2021 update on clinical trials in β‐thalassemia

Abstract

The treatment landscape for patients with β-thalassemia is witnessing a swift evolution, yet several unmet needs continue to persist. Patients with transfusiondependent β-thalassemia (TDT) primarily rely on regular transfusion and iron chelation therapy, which can be associated with considerable treatment burden and cost.Patients with non-transfusion-dependent β-thalassemia (NTDT) are also at risk of significant morbidity due to the underlying anemia and iron overload, but treatment options in this patient subgroup are limited. In this review, we provide updates on clinical trials of novel therapies targeting the underlying pathology in β-thalassemia, including the α/non-α-globin chain imbalance, ineffective erythropoiesis, and iron dysregulation. | INTRODUCTIONThe β-thalassemias are a group of inherited disorders of hemoglobin (Hb) synthesis characterized by chronic anemia of varying severity.The degree of anemia relies on several genetic and environmental factors and determines the need for regular transfusion therapy. It is now common practice to classify patients as having transfusion-The TDT patients (β-thalassemia major and severe forms of HbE/β-thalassemia) are those who commonly present in early childhood with severe anemia and require lifelong transfusion therapy for survival. 1 Although the introduction of transfusions improved survival in TDT patients, it did not come without its own side-effect, systemic iron overload leading to end-organ damage and increased mortality from cardiac or hepatic disease. [2][3][4] Advances in iron chelation therapy and the introduction of MRI techniques to detect organ-specific iron overload have led to improved management and patient outcomes. 5,6 Still, TDT comes with considerable burden to the patient, clinician, and overall healthcare system owing to persistent morbidity and high healthcare utilization, poor access to optimal care and high treatment cost especially in resource-limited countries, and several unmet needs in terms of efficacy, safety and adherence to conventional therapies. 7 Allogeneic hematopoietic stem-cell transplantation (HSCT) has been used successfully for the past few decades to offer curative therapy for patients with TDT, but is only available to a minority of patients with compatible donors. 1 Patients with NTDT (β-thalassemia intermedia and mildmoderate forms of HbE/β-thalassemia) usually present later in childhood or even in adolescence with mild-moderate anemia that does not require immediate placement on a regular transfusion program. 1,8 Progress made over the past few decades has indicated that the diagnosis of NTDT carries greater morbidity than previously recognized.Ineffective erythropoiesis and anemia have been linked to an array of morbidities stemming from chronic hypoxia and an established hypercoagulable state. 1 Patients with Hb levels < 10 g/dl are at an increased risk of morbidity development, and variations of 1 g/dl can change a patient's morbidity risk. 9,10 There are currently no approved agents for the management of anem...

Real‐world experience with luspatercept and predictors of response in myelodysplastic syndromes with ring sideroblasts

“…15,16 The latter approach has proven more successful in anemias associated with beta-thalassemia. 17…”

New Insights Into Pathophysiology of β-Thalassemia

“…All of them are being developed and in the future may change the quality of life of these patients and we aim to be part of this scenario. All of them summarized in a succinct way by Musallam et al ( 33 ).…”

Cell erythroid maturation approach: a new paradigm in the road map towards a cure for β‐thalassaemia syndromes

“…Mitapivat has already shown efficacy and safety in clinical trials of patients with PK deficiency. 7 In mouse models of bthalassaemia, mitapivat increased ATP levels, reduced markers of ineffective erythropoiesis, and improved anaemia, RBC survival, and indexes of iron overload. 9 An ongoing phase II, open-label, multicentre study (NCT03692052) is evaluating mitapivat in 20 NTDT (including a-thalassaemia) adults with a Hb level of ≤100 g/l, and assessing safety and efficacy in achieving Hb increases of ≥10 g/l and changes in markers of haemolysis and ineffective erythropoiesis.…”

“…9 An ongoing phase II, open-label, multicentre study (NCT03692052) is evaluating mitapivat in 20 NTDT (including a-thalassaemia) adults with a Hb level of ≤100 g/l, and assessing safety and efficacy in achieving Hb increases of ≥10 g/l and changes in markers of haemolysis and ineffective erythropoiesis. 7 ENERGIZE-T (NCT04770779) a phase III, double-blind, randomised, placebo-controlled, multicentre study evaluating the efficacy and safety of mitapivat (100 mg orally, twice daily) in adult patients with TDT (a-and b-thalassaemia) is due to start recruitment in 2021 to enrol 240 patients over 48 weeks with an open-label extension for 5 years, while ENERGIZE (NCT04770753) is another phase III trial with a similar design to be conducted in adult patients with NTDT (a-and b-thalassaemia) that plans to enrol 171 patients over 24 weeks with an open-label extension for 5 years. 7 In b-thalassaemia, ineffective erythropoiesis and hypoxia lead to decreased production of the hepatic hormone hepcidin, which in turn results in increased intestinal iron absorption and its release from macrophages in the reticuloendothelial system, contributing to a state of iron overload with preferential hepatic iron storage.…”

“…7 Moreover, luspatercept showed its effectiveness, determined as a mean Hb increase of ≥100 g/l from baseline in patients with non-TDT (NTDT; NCT03342404). 7 Finally, luspatercept is not alone in this superfamily because another ligand-trap fusion protein containing the modified extracellular domain of activin receptor type IIA, sotatercept (ACE-011) has been evaluated in up to a phase II trial (NCT01571635) in adults with b-thalassaemia with positive findings, but the sponsor made a decision not to advance trials with this drug. 7 Preclinical studies on pyruvate kinase (PK)-deficient mice have shown that the metabolic disturbance in PK deficiency alters not only the survival of red blood cells (RBCs) but also the maturation of erythroid progenitors.…”