LAUSR

To the Editor: Management of patients with β-thalassemia is undergoing a swift evolution, considering the number of novel agents recently receiving marketing approval or entering clinical development. Although (thankfully) the availability of new treatment options will address several persisting unmet needs in this patient population, several questions remain on how such advances should be optimally integrated into standard of care. The only currently approved therapy for patients with non-transfusion-dependent β-thalassemia (NTDT) is iron chelation (for patients ≥ 10 years). This only followed recent evidence of clinically significant iron overload and subsