{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T10:31:08Z","timestamp":1792751468508,"version":"4.5.0"},"reference-count":45,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,12,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Hemoglobin S (HbS) polymerization, red blood cell (RBC) sickling, chronic anemia, and vaso-occlusion are core to sickle cell disease (SCD) pathophysiology. Pyruvate kinase (PK) activators are a novel class of drugs that target RBC metabolism by reducing the buildup of the glycolytic intermediate 2,3-diphosphoglycerate (2,3-DPG) and increasing production of adenosine triphosphate (ATP). Lower 2,3-DPG level is associated with an increase in oxygen affinity and reduction in HbS polymerization, while increased RBC ATP may improve RBC membrane integrity and survival. There are currently 3 PK activators in clinical development for SCD: mitapivat (AG-348), etavopivat (FT-4202), and the second-generation molecule AG-946. Preclinical and clinical data from these 3 molecules demonstrate the ability of PK activators to lower 2,3-DPG levels and increase ATP levels in animal models and patients with SCD, as well as influence a number of potential pathways in SCD, including hemoglobin oxygen affinity, RBC sickling, RBC deformability, RBC hydration, inflammation, oxidative stress, hypercoagulability, and adhesion. Furthermore, early-phase clinical trials of mitapivat and etavopivat have demonstrated the safety and tolerability of PK activators in patients with SCD, and phase 2\/3 trials for both drugs are ongoing. Additional considerations for this novel therapeutic approach include the balance between increasing hemoglobin oxygen affinity and tissue oxygen delivery, the cost and accessibility of these drugs, and the potential of multimodal therapy with existing and novel therapies targeting different disease mechanisms in SCD.<\/jats:p>","DOI":"10.1182\/hematology.2023000467","type":"journal-article","created":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T15:05:28Z","timestamp":1702047928000},"page":"107-113","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":17,"title":["Pyruvate kinase activators: targeting red cell metabolism in sickle cell disease"],"prefix":"10.1182","volume":"2023","author":[{"given":"Julia Z.","family":"Xu","sequence":"first","affiliation":[{"name":"1 Division of Hematology\/Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA"},{"name":"2 Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory M.","family":"Vercellotti","sequence":"additional","affiliation":[{"name":"3 Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2023,12,8]]},"reference":[{"issue":"20","key":"2023120815052208300_hem2023000467C1","doi-asserted-by":"crossref","first-page":"3030","DOI":"10.1182\/blood.2021013873","article-title":"Revisiting anemia in sickle cell disease and finding the balance with therapeutic approaches","volume":"139","author":"Xu","year":"2022","journal-title":"Blood"},{"issue":"2","key":"2023120815052208300_hem2023000467C2","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1002\/pbc.22892","article-title":"Neurocognitive deficits in children with sickle cell disease are associated with the severity of anemia","volume":"57","author":"Hijmans","year":"2011","journal-title":"Pediatr Blood Cancer"},{"issue":"4","key":"2023120815052208300_hem2023000467C3","doi-asserted-by":"crossref","first-page":"e0229959","DOI":"10.1371\/journal.pone.0229959","article-title":"Low hemoglobin increases risk for cerebrovascular disease, kidney disease, pulmonary vasculopathy, and mortality in sickle cell disease: a systematic literature review and meta-analysis","volume":"15","author":"Ataga","year":"2020","journal-title":"PLoS One"},{"issue":"6, suppl 4","key":"2023120815052208300_hem2023000467C4","doi-asserted-by":"crossref","first-page":"S390","DOI":"10.1016\/j.amepre.2011.09.006","article-title":"Disability among individuals with sickle cell disease: literature review from a public health perspective","volume":"41","author":"Swanson","year":"2011","journal-title":"Am J Prev Med"},{"issue":"8","key":"2023120815052208300_hem2023000467C5","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1097\/MPH.0000000000000431","article-title":"Fatigue in children with sickle cell disease: association with neurocognitive and social-emotional functioning and quality of life","volume":"37","author":"Anderson","year":"2015","journal-title":"J Pediatr Hematol Oncol"},{"issue":"9369","key":"2023120815052208300_hem2023000467C6","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1016\/S0140-6736(03)13293-X","article-title":"Blood transfusion in sickle cell disease: a cautionary tale","volume":"361","author":"Serjeant","year":"2003","journal-title":"Lancet"},{"issue":"6","key":"2023120815052208300_hem2023000467C7","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1016\/S0022-3476(05)81954-7","article-title":"Neurologic events after partial exchange transfusion for priapism in sickle cell disease","volume":"120","author":"Rackoff","year":"1992","journal-title":"J Pediatr"},{"issue":"8101","key":"2023120815052208300_hem2023000467C8","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1016\/S0140-6736(78)92193-1","article-title":"Hypertension, convulsions, and cerebral haemorrhage in sickle-cell anaemia patients after blood-transfusions","volume":"2","author":"Royal","year":"1978","journal-title":"Lancet"},{"issue":"7","key":"2023120815052208300_hem2023000467C9","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1001\/archinte.1987.00370070045007","article-title":"The painful crisis of homozygous sickle cell disease. A study of the risk factors","volume":"147","author":"Baum","year":"1987","journal-title":"Arch Intern Med"},{"issue":"1","key":"2023120815052208300_hem2023000467C10","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1056\/NEJM199107043250103","article-title":"Pain in sickle cell disease. Rates and risk factors","volume":"325","author":"Platt","year":"1991","journal-title":"N Engl J Med"},{"issue":"1","key":"2023120815052208300_hem2023000467C11","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1111\/j.1365-2141.2010.08520.x","article-title":"Improvements in haemolysis and indicators of erythrocyte survival do not correlate with acute vaso-occlusive crises in patients with sickle cell disease: a phase III randomized, placebo-controlled, double-blind study of the Gardos channel blocker senicapoc (ICA-17043)","volume":"153","author":"Ataga","year":"2011","journal-title":"Br J Haematol"},{"issue":"6","key":"2023120815052208300_hem2023000467C12","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1056\/NEJM199008093230602","article-title":"Treatment of sickle cell anemia with hydroxyurea and erythropoietin","volume":"323","author":"Goldberg","year":"1990","journal-title":"N Engl J Med"},{"issue":"8","key":"2023120815052208300_hem2023000467C13","first-page":"1076","article-title":"Combination erythropoietin-hydroxyurea therapy in sickle cell disease: experience from the National Institutes of Health and a literature review","volume":"91","author":"Little","year":"2006","journal-title":"Haematologica"},{"key":"2023120815052208300_hem2023000467C14","doi-asserted-by":"crossref","unstructured":"Nagel\n              RL\n            , VichinskyE, ShahM, et al.\n          F reticulocyte response in sickle cell anemia treated with recombinant human erythropoietin: a double-blind study. Blood. 1993;81(1):9-14. https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/8417806.","DOI":"10.1182\/blood.V81.1.9.bloodjournal8119"},{"issue":"2","key":"2023120815052208300_hem2023000467C15","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1056\/NEJM199301143280201","article-title":"Augmentation by erythropoietin of the fetal-hemoglobin response to hydroxyurea in sickle cell disease","volume":"328","author":"Rodgers","year":"1993","journal-title":"N Engl J Med"},{"issue":"6","key":"2023120815052208300_hem2023000467C16","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1056\/NEJMoa1903212","article-title":"A phase 3 randomized trial of voxelotor in sickle cell disease","volume":"381","author":"Vichinsky","year":"2019","journal-title":"N Engl J Med"},{"key":"2023120815052208300_hem2023000467C17","first-page":"451","article-title":"Pathobiology of the human erythrocyte and its hemoglobins","volume-title":"Hematology: Basic Principles and Practice","author":"Steinberg","year":"2023","edition":"8th"},{"issue":"5","key":"2023120815052208300_hem2023000467C18","doi-asserted-by":"crossref","first-page":"E117","DOI":"10.1002\/ajh.25419","article-title":"Erythrocyte ATP, a possible therapeutic approach for sickle cell disease","volume":"94","author":"Hoffman","year":"2019","journal-title":"Am J Hematol"},{"issue":"9","key":"2023120815052208300_hem2023000467C19","doi-asserted-by":"crossref","first-page":"2229","DOI":"10.3324\/haematol.2019.240846","article-title":"The variable manifestations of disease in pyruvate kinase deficiency and their management","volume":"105","author":"Al-Samkari","year":"2020","journal-title":"Haematologica"},{"issue":"4","key":"2023120815052208300_hem2023000467C20","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1172\/JCI106294","article-title":"Effect of 2,3-diphosphoglycerate on oxygen affinity of blood in sickle cell anemia","volume":"49","author":"Charache","year":"1970","journal-title":"J Clin Invest"},{"key":"2023120815052208300_hem2023000467C21","doi-asserted-by":"crossref","unstructured":"Jensen\n              M\n            , ShohetSB, NathanDG. The role of red cell energy metabolism in the generation of irreversibly sickled cells in vitro. Blood. 1973;42(6):835-842. https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/4202454.","DOI":"10.1182\/blood.V42.6.835.835"},{"issue":"21","key":"2023120815052208300_hem2023000467C22","doi-asserted-by":"crossref","first-page":"2997","DOI":"10.1182\/blood.2020008635","article-title":"Decreased activity and stability of pyruvate kinase in sickle cell disease: a novel target for mitapivat therapy","volume":"137","author":"Rab","year":"2021","journal-title":"Blood"},{"issue":"6","key":"2023120815052208300_hem2023000467C23","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1179\/102453308X343536","article-title":"Sickle cell disease in a carrier with pyruvate kinase deficiency","volume":"13","author":"Alli","year":"2008","journal-title":"Hematology"},{"key":"2023120815052208300_hem2023000467C24","doi-asserted-by":"crossref","unstructured":"Cohen-Solal\n              M\n            , PrehuC, WajcmanH, et al.\n          A new sickle cell disease phenotype associating Hb S trait, severe pyruvate kinase deficiency (PK Conakry), and an alpha2 globin gene variant (Hb Conakry). Br J Haematol. 1998;103(4):950-956. https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/9886305.","DOI":"10.1046\/j.1365-2141.1998.01094.x"},{"issue":"11","key":"2023120815052208300_hem2023000467C25","doi-asserted-by":"crossref","first-page":"3535","DOI":"10.1182\/bloodadvances.2021006668","article-title":"Genetic variants of PKLR are associated with acute pain in sickle cell disease","volume":"6","author":"Wang","year":"2022","journal-title":"Blood Adv"},{"key":"2023120815052208300_hem2023000467C26","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.semcdb.2015.08.004","article-title":"Pyruvate kinase: function, regulation and role in cancer","volume":"43","author":"Israelsen","year":"2015","journal-title":"Semin Cell Dev Biol"},{"issue":"15","key":"2023120815052208300_hem2023000467C27","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1056\/NEJMoa2116634","article-title":"Mitapivat versus placebo for pyruvate kinase deficiency","volume":"386","author":"Al-Samkari","year":"2022","journal-title":"N Engl J Med"},{"key":"2023120815052208300_hem2023000467C28","doi-asserted-by":"crossref","first-page":"102660","DOI":"10.1016\/j.bcmd.2022.102660","article-title":"Mitapivat increases ATP and decreases oxidative stress and erythrocyte mitochondria retention in a SCD mouse model","volume":"95","author":"Quezado","year":"2022","journal-title":"Blood Cells Mol Dis"},{"issue":"19","key":"2023120815052208300_hem2023000467C29","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.1182\/blood.2022015403","article-title":"A phase 1 dose escalation study of the pyruvate kinase activator mitapivat (AG-348) in sickle cell disease","volume":"140","author":"Xu","year":"2022","journal-title":"Blood"},{"issue":"7","key":"2023120815052208300_hem2023000467C30","doi-asserted-by":"crossref","first-page":"E226","DOI":"10.1002\/ajh.26554","article-title":"Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in sickle cell disease: a phase 2, open-label study","volume":"97","author":"van Dijk","year":"2022","journal-title":"Am J Hematol"},{"issue":"suppl 3","key":"2023120815052208300_hem2023000467C31","first-page":"9","article-title":"One-year follow-up of a phase 2 study of mitapivat, an oral pyruvate kinase activator, for the treatment of sickle cell disease","volume":"7","author":"Van Dijk","year":"2023","journal-title":"HemaSphere"},{"issue":"9","key":"2023120815052208300_hem2023000467C32","doi-asserted-by":"crossref","first-page":"2385","DOI":"10.1182\/bloodadvances.2020003604","article-title":"FT-4202, an oral PKR activator, has potent antisickling effects and improves RBC survival and Hb levels in SCA mice","volume":"5","author":"Shrestha","year":"2021","journal-title":"Blood Adv"},{"issue":"3","key":"2023120815052208300_hem2023000467C33","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1124\/jpet.121.000743","article-title":"Etavopivat, a pyruvate kinase activator in red blood cells, for the treatment of sickle cell disease","volume":"380","author":"Schroeder","year":"2022","journal-title":"J Pharmacol Exp Ther"},{"issue":"suppl","key":"2023120815052208300_hem2023000467C34","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1097\/01.HS9.0000848836.01685.87","article-title":"Etavopivat treatment for up to 12 weeks in patients with sickle cell disease was well tolerated and improved red blood cell health","volume":"6","author":"Saraf","year":"2022","journal-title":"HemaSphere"},{"issue":"suppl 1","key":"2023120815052208300_hem2023000467C35","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1182\/blood-2021-147078","article-title":"Etavopivat, an