Advertisement
Review Article| Volume 37, ISSUE 2, P449-462, April 2023

Emerging Therapies in β-Thalassemia

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribers receive full online access to your subscription and archive of back issues up to and including 2002.

      Content published before 2002 is available via pay-per-view purchase only.

      Subscribe:

      Subscribe to Hematology/Oncology Clinics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Bou-Fakhredin R.
        • Motta I.
        • Cappellini M.D.
        Advancing the care of beta-thalassaemia patients with novel therapies.
        Blood Transfus. 2022; 20: 78-88
        • Musallam K.M.
        • Bou-Fakhredin R.
        • Cappellini M.D.
        • et al.
        2021 update on clinical trials in beta-thalassemia.
        Am J Hematol. 2021; 96: 1518-1531
        • Bou-Fakhredin R.
        • Tabbikha R.
        • Daadaa H.
        • et al.
        Emerging therapies in beta-thalassemia: toward a new era in management.
        Expert Opin Emerg Drugs. 2020; 25: 113-122
        • Motta I.
        • Bou-Fakhredin R.
        • Taher A.T.
        • et al.
        beta thalassemia: new therapeutic options beyond transfusion and iron chelation.
        Drugs. 2020; 80: 1053-1063
        • Bou-Fakhredin R.
        • De Franceschi L.
        • Motta I.
        • et al.
        Pharmacological Induction of Fetal Hemoglobin in beta-Thalassemia and Sickle Cell Disease: An Updated Perspective.
        Pharmaceuticals (Basel). 2022; 15: 753
        • McArthur J.G.
        • Svenstrup N.
        • Chen C.
        • et al.
        A novel, highly potent and selective phosphodiesterase-9 inhibitor for the treatment of sickle cell disease.
        Haematologica. 2020; 105: 623-631
      1. Imara announces results of interim analyses of Tovinontrine (IMR-687) Phase 2B clinical trials in Sickle Cell Disease and Beta-Thalassemia. Press Release.
        (Available at:) (Accessed October 1, 2022)
        • Cappellini M.D.
        • Porter J.
        • Origa R.
        • et al.
        Sotatercept, a novel transforming growth factor beta ligand trap, improves anemia in beta-thalassemia: a phase II, open-label, dose-finding study.
        Haematologica. 2019; 104: 477-484
        • Cappellini M.D.
        • Taher A.T.
        The use of luspatercept for thalassemia in adults.
        Blood Adv. 2021; 5: 326-333
        • Taher A.T.
        • Cappellini M.D.
        Luspatercept for beta-thalassemia: beyond red blood cell transfusions.
        Expert Opin Biol Ther. 2021; 21: 1363-1371
        • Suragani R.N.
        • Cadena S.M.
        • Cawley S.M.
        • et al.
        Transforming growth factor-beta superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis.
        Nat Med. 2014; 20: 408-414
        • Suragani R.N.
        • Cawley S.M.
        • Li R.
        • et al.
        Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine β-thalassemia.
        Blood. 2014; 123: 3864-3872
        • Martinez P.A.
        • Li R.
        • Ramanathan H.N.
        • et al.
        Smad2/3-pathway ligand trap luspatercept enhances erythroid differentiation in murine beta-thalassaemia by increasing GATA-1 availability.
        J Cell Mol Med. 2020; 24: 6162-6177
        • Piga A.
        • Perrotta S.
        • Gamberini M.R.
        • et al.
        Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with β-thalassemia.
        Blood. 2019; 133: 1279-1289
        • Cappellini M.D.
        • Viprakasit V.
        • Taher A.T.
        • et al.
        A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent beta-Thalassemia.
        N Engl J Med. 2020; 382: 1219-1231
        • Cappellini M.D.
        • Taher A.T.
        • Piga A.
        • et al.
        Health-Related Quality of Life Outcomes for Patients with Transfusion-Dependent Beta-Thalassemia Treated with Luspatercept in the Believe Trial [abstract].
        Blood. 2020; 136: 8-9
        • Taher A.T.
        • Viprakasit V.
        • Hermine O.
        • et al.
        Sustained Reductions in Red Blood Cell (RBC) Transfusion Burden and Events in β-Thalassemia with Luspatercept: Longitudinal Results of the Believe Trial [abstract].
        Blood. 2020; 136: 45-46
        • Hermine O.
        • Cappellini M.D.
        • Taher A.T.
        • et al.
        Longitudinal effect of luspatercept treatment on iron overload and iron chelation therapy (ICT) in adult patients (pts) with β-thalassemia in the BELIEVE trial [abstract].
        Blood. 2020; 136: 47-48
        • REBLOZYL F.D.A.
        label. Silver Spring, MD: FDA.
        (Available at:) (Accessed October 1, 2022)
        • European Medicines Agency (EMA)
        Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 28-30 April 2020. Amsterdam: EMA.
        (Available at:) (Accessed October 1, 2022)
        • Cappellini M.D.
        • Taher A.T.
        • Porter J.B.
        • et al.
        S270: Longer-term analysis of efficacy of luspatercept versus placebo in patients with transfusion-dependent beta-thalassemia enrolled in the BELIEVE study.
        HemaSphere. 2022; 6: 171-172
        • Viprakasit V.
        • Cappellini M.D.
        • Porter J.B.
        • et al.
        P1518: Long-term safety results of the BELIEVE study of Luspatercept in adults with Beta-Thalassemia.
        HemaSphere. 2022; 6: 1399-1400
        • Taher A.T.
        • Cappellini M.D.
        • Kattamis A.
        • et al.
        Luspatercept 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; 9: e733-e744
        • Yang H.
        • Merica E.
        • Chen Y.
        • et al.
        Phase 1 Single- and Multiple-Ascending-Dose Randomized Studies of the Safety, Pharmacokinetics, and Pharmacodynamics of AG-348, a First-in-Class Allosteric Activator of Pyruvate Kinase R, in Healthy Volunteers.
        Clin Pharmacol Drug Dev. 2019; 8: 246-259
        • Grace R.F.
        • Rose C.
        • Layton D.M.
        • et al.
        Safety and Efficacy of Mitapivat in Pyruvate Kinase Deficiency.
        N Engl J Med. 2019; 381: 933-944
        • Al-Samkari H.
        • Galacteros F.
        • Glenthoj A.
        • et al.
        Mitapivat versus Placebo for Pyruvate Kinase Deficiency.
        N Engl J Med. 2022; 386: 1432-1442
        • Glenthøj A.
        • Van Beers E.
        • Al-Samkari H.
        ACTIVATE-T: a phase 3, open-label, multicenter study of mitapivat in adults with pyruvate kinase deficiency who are regularly transfused.
        Eur Hematol Assoc. 2021; 9: 17
        • Xu J.Z.
        • Conrey A.
        • Frey I.
        • et al.
        Phase 1 multiple ascending dose study of safety, tolerability, and pharmacokinetics/pharmacodynamics of Mitapivat (AG-348) in subjects with sickle cell disease.
        Blood. 2020; 136: 21-22
        • Rab M.A.
        • van Oirschot B.A.
        • van Straaten S.
        • et al.
        Decreased activity and stability of pyruvate kinase in hereditary hemolytic anemia: a potential target for therapy by AG-348 (Mitapivat), an allosteric activator of red blood cell pyruvate kinase.
        Blood. 2019; 134: 3506
        • Matte A.
        • Federti E.
        • Kung C.
        • et al.
        The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a beta-thalassemia mouse model.
        J Clin Invest. 2021; 131: e144206
        • Kuo K.H.M.
        • Layton D.M.
        • Lal A.
        • et al.
        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: 493-501
        • Lal A.
        • Brown C.
        • Coates T.
        • et al.
        S103: trial in progress: a phase 2, open-label study evaluating the safety and efficacy of the pkr activator etavopivat (ft-4202) in patients with thalassemia or sickle cell disease.
        HemaSphere. 2022; 6: 2
        • Lal A.
        • Brown R.C.C.
        • Coates T.D.
        • et al.
        Trial in Progress: A Phase 2, Open-Label Study Evaluating the Safety and Efficacy of the PKR Activator Etavopivat (FT-4202) in Patients with Thalassemia or Sickle Cell Disease.
        Blood. 2021; 138: 4162
        • Libani I.V.
        • Guy E.C.
        • Melchiori L.
        • et al.
        Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in beta-thalassemia.
        Blood. 2008; 112: 875-885
        • Casu C.
        • Presti V.L.
        • Oikonomidou P.R.
        • et al.
        Short-term administration of JAK2 inhibitors reduces splenomegaly in mouse models of beta-thalassemia intermedia and major.
        Haematologica. 2018; 103: e46-e49
        • Taher A.T.
        • Karakas Z.
        • Cassinerio E.
        • et al.
        Efficacy and safety of ruxolitinib in regularly transfused patients with thalassemia: results from a phase 2a study.
        Blood. 2018; 131: 263-265
        • Ovsyannikova G.
        • Balashov D.
        • Demina I.
        • et al.
        Efficacy and safety of ruxolitinib in ineffective erythropoiesis suppression as a pretransplantation treatment for pediatric patients with beta-thalassemia major.
        Pediatr Blood Cancer. 2021; 68: e29338
        • Matte A.
        • Federti E.
        • Winter M.
        • et al.
        Bitopertin, a selective oral GLYT1 inhibitor, improves anemia in a mouse model of β-thalassemia.
        JCI Insight. 2019; 4: e130111
        • Taher A.T.
        • Viprakasit V.
        • Cappellini M.D.
        • et al.
        Haematological effects of oral administration of bitopertin, a glycine transport inhibitor, in patients with non-transfusion-dependent beta-thalassaemia.
        Br J Haematol. 2021; 194: 474-477
        • Preza G.C.
        • Ruchala P.
        • Pinon R.
        • et al.
        Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload.
        J Clin Invest. 2011; 121: 4880-4888
        • Casu C.
        • Oikonomidou P.R.
        • Chen H.
        • et al.
        Minihepcidin peptides as disease modifiers in mice affected by beta-thalassemia and polycythemia vera.
        Blood. 2016; 128: 265-276
        • Casu C.
        • Chessa R.
        • Liu A.
        • et al.
        Minihepcidins improve ineffective erythropoiesis and splenomegaly in a new mouse model of adult beta-thalassemia major.
        Haematologica. 2020; 105: 1835-1844
        • Nai A.
        • Pagani A.
        • Mandelli G.
        • et al.
        Deletion of TMPRSS6 attenuates the phenotype in a mouse model of beta-thalassemia.
        Blood. 2012; 119: 5021-5029
        • Nai A.
        • Rubio A.
        • Campanella A.
        • et al.
        Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice.
        Blood. 2016; 127: 2327-2336
        • Guo S.
        • Casu C.
        • Gardenghi S.
        • et al.
        Reducing TMPRSS6 ameliorates hemochromatosis and beta-thalassemia in mice.
        J Clin Invest. 2013; 123: 1531-1541
        • Schmidt P.J.
        • Toudjarska I.
        • Sendamarai A.K.
        • et al.
        An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe(-/-) mice and ameliorates anemia and iron overload in murine beta-thalassemia intermedia.
        Blood. 2013; 121: 1200-1208
        • Porter J.
        • Taher A.
        • Viprakasit V.
        • et al.
        Oral ferroportin inhibitor vamifeport for improving iron homeostasis and erythropoiesis in beta-thalassemia: current evidence and future clinical development.
        Expert Rev Hematol. 2021; 14: 633-644
        • Manolova V.
        • Nyffenegger N.
        • Flace A.
        • et al.
        Oral ferroportin inhibitor ameliorates ineffective erythropoiesis in a model of beta-thalassemia.
        J Clin Invest. 2019; 130: 491-506
        • Nyffenegger N.
        • Flace A.
        • Doucerain C.
        • et al.
        The Oral Ferroportin Inhibitor VIT-2763 Improves Erythropoiesis without Interfering with Iron Chelation Therapy in a Mouse Model of beta-Thalassemia.
        Int J Mol Sci. 2021; 22
        • Richard F.
        • van Lier J.J.
        • Roubert B.
        • et al.
        Oral ferroportin inhibitor VIT-2763: First-in-human, phase 1 study in healthy volunteers.
        Am J Hematol. 2020; 95: 68-77
        • Taher A.
        • Kourakli-Symeonidis A.
        • Tantiworawit A.
        • et al.
        S272: safety and preliminary pharmacodynamic effects of the ferroportin inhibitor vamifeport (VIT-2763) in patients with non-transfusion-dependent beta thalassemia (NTDT): results from a phase 2A study.
        HemaSphere. 2022; 6: 173-174