Right in time: Mitapivat for the treatment of anemia in α- and β-thalassemia

Abstract

Kuo and colleagues1Kuo 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 alpha-thalassaemia or beta-thalassaemia: an open-label, multicentre, phase 2 study.Lancet. 2022; 400: 493-501https://doi.org/10.1016/s0140-6736(22)01337-xAbstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar evaluated the safety and efficacy of mitapivat, an oral pyruvate kinase activator, in adults with non-transfusion-dependent α-thalassemia or β-thalassemia. The high rate of hemoglobin response and good tolerability encourages further development in thalassemia. Kuo and colleagues1Kuo 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 alpha-thalassaemia or beta-thalassaemia: an open-label, multicentre, phase 2 study.Lancet. 2022; 400: 493-501https://doi.org/10.1016/s0140-6736(22)01337-xAbstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar evaluated the safety and efficacy of mitapivat, an oral pyruvate kinase activator, in adults with non-transfusion-dependent α-thalassemia or β-thalassemia. The high rate of hemoglobin response and good tolerability encourages further development in thalassemia. Main textKuo and colleagues1Kuo 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 alpha-thalassaemia or beta-thalassaemia: an open-label, multicentre, phase 2 study.Lancet. 2022; 400: 493-501https://doi.org/10.1016/s0140-6736(22)01337-xAbstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar recently reported safety and efficacy data of mitapivat in adults with non-transfusion-dependent thalassemia (NTDT; α-thalassemia and β-thalassemia) from an open-label, multicenter, phase 2 study. The thalassemias are among the most common monogenetic diseases worldwide. They are recessively inherited disorders of hemoglobin production, classified into α- and β-thalassemia based on the affected globin gene. Most patients are found in the regional belt extending from the Mediterranean to South East Asia, although population migrations have introduced the disorder into large multiethnic cities in Northern Europe and the United States.2Taher A.T. Musallam K.M. Cappellini M.D. β-Thalassemias.N. Engl. J. Med. 2021; 384: 727-743https://doi.org/10.1056/nejmra2021838Crossref PubMed Scopus (0) Google Scholar The hallmark of disease is ineffective erythropoiesis leading to a chronic hemolytic anemia, with a severity largely dependent on the type of inherited mutations and secondary molecular modifiers. The degree of anemia, among other factors, determines the need for transfusion therapy. Today, patients are recognized as having NTDT and transfusion-dependent thalassemia (TDT), as the transfusion requirement reflects the underlying pathophysiology and overall management needs.2Taher A.T. Musallam K.M. Cappellini M.D. β-Thalassemias.N. Engl. J. Med. 2021; 384: 727-743https://doi.org/10.1056/nejmra2021838Crossref PubMed Scopus (0) Google ScholarPatients with NTDT usually present later in childhood (compared to those with TDT, which are commonly diagnosed by the age of 2 years) with mild-to-moderate anemia. Accordingly, care providers have historically kept these patients transfusion independent except in specific clinical scenarios like infection, pregnancy, or surgery when occasional transfusions are administered or in cases requiring more frequent transfusions to manage specific morbidities.3Taher A. Musallam K. Cappellini M.D. Guidelines for the Management of Non Transfusion Dependent Thalassaemia (NTDT).2nd ed. Thalassaemia International Federation, 2017Google Scholar This conservative approach to managing anemia in NTDT, however, is now being challenged with the expanding body of evidence linking low hemoglobin levels (<10 g/dL) to a high risk of serious morbidity and mortality in the long term, and the ability of increases by 1 g/dL to mitigate these risks.4Musallam K.M. Cappellini M.D. Daar S. Taher A.T. Morbidity-free survival and hemoglobin level in non-transfusion-dependent beta-thalassemia: A 10-year cohort study.Ann. Hematol. 2022; 101: 203-204https://doi.org/10.1007/s00277-020-04370-2Crossref PubMed Scopus (9) Google Scholar,5Musallam K.M. Vitrano A. Meloni A. Pollina S.A. Karimi M. El-Beshlawy A. Hajipour M. Di Marco V. Ansari S.H. Filosa A. et al.International Working Group on Thalassemia IWG-THALRisk of mortality from anemia and iron overload in nontransfusion-dependent beta-thalassemia.Am. J. Hematol. 2022; 97: E78-E80https://doi.org/10.1002/ajh.26428Crossref PubMed Scopus (3) Google Scholar Although transfusions remain an option, there is hesitancy to widely adopt such a strategy because of the associated clinical and economic burdens of regular transfusion requirements and secondary iron overload.6Taher A.T. Musallam K.M. Karimi M. El-Beshlawy A. Belhoul K. Daar S. Saned M.S. El-Chafic A.H. Fasulo M.R. Cappellini M.D. Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: The OPTIMAL CARE study.Blood. 2010; 115: 1886-1892https://doi.org/10.1182/blood-2009-09-243154Crossref PubMed Scopus (272) Google Scholar,7Musallam K.M. Vitrano A. Meloni A. Pollina W.A. Karimi M. El-Beshlawy A. Hajipour M. Di Marco V. Ansari S.H. Filosa A. et al.Survival and causes of death in 2, 033 patients with non-transfusion-dependent beta-thalassemia.Haematologica. 2021; 106: 2489-2492https://doi.org/10.3324/haematol.2021.278684Crossref PubMed Scopus (10) Google Scholar Thus, treating chronic anemia in individuals with NTDT remains a largely unmet medical need.Mitapivat (AG-348) is a first-in-class oral, small-molecule, allosteric activator of the red blood cell (RBC)-specific form of pyruvate kinase (PK-R), which has shown efficacy and safety and has received US approval for the treatment of anemia in adults with PK deficiency.8Grace R.F. Rose C. Layton D.M. Galacteros F. Barcellini W. Morton D.H. van Beers E.J. Yaish H. Ravindranath Y. Kuo K.H. et al.Safety and efficacy of mitapivat in pyruvate kinase deficiency.N. Engl. J. Med. 2019; 381: 933-944https://doi.org/10.1056/nejmoa1902678Crossref PubMed Scopus (0) Google Scholar In thalassemia mouse models, it reduced markers of ineffective erythropoiesis and improved anemia. In the featured phase 2 study,1Kuo 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 alpha-thalassaemia or beta-thalassaemia: an open-label, multicentre, phase 2 study.Lancet. 2022; 400: 493-501https://doi.org/10.1016/s0140-6736(22)01337-xAbstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar 20 adults with NTDT (median age 44 years, 50% identifying as Asian; 15 with β-thalassemia and 5 with α-thalassemia) and a hemoglobin level ≤ 10 g/dL were enrolled to evaluate mitapivat’s safety and efficacy in achieving a hemoglobin increase by ≥1.0 g/dL. Sixteen (80%) individuals had a response (5/5 in α-thalassemia and 11/15 in β-thalassemia). Favorable changes in markers of erythropoiesis and hemolysis were also noted. The most common treatment-emergent adverse events were initial insomnia (50%), dizziness (30%), and headache (25%).These data are met with high enthusiasm considering the current absence of therapeutic options for the management of anemia in NTDT. The high hemoglobin response rate and favorable changes in markers of ineffective erythropoiesis are reflective of the drug’s effect on the underlying pathophysiology. So, what is next for mitapivat? Two phase 3 double-blind, randomized, placebo-controlled, multicenter clinical trials are now underway in adults with NTDT (ENERGIZE, NCT04770753, n = 171) and TDT (ENERGIZE-T, NCT04770779, n = 240). The primary endpoint in ENERGIZE (NTDT) is hemoglobin response defined as a ≥1.0 g/dL increase in average hemoglobin concentration from week 12 through week 24 compared with baseline, while change in Functional Assessment of Chronic Illness Therapy (FACIT) – Fatigue Subscale will also be assessed. The latter is imperative considering the true benefits of anemia in reducing long-term morbidity and mortality in this patient population cannot be assessed in the context of clinical trials. Instead, the impact on short-term symptoms and patient-reported outcomes (PRO) can provide objective evidence of clinical benefit. Recently, the erythroid maturation agent luspatercept had its FDA application withdrawn in June 2022 for lack of agreement on benefit/risk.9Bristol Myers SquibbBristol Myers Squibb withdraws supplemental biologics license application (sBLA) for reblozyl (luspatercept-aamt) for non-transfusion dependent (NTD) beta thalassemia.https://investors.bms.com/iframes/press-releases/press-release-details/2022/Bristol-Myers-Squibb-Withdraws-Supplemental-Biologics-License-Application-sBLA-for-Reblozyl-luspatercept-aamt-for-Non-transfusion-Dependent-NTD-Beta-Thalassemia/default.aspxDate: 2022Google Scholar In the BEYOND trial, luspatercept has shown a hemoglobin response (≥1 g/dL increase) of 77% vs. 0% in placebo, but changes in a dedicated PRO tool for tiredness and weakness did not show statistical significance.10Taher A.T. Cappellini M.D. Kattamis A. Voskaridou E. Perrotta S. Piga A.G. Filosa A. Porter J.B. Coates T.D. Forni G.L. et al.BEYOND InvestigatorsLuspatercept for the treatment of anaemia in non-transfusion-dependent beta-thalassaemia (BEYOND): a phase 2, randomised, double-blind, multicentre, placebo-controlled trial.Lancet Haematol. 2022; https://doi.org/10.1016/S2352-3026(22)00208-3Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar This may reflect the importance regulators are placing on showing a short-term PRO benefit, despite the proposed long-term benefits from treating anemia as a medical condition. Alternately, evidence of improvement in other markers of ineffective erythropoiesis or organ function could be considered. The extension of clinical development of mitapivat to patients with TDT is supported by its role in ameliorating ineffective erythropoiesis, the common underlying mechanisms in both NTDT and TDT patients. The primary endpoint in the ENERGIZE-T (TDT) study will be a transfusion reduction response defined as ≥50% reduction in transfused units with a reduction of ≥2 units of transfused RBCs in any consecutive through week compared with in an and of development for with disease The of mitapivat is it is also being in patients with a not in therapeutic options but also in the when compared to β-thalassemia. as more to patients with it will be imperative to or trials other or with to the most treatment strategy for the patient This also need to be with to for these in care in the disease is Main textKuo and colleagues1Kuo 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 alpha-thalassaemia or beta-thalassaemia: an open-label, multicentre, phase 2 study.Lancet. 2022; 400: 493-501https://doi.org/10.1016/s0140-6736(22)01337-xAbstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar recently reported safety and efficacy data of mitapivat in adults with non-transfusion-dependent thalassemia (NTDT; α-thalassemia and β-thalassemia) from an open-label, multicenter, phase 2 study. The thalassemias are among the most common monogenetic diseases worldwide. They are recessively inherited disorders of hemoglobin production, classified into α- and β-thalassemia based on the affected globin gene. Most patients are found in the regional belt extending from the Mediterranean to South East Asia, although population migrations have introduced the disorder into large multiethnic cities in Northern Europe and the United States.2Taher A.T. Musallam K.M. Cappellini M.D. β-Thalassemias.N. Engl. J. Med. 2021; 384: 727-743https://doi.org/10.1056/nejmra2021838Crossref PubMed Scopus (0) Google Scholar The hallmark of disease is ineffective erythropoiesis leading to a chronic hemolytic anemia, with a severity largely dependent on the type of inherited mutations and secondary molecular modifiers. The degree of anemia, among other factors, determines the need for transfusion therapy. Today, patients are recognized as having NTDT and transfusion-dependent thalassemia (TDT), as the transfusion requirement reflects the underlying pathophysiology and overall management needs.2Taher A.T. Musallam K.M. Cappellini M.D. β-Thalassemias.N. Engl. J. Med. 2021; 384: 727-743https://doi.org/10.1056/nejmra2021838Crossref PubMed Scopus (0) Google ScholarPatients with NTDT usually present later in childhood (compared to those with TDT, which are commonly diagnosed by the age of 2 years) with mild-to-moderate anemia. Accordingly, care providers have historically kept these patients transfusion independent except in specific clinical scenarios like infection, pregnancy, or surgery when occasional transfusions are administered or in cases requiring more frequent transfusions to manage specific morbidities.3Taher A. Musallam K. Cappellini M.D. Guidelines for the Management of Non Transfusion Dependent Thalassaemia (NTDT).2nd ed. Thalassaemia International Federation, 2017Google Scholar This conservative approach to managing anemia in NTDT, however, is now being challenged with the expanding body of evidence linking low hemoglobin levels (<10 g/dL) to a high risk of serious morbidity and mortality in the long term, and the ability of increases by 1 g/dL to mitigate these risks.4Musallam K.M. Cappellini M.D. Daar S. Taher A.T. Morbidity-free survival and hemoglobin level in non-transfusion-dependent beta-thalassemia: A 10-year cohort study.Ann. Hematol. 2022; 101: 203-204https://doi.org/10.1007/s00277-020-04370-2Crossref PubMed Scopus (9) Google Scholar,5Musallam K.M. Vitrano A. Meloni A. Pollina S.A. Karimi M. El-Beshlawy A. Hajipour M. Di Marco V. Ansari S.H. Filosa A. et al.International Working Group on Thalassemia IWG-THALRisk of mortality from anemia and iron overload in nontransfusion-dependent beta-thalassemia.Am. J. Hematol. 2022; 97: E78-E80https://doi.org/10.1002/ajh.26428Crossref PubMed Scopus (3) Google Scholar Although transfusions remain an option, there is hesitancy to widely adopt such a strategy because of the associated clinical and economic burdens of regular transfusion requirements and secondary iron overload.6Taher A.T. Musallam K.M. Karimi M. El-Beshlawy A. Belhoul K. Daar S. Saned M.S. El-Chafic A.H. Fasulo M.R. Cappellini M.D. Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: The OPTIMAL CARE study.Blood. 2010; 115: 1886-1892https://doi.org/10.1182/blood-2009-09-243154Crossref PubMed Scopus (272) Google Scholar,7Musallam K.M. Vitrano A. Meloni A. Pollina W.A. Karimi M. El-Beshlawy A. Hajipour M. Di Marco V. Ansari S.H. Filosa A. et al.Survival and causes of death in 2, 033 patients with non-transfusion-dependent beta-thalassemia.Haematologica. 2021; 106: 2489-2492https://doi.org/10.3324/haematol.2021.278684Crossref PubMed Scopus (10) Google Scholar Thus, treating chronic anemia in individuals with NTDT remains a largely unmet medical need.Mitapivat (AG-348) is a first-in-class oral, small-molecule, allosteric activator of the red blood cell (RBC)-specific form of pyruvate kinase (PK-R), which has shown efficacy and safety and has received US approval for the treatment of anemia in adults with PK deficiency.8Grace R.F. Rose C. Layton D.M. Galacteros F. Barcellini W. Morton D.H. van Beers E.J. Yaish H. Ravindranath Y. Kuo K.H. et al.Safety and efficacy of mitapivat in pyruvate kinase deficiency.N. Engl. J. Med. 2019; 381: 933-944https://doi.org/10.1056/nejmoa1902678Crossref PubMed Scopus (0) Google Scholar In thalassemia mouse models, it reduced markers of ineffective erythropoiesis and improved anemia. In the featured phase 2 study,1Kuo 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 alpha-thalassaemia or beta-thalassaemia: an open-label, multicentre, phase 2 study.Lancet. 2022; 400: 493-501https://doi.org/10.1016/s0140-6736(22)01337-xAbstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar 20 adults with NTDT (median age 44 years, 50% identifying as Asian; 15 with β-thalassemia and 5 with α-thalassemia) and a hemoglobin level ≤ 10 g/dL were enrolled to evaluate mitapivat’s safety and efficacy in achieving a hemoglobin increase by ≥1.0 g/dL. Sixteen (80%) individuals had a response (5/5 in α-thalassemia and 11/15 in β-thalassemia). Favorable changes in markers of erythropoiesis and hemolysis were also noted. The most common treatment-emergent adverse events were initial insomnia (50%), dizziness (30%), and headache (25%).These data are met with high enthusiasm considering the current absence of therapeutic options for the management of anemia in NTDT. The high hemoglobin response rate and favorable changes in markers of ineffective erythropoiesis are reflective of the drug’s effect on the underlying pathophysiology. So, what is next for mitapivat? Two phase 3 double-blind, randomized, placebo-controlled, multicenter clinical trials are now underway in adults with NTDT (ENERGIZE, NCT04770753, n = 171) and TDT (ENERGIZE-T, NCT04770779, n = 240). The primary endpoint in ENERGIZE (NTDT) is hemoglobin response defined as a ≥1.0 g/dL increase in average hemoglobin concentration from week 12 through week 24 compared with baseline, while change in Functional Assessment of Chronic Illness Therapy (FACIT) – Fatigue Subscale will also be assessed. The latter is imperative considering the true benefits of anemia in reducing long-term morbidity and mortality in this patient population cannot be assessed in the context of clinical trials. Instead, the impact on short-term symptoms and patient-reported outcomes (PRO) can provide objective evidence of clinical benefit. Recently, the erythroid maturation agent luspatercept had its FDA application withdrawn in June 2022 for lack of agreement on benefit/risk.9Bristol Myers SquibbBristol Myers Squibb withdraws supplemental biologics license application (sBLA) for reblozyl (luspatercept-aamt) for non-transfusion dependent (NTD) beta thalassemia.https://investors.bms.com/iframes/press-releases/press-release-details/2022/Bristol-Myers-Squibb-Withdraws-Supplemental-Biologics-License-Application-sBLA-for-Reblozyl-luspatercept-aamt-for-Non-transfusion-Dependent-NTD-Beta-Thalassemia/default.aspxDate: 2022Google Scholar In the BEYOND trial, luspatercept has shown a hemoglobin response (≥1 g/dL increase) of 77% vs. 0% in placebo, but changes in a dedicated PRO tool for tiredness and weakness did not show statistical significance.10Taher A.T. Cappellini M.D. Kattamis A. Voskaridou E. Perrotta S. Piga A.G. Filosa A. Porter J.B. Coates T.D. Forni G.L. et al.BEYOND InvestigatorsLuspatercept for the treatment of anaemia in non-transfusion-dependent beta-thalassaemia (BEYOND): a phase 2, randomised, double-blind, multicentre, placebo-controlled trial.Lancet Haematol. 2022; https://doi.org/10.1016/S2352-3026(22)00208-3Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar This may reflect the importance regulators are placing on showing a short-term PRO benefit, despite the proposed long-term benefits from treating anemia as a medical condition. Alternately, evidence of improvement in other markers of ineffective erythropoiesis or organ function could be considered. The extension of clinical development of mitapivat to patients with TDT is supported by its role in ameliorating ineffective erythropoiesis, the common underlying mechanisms in both NTDT and TDT patients. The primary endpoint in the ENERGIZE-T (TDT) study will be a transfusion reduction response defined as ≥50% reduction in transfused units with a reduction of ≥2 units of transfused RBCs in any consecutive through week compared with in an and of development for with disease The of mitapivat is it is also being in patients with a not in therapeutic options but also in the when compared to β-thalassemia. as more to patients with it will be imperative to or trials other or with to the most treatment strategy for the patient This also need to be with to for these in care in the disease is Kuo and colleagues1Kuo 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 alpha-thalassaemia or beta-thalassaemia: an open-label, multicentre, phase 2 study.Lancet. 2022; 400: 493-501https://doi.org/10.1016/s0140-6736(22)01337-xAbstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar recently reported safety and efficacy data of mitapivat in adults with non-transfusion-dependent thalassemia (NTDT; α-thalassemia and β-thalassemia) from an open-label, multicenter, phase 2 study. The thalassemias are among the most common monogenetic diseases worldwide. They are recessively inherited disorders of hemoglobin production, classified into α- and β-thalassemia based on the affected globin gene. Most patients are found in the regional belt extending from the Mediterranean to South East Asia, although population migrations have introduced the disorder into large multiethnic cities in Northern Europe and the United States.2Taher A.T. Musallam K.M. Cappellini M.D. β-Thalassemias.N. Engl. J. Med. 2021; 384: 727-743https://doi.org/10.1056/nejmra2021838Crossref PubMed Scopus (0) Google Scholar The hallmark of disease is ineffective erythropoiesis leading to a chronic hemolytic anemia, with a severity largely dependent on the type of inherited mutations and secondary molecular modifiers. The degree of anemia, among other factors, determines the need for transfusion therapy. Today, patients are recognized as having NTDT and transfusion-dependent thalassemia (TDT), as the transfusion requirement reflects the underlying pathophysiology and overall management needs.2Taher A.T. Musallam K.M. Cappellini M.D. β-Thalassemias.N. Engl. J. Med. 2021; 384: 727-743https://doi.org/10.1056/nejmra2021838Crossref PubMed Scopus (0) Google Scholar with NTDT usually present later in childhood (compared to those with TDT, which are commonly diagnosed by the age of 2 years) with mild-to-moderate anemia. Accordingly, care providers have historically kept these patients transfusion independent except in specific clinical scenarios like infection, pregnancy, or surgery when occasional transfusions are administered or in cases requiring more frequent transfusions to manage specific morbidities.3Taher A. Musallam K. Cappellini M.D. Guidelines for the Management of Non Transfusion Dependent Thalassaemia (NTDT).2nd ed. Thalassaemia International Federation, 2017Google Scholar This conservative approach to managing anemia in NTDT, however, is now being challenged with the expanding body of evidence linking low hemoglobin levels (<10 g/dL) to a high risk of serious morbidity and mortality in the long term, and the ability of increases by 1 g/dL to mitigate these risks.4Musallam K.M. Cappellini M.D. Daar S. Taher A.T. Morbidity-free survival and hemoglobin level in non-transfusion-dependent beta-thalassemia: A 10-year cohort study.Ann. Hematol. 2022; 101: 203-204https://doi.org/10.1007/s00277-020-04370-2Crossref PubMed Scopus (9) Google Scholar,5Musallam K.M. Vitrano A. Meloni A. Pollina S.A. Karimi M. El-Beshlawy A. Hajipour M. Di Marco V. Ansari S.H. Filosa A. et al.International Working Group on Thalassemia IWG-THALRisk of mortality from anemia and iron overload in nontransfusion-dependent beta-thalassemia.Am. J. Hematol. 2022; 97: E78-E80https://doi.org/10.1002/ajh.26428Crossref PubMed Scopus (3) Google Scholar Although transfusions remain an option, there is hesitancy to widely adopt such a strategy because of the associated clinical and economic burdens of regular transfusion requirements and secondary iron overload.6Taher A.T. Musallam K.M. Karimi M. El-Beshlawy A. Belhoul K. Daar S. Saned M.S. El-Chafic A.H. Fasulo M.R. Cappellini M.D. Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: The OPTIMAL CARE study.Blood. 2010; 115: 1886-1892https://doi.org/10.1182/blood-2009-09-243154Crossref PubMed Scopus (272) Google Scholar,7Musallam K.M. Vitrano A. Meloni A. Pollina W.A. Karimi M. El-Beshlawy A. Hajipour M. Di Marco V. Ansari S.H. Filosa A. et al.Survival and causes of death in 2, 033 patients with non-transfusion-dependent beta-thalassemia.Haematologica. 2021; 106: 2489-2492https://doi.org/10.3324/haematol.2021.278684Crossref PubMed Scopus (10) Google Scholar Thus, treating chronic anemia in individuals with NTDT remains a largely unmet medical (AG-348) is a first-in-class oral, small-molecule, allosteric activator of the red blood cell (RBC)-specific form of pyruvate kinase (PK-R), which has shown efficacy and safety and has received US approval for the treatment of anemia in adults with PK deficiency.8Grace R.F. Rose C. Layton D.M. Galacteros F. Barcellini W. Morton D.H. van Beers E.J. Yaish H. Ravindranath Y. Kuo K.H. et al.Safety and efficacy of mitapivat in pyruvate kinase deficiency.N. Engl. J. Med. 2019; 381: 933-944https://doi.org/10.1056/nejmoa1902678Crossref PubMed Scopus (0) Google Scholar In thalassemia mouse models, it reduced markers of ineffective erythropoiesis and improved anemia. In the featured phase 2 study,1Kuo 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 alpha-thalassaemia or beta-thalassaemia: an open-label, multicentre, phase 2 study.Lancet. 