allosteric activator of pyruvate kinase-R, improves sickle RBC functional health and survival and reduces systemic markers of inflammation and hypercoagulability in patients with sickle cell disease: an analysis of exploratory studies in a phase 1 study","volume":"138","author":"Kalfa","year":"2021","journal-title":"Blood"},{"issue":"suppl 1","key":"2023120815052208300_hem2023000467C36","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1182\/blood-2021-147091","article-title":"Activation of pyruvate kinase-R with etavopivat (FT-4202) is well tolerated, improves anemia, and decreases intravascular hemolysis in patients with sickle cell disease treated for up to 12 weeks","volume":"138","author":"Brown","year":"2021","journal-title":"Blood"},{"issue":"suppl 1","key":"2023120815052208300_hem2023000467C37","doi-asserted-by":"crossref","first-page":"5426","DOI":"10.1182\/blood-2022-157719","article-title":"Results from the single and multiple ascending dose study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of AG-946 in healthy volunteers","volume":"140","author":"Gurov","year":"2022","journal-title":"Blood"},{"issue":"suppl 1","key":"2023120815052208300_hem2023000467C38","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1182\/blood-2022-156591","article-title":"AG-946 normalizes glycolysis and improves red cell indices in a humanized sickle cell mouse model","volume":"140","author":"Jamwal","year":"2022","journal-title":"Blood"},{"issue":"suppl 1","key":"2023120815052208300_hem2023000467C39","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.1182\/blood-2021-145374","article-title":"Pharmacodynamic effects of AG-946, a highly potent novel activator of pyruvate kinase, in ex vivo treatment of red blood cells from sickle cell disease patients","volume":"138","author":"Rab","year":"2021","journal-title":"Blood"},{"issue":"25","key":"2023120815052208300_hem2023000467C40","doi-asserted-by":"crossref","first-page":"2362","DOI":"10.1056\/NEJMra2212266","article-title":"Oxygen delivery in the treatment of anemia","volume":"387","author":"Bunn","year":"2022","journal-title":"N Engl J Med"},{"issue":"3","key":"2023120815052208300_hem2023000467C41","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1002\/ajh.24975","article-title":"Sickle hemoglobin oxygen affinity-shifting strategies have unequal cerebrovascular risks","volume":"93","author":"Hebbel","year":"2018","journal-title":"Am J Hematol"},{"issue":"suppl 1","key":"2023120815052208300_hem2023000467C42","doi-asserted-by":"crossref","first-page":"8296","DOI":"10.1182\/blood-2022-169025","article-title":"Cerebral metabolic stress improves after voxelotor treatment in pediatric sickle cell disease","volume":"140","author":"Brothers","year":"2022","journal-title":"Blood"},{"issue":"suppl 1","key":"2023120815052208300_hem2023000467C43","doi-asserted-by":"crossref","first-page":"2535","DOI":"10.1182\/blood-2022-168997","article-title":"Effect of voxelotor on cerebral perfusion and cerebral oxygen metabolism in adult patients with sickle cell disease; preliminary results of the coverage study","volume":"140","author":"Kont\u00e9","year":"2022","journal-title":"Blood"},{"issue":"10","key":"2023120815052208300_hem2023000467C44","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1056\/NEJMoa1902678","article-title":"Safety and efficacy of mitapivat in pyruvate kinase deficiency","volume":"381","author":"Grace","year":"2019","journal-title":"N Engl J Med"},{"issue":"2","key":"2023120815052208300_hem2023000467C45","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1038\/s41573-018-0003-2","article-title":"Therapeutic strategies for sickle cell disease: towards a multi-agent approach","volume":"18","author":"Telen","year":"2019","journal-title":"Nat Rev Drug Discov"}],"container-title":["Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/hematology\/article-pdf\/2023\/1\/107\/2175677\/107xu.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/hematology\/article-pdf\/2023\/1\/107\/2175677\/107xu.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T15:05:50Z","timestamp":1702047950000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/hematology\/article\/2023\/1\/107\/506439\/Pyruvate-kinase-activators-targeting-red-cell"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,8]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12,8]]},"published-print":{"date-parts":[[2023,12,8]]}},"URL":"https:\/\/doi.org\/10.1182\/hematology.2023000467","relation":{},"ISSN":["1520-4391","1520-4383"],"issn-type":[{"value":"1520-4391","type":"print"},{"value":"1520-4383","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,12,8]]},"published":{"date-parts":[[2023,12,8]]}}}