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Current Medicinal Chemistry

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ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

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Perspective

Mitapivat: A Novel Treatment of Hemolytic Anemia in Adults with Pyruvate Kinase Deficiency

Author(s): Surya K. De*

Volume 31, Issue 6, 2024

Published on: 26 May, 2023

Page: [683 - 687] Pages: 5

DOI: 10.2174/0929867330666230430002709

Abstract

Mitapivat is an orally bioavailable small molecule allosteric activator of pyruvate kinase. It was approved by the US FDA on February 17, 2022, and the European Union in November 2022 for the treatment of hemolytic anemia in adult patients with pyruvate kinase deficiency. In this short perspective, physicochemical properties, synthesis, dosage and administration, mechanism of action, pharmacodynamics, pharmacokinetics, drug interactions, and adverse reactions of mitapivat are described.

Keywords: Hemolytic anemia, pyruvate kinase deficiency, mitapivat, sickle cell disease, thalassemia, red blood cells, hemoglobin.

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[1]
Koralkova, P.; van Solinge, W.W.; van Wijk, R. Rare hereditary red blood cell enzymopathies associated with hemolytic anemia - pathophysiology, clinical aspects, and laboratory diagnosis. Int. J. Lab. Hematol., 2014, 36(3), 388-397.
[http://dx.doi.org/10.1111/ijlh.12223] [PMID: 24750686]
[2]
Kanno, H.; Fujii, H.; Miwa, S. Structural analysis of human pyruvate kinase L-gene and identification of the promoter activity in erythroid cells. Biochem. Biophys. Res. Commun., 1992, 188(2), 516-523.
[http://dx.doi.org/10.1016/0006-291X(92)91086-6] [PMID: 1445295]
[3]
Secrest, M.H.; Storm, M.; Carrington, C.; Casso, D.; Gilroy, K.; Pladson, L.; Boscoe, A.N. Prevalence of pyruvate kinase deficiency: A systematic literature review. Eur. J. Haematol., 2020, 105(2), 173-184.
[http://dx.doi.org/10.1111/ejh.13424] [PMID: 32279356]
[4]
Bianchi, P.; Fermo, E.; Lezon-Geyda, K.; Beers, E.J.; Morton, H.D.; Barcellini, W.; Glader, B.; Chonat, S.; Ravindranath, Y.; Newburger, P.E.; Kollmar, N.; Despotovic, J.M.; Verhovsek, M.; Sharma, M.; Kwiatkowski, J.L.; Kuo, K.H.M.; Wlodarski, M.W.; Yaish, H.M.; Holzhauer, S.; Wang, H.; Kunz, J.; Addonizio, K.; Al-Sayegh, H.; London, W.B.; Andres, O.; Wijk, R.; Gallagher, P.G.; Grace, R.F.F. Genotype-phenotype correlation and molecular heterogeneity in pyruvate kinase deficiency. Am. J. Hematol., 2020, 95(5), 472-482.
[http://dx.doi.org/10.1002/ajh.25753] [PMID: 32043619]
[5]
Rab, M.A.E.; Van Oirschot, B.A.; Kosinski, P.A.; Hixon, J.; Johnson, K.; Chubukov, V.; Dang, L.; Pasterkamp, G.; Van Straaten, S.; Van Solinge, W.W.; Van Beers, E.J.; Kung, C.; Van Wijk, R. AG-348 (Mitapivat), an allosteric activator of red blood cell pyruvate kinase, increases enzymatic activity, protein stability, and ATP levels over a broad range of PKLR genotypes. Haematologica, 2020, 106(1), 238-249.
[http://dx.doi.org/10.3324/haematol.2019.238865] [PMID: 31974203]
[6]
Glenthøj, A.; van Beers, E.J.; Al-Samkari, H.; Viprakasit, V.; Kuo, K.H.M.; Galactéros, F.; Chonat, S.; Porter, J.; Zagadailov, E.; Xu, R.; Oluyadi, A.; Hawkins, P.; Gheuens, S.; Beynon, V.; Barcellini, W. Mitapivat in adult patients with pyruvate kinase deficiency receiving regular transfusions (ACTIVATE-T): A multicentre, open-label, single-arm, phase 3 trial. Lancet Haematol., 2022, 9(10), e724-e732.
[http://dx.doi.org/10.1016/S2352-3026(22)00214-9] [PMID: 35988546]