2022; 400: 493-501https://doi.org/10.1016/s0140-6736(22)01337-xAbstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar 20 adults with NTDT (median age 44 years, 50% identifying as Asian; 15 with β-thalassemia and 5 with α-thalassemia) and a hemoglobin level ≤ 10 g/dL were enrolled to evaluate mitapivat’s safety and efficacy in achieving a hemoglobin increase by ≥1.0 g/dL. Sixteen (80%) individuals had a response (5/5 in α-thalassemia and 11/15 in β-thalassemia). Favorable changes in markers of erythropoiesis and hemolysis were also noted. The most common treatment-emergent adverse events were initial insomnia (50%), dizziness (30%), and headache data are met with high enthusiasm considering the current absence of therapeutic options for the management of anemia in NTDT. The high hemoglobin response rate and favorable changes in markers of ineffective erythropoiesis are reflective of the drug’s effect on the underlying pathophysiology. So, what is next for mitapivat? Two phase 3 double-blind, randomized, placebo-controlled, multicenter clinical trials are now underway in adults with NTDT (ENERGIZE, NCT04770753, n = 171) and TDT (ENERGIZE-T, NCT04770779, n = 240). The primary endpoint in ENERGIZE (NTDT) is hemoglobin response defined as a ≥1.0 g/dL increase in average hemoglobin concentration from week 12 through week 24 compared with baseline, while change in Functional Assessment of Chronic Illness Therapy (FACIT) – Fatigue Subscale will also be assessed. The latter is imperative considering the true benefits of anemia in reducing long-term morbidity and mortality in this patient population cannot be assessed in the context of clinical trials. Instead, the impact on short-term symptoms and patient-reported outcomes (PRO) can provide objective evidence of clinical benefit. Recently, the erythroid maturation agent luspatercept had its FDA application withdrawn in June 2022 for lack of agreement on benefit/risk.9Bristol Myers SquibbBristol Myers Squibb withdraws supplemental biologics license application (sBLA) for reblozyl (luspatercept-aamt) for non-transfusion dependent (NTD) beta thalassemia.https://investors.bms.com/iframes/press-releases/press-release-details/2022/Bristol-Myers-Squibb-Withdraws-Supplemental-Biologics-License-Application-sBLA-for-Reblozyl-luspatercept-aamt-for-Non-transfusion-Dependent-NTD-Beta-Thalassemia/default.aspxDate: 2022Google Scholar In the BEYOND trial, luspatercept has shown a hemoglobin response (≥1 g/dL increase) of 77% vs. 0% in placebo, but changes in a dedicated PRO tool for tiredness and weakness did not show statistical significance.10Taher A.T. Cappellini M.D. Kattamis A. Voskaridou E. Perrotta S. Piga A.G. Filosa A. Porter J.B. Coates T.D. Forni G.L. et al.BEYOND InvestigatorsLuspatercept for the treatment of anaemia in non-transfusion-dependent beta-thalassaemia (BEYOND): a phase 2, randomised, double-blind, multicentre, placebo-controlled trial.Lancet Haematol. 2022; https://doi.org/10.1016/S2352-3026(22)00208-3Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar This may reflect the importance regulators are placing on showing a short-term PRO benefit, despite the proposed long-term benefits from treating anemia as a medical condition. Alternately, evidence of improvement in other markers of ineffective erythropoiesis or organ function could be considered. The extension of clinical development of mitapivat to patients with TDT is supported by its role in ameliorating ineffective erythropoiesis, the common underlying mechanisms in both NTDT and TDT patients. The primary endpoint in the ENERGIZE-T (TDT) study will be a transfusion reduction response defined as ≥50% reduction in transfused units with a reduction of ≥2 units of transfused RBCs in any consecutive through week compared with in an and of development for with disease The of mitapivat is it is also being in patients with a not in therapeutic options but also in the when compared to β-thalassemia. as more to patients with it will be imperative to or trials other or with to the most treatment strategy for the patient This also need to be with to for these in care in the disease is from Myers and from Myers and and from Myers and from Myers and and from Myers and

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