Mitapivat for phosphofructokinase deficiency
Authors: Hanny Al‐Samkari
Journal: American Journal of Hematology (2024)

Pyruvate kinase activation is an emerging therapeutic modality under evaluation to treat congenital hemolytic anemias, including pyruvate kinase deficiency, thalassemia, and sickle cell disease, among others.1, 2 The results of a phase 3, randomized, placebo-controlled clinical trial of the pyruvate kinase activator mitapivat to treat the most common glycolytic enzyme defect, pyruvate kinase deficiency, were previously published.1 Because mitapivat increases glycolytic flux via allosteric activation of multiple isoforms of pyruvate kinase, it may provide therapeutic benefit in other glycolytic disorders, particularly those resulting in pathologic accumulation of glycolytic intermediates. Phosphofructokinase, another critical glycolytic enzyme, catalyzes the conversion of fructose-6-phosphate to fructose-1,6-bisphosphate. Phosphofructokinase deficiency (glycogen storage disease type VII, Tarui disease), an ultrarare enzymopathy occurring in fewer than 1 in 1 000 000 people, causes accumulation of fructose-6-phosphate which is ultimately converted to glycogen that builds up in muscle tissue, resulting in easy fatigability, muscle weakness and pain, myoglobinuria, rhabdomyolysis, and hemolysis.3 Phosphofructokinase deficiency has no known effective treatments. The safety and effectiveness of mitapivat in a patient with phosphofructokinase deficiency are described herein. A 29-year-old man with classic phosphofructokinase deficiency presenting with lifelong easy fatigability, muscle weakness and pain, and hemolysis (without anemia) resulting in severe physical activity limitation and poor health-related quality of life was treated with oral mitapivat with close monitoring for safety and effectiveness. The patient's diagnosis was confirmed via genetic testing demonstrating two known pathogenic mutations in the M isoform of phosphofructokinase (PFKM c.2003delC [p.Pro668Glnfs*17] and PFKM c.237+1G>A [splice donor variant]). At baseline, the patient scored poorly across all eight domains of the well-validated Short Form-36 Health Survey (SF-36), but dose-dependent and ultimately marked improvements across all eight domains were observed with mitapivat treatment (Figure 1). Mitapivat was well-tolerated with no adverse events except mild transient erythrocytosis (hematocrit 61%, up from pretreatment baseline of 46%) after initial dose escalation to 20 mg twice daily; this resolved with a temporary dose decrease to 20 mg once daily and did not recur following resumption of 20 mg twice daily or dose escalation to 50 mg once daily. While the maximum approved mitapivat dose for pyruvate kinase deficiency is 50 mg twice daily, the decision was made to stay at 50 mg daily and not dose escalate to 50 mg twice daily because the patient felt markedly improved on 50 mg once daily and there was a desire to avoid potential recurrence of erythrocytosis. Consistent with SF-36 results, the patient reported substantially improved exercise tolerance and social participation and greatly reduced muscular symptoms and physical limitations. Despite considerably increased physical activity, serum levels of creatine kinase, aldolase, lactate dehydrogenase, and aminotransferases remained stable on mitapivat, in contrast to the activity-dependent elevations in these markers observed prior to mitapivat treatment. Notably, every-other-week measurements of creatine kinase were uniformly lower (222–1260 U/L, reference range 60–400 U/L) following initiation of mitapivat than at the pre-mitapivat baseline (1536 U/L), with multiple normal measurements on mitapivat (which had never been previously documented in the patient). Although mitapivat was not used specifically to treat hemolysis in this case, relevant hemolysis parameters, including bilirubin, lactate dehydrogenase, and reticulocytes, were followed. Compared with baseline, total bilirubin improved (2.7 mg/dL at baseline to 1.8 mg/dL on mitapivat 50 mg), reticulocytes improved (7.1% at baseline to 4.4% on mitapivat 50 mg) while lactate dehydrogenase remained stable. Given that the primary clinical manifestations of phosphofructokinase deficiency result from increased glycogen formation and buildup in muscle tissue, mitapivat may be effective in treating this condition via allosteric activation of the PKM2 isoform of pyruvate kinase in skeletal muscle and thereby increasing glycolytic flux, reducing this buildup. The observation of dose-dependent therapeutic benefit of mitapivat in this patient with phosphofructokinase deficiency suggests its potential clinical utility in other patients with phosphofructokinase deficiency (and possibly other rare glycolytic disorders) for which no effective treatments exist. H.A. was responsible for all aspects of this manuscript from conception to completion. H.A. is funded by the National Heart, Lung, and Blood Institute (1K23HL159313). Dr. Hanny Al-Samkari reports research funding to his institution (Agios, Sobi, Novartis, Vaderis, and Amgen) and consultancy (Agios, Sobi, Alnylam, Novartis, Alpine, argenx, Amgen, and Pharmacosmos). Mitapivat for phosphofructokinase deficiency is an off-label use. Not applicable (case report). For data inquiries, please email [email protected].