[7]
Kuo, K.H.M.; Layton, D.M.; Lal, A.; Al-Samkari, H.; Bhatia, J.; Kosinski, P.A.; Tong, B.; Lynch, M.; Uhlig, K.; Vichinsky, E.P. Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in adults with non-transfusion dependent α-thalassaemia or β-thalassaemia: An open-label, multicentre, phase 2 study. Lancet, 2022, 400(10351), 493-501.
[http://dx.doi.org/10.1016/S0140-6736(22)01337-X] [PMID: 35964609]
[8]
Shah, A.J.; Schwartz, J.D.; Segovia, J.C. Mitapivat versus placebo for pyruvate kinase deficiency. N. Engl. J. Med., 2022, 386(26), 2538-2539.
[http://dx.doi.org/10.1056/NEJMc2206275] [PMID: 35767453]
[9]
Kung, C.; Hixon, J.; Kosinski, P.A.; Cianchetta, G.; Histen, G.; Chen, Y.; Hill, C.; Gross, S.; Si, Y.; Johnson, K.; DeLaBarre, B.; Luo, Z.; Gu, Z.; Yao, G.; Tang, H.; Fang, C.; Xu, Y.; Lv, X.; Biller, S.; Su, S.S.M.; Yang, H.; Popovici-Muller, J.; Salituro, F.; Silverman, L.; Dang, L. AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency. Blood, 2017, 130(11), 1347-1356.
[http://dx.doi.org/10.1182/blood-2016-11-753525] [PMID: 28760888]
[10]
Al-Samkari, H.; van Beers, E.J. Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias. Ther. Adv. Hematol., 2021, 12.
[http://dx.doi.org/10.1177/20406207211066070] [PMID: 34987744]
[11]
Sizemore, J.; Guo, L.; Mirmehrabi, M.; Su, Y. Crystalline Forms of N-(4-(4-(Cyclopropylmethyl) Piperazine-1-Carbonyl)Phenyl)Quinoline-8-Sulfonamide. WO2019104134A1, 2019.
[12]
Matte, A.; Federti, E.; Kung, C.; Kosinski, P.A.; Narayanaswamy, R.; Russo, R.; Federico, G.; Carlomagno, F.; Desbats, M.A.; Salviati, L.; Leboeuf, C.; Valenti, M.T.; Turrini, F.; Janin, A.; Yu, S.; Beneduce, E.; Ronseaux, S.; Iatcenko, I.; Dang, L.; Ganz, T.; Jung, C.L.; Iolascon, A.; Brugnara, C.; De Franceschi, L. The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a β-thalassemia mouse model. J. Clin. Invest., 2021, 131(10), e144206.
[http://dx.doi.org/10.1172/JCI144206] [PMID: 33822774]
[13]
Idris, I.M.; Burnett, A.L.; DeBaun, M.R. Epidemiology and treatment of priapism in sickle cell disease. Hematology, 2022, 2022(1), 450-458.
[http://dx.doi.org/10.1182/hematology.2022000380] [PMID: 36485155]
[14]
Musallam, K.M.; Taher, A.T.; Cappellini, M.D. Right in time: Mitapivat for the treatment of anemia in α - and β-thalassemia. Cell Rep. Med., 2022, 3(10), 100790.
[http://dx.doi.org/10.1016/j.xcrm.2022.100790] [PMID: 36260990]
[15]
Xu, J.Z.; Conrey, A.; Frey, I.; Gwaabe, E.; Menapace, L.A.; Tumburu, L.; Lundt, M.; Lequang, T.; Li, Q.; Glass, K.; Dunkelberger, E.B.; Iyer, V.; Mangus, H.; Kung, C.; Dang, L.; Kosinski, P.A.; Hawkins, P.; Jeffries, N.; Eaton, W.A.; Lay Thein, S. A phase 1 dose escalation study of the pyruvate kinase activator mitapivat (AG-348) in sickle cell disease. Blood, 2022, 140(19), 2053-2062.
[http://dx.doi.org/10.1182/blood.2022015403] [PMID: 35576529]
[16]
van Dijk, M.J.; Rab, M.A.E.; van Oirschot, B.A.; Bos, J.; Derichs, C.; Rijneveld, A.W.; Cnossen, M.H.; Nur, E.; Biemond, B.J.; Bartels, M.; Jans, J.J.M.; van Solinge, W.W.; Schutgens, R.E.G.; van Wijk, R.; van Beers, E.J. Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in sickle cell disease: A phase 2, open-label study. Am. J. Hematol., 2022, 97(7), E226-E229.
[http://dx.doi.org/10.1002/ajh.26554] [PMID: 35384026]
[17]
Langer, A.L. Esrick, E.B. β-Thalassemia: Evolving treatment options beyond transfusion and iron chelation. Hematology, 2021, 2021(1), 600-606.
[http://dx.doi.org/10.1182/hematology.2021000313] [PMID: 34889443]

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