 years old (range, 25 – 57) a majority (n = 10) were male and were receiving hydroxyurea (n = 11). Median duration of mitapivat treatment for patients who entered the extension period was 84 weeks (range, 48 – 108); 1 patient discontinued the therapy after 2 years on their own decision, and 10 patients received ≥72 weeks of therapy.

Lay Thein and colleagues observed generally good tolerance for mitapivat, with no discontinuations nor study deaths linked to treatment emergent adverse events (TEAEs) through the extension period. The most common TEAEs in ≥5 patients included VOCs (n = 8), estrone decrease (n = 7), testosterone increase (n = 6), and cough (n = 5). The most common serious TEAEs reported in ≥2 patients were again VOCs (n = 8) and lung infection (n = 2).

Among the 3 patients requiring a dose reduction, 2 were subsequently increased back to 100 mg mitapivat once TEAEs resolved.

Mean hemoglobin levels increased significantly from baseline to week 24 (1.38 g/dL; P <.0001), a result generally upheld at other follow-up periods. All but 1 patient achieved a ≥1 g/dL increase at any timepoint within the core study period, versus baseline. Investigators also observed concurrent or sustained improvements in markers of hemolysis, oxygen affinity, sickling kinetics, and increases in ATP levels during the extension period.

“Long-term use of mitapivat is safe and well tolerated in patients with sickle cell disease with evidence of sustained long-term improvements in Hb, hemolytic and sickling kinetics,” investigators concluded. “Mitapivat offers a novel disease-modifying approach.”


  1. Conrey A, Frey I, Asomaning N, Charles RP, et al. Long-Term Safety and Efficacy of Mitapivat, an Oral Pyruvate Kinase Activator, in Adults with Sickle Cell Disease: Extension of a Phase 1 Dose Escalation Study. Paper presented at: American Society of Hematology 2023 Annual Meeting, December 9 – 13, 2023. San Diego, CA.
  2. Campbell P. Mitapivat Shows Promise for Sickle Cell Disease in Phase 2 RISE UP Trial. HCPLive. Published December 9, 2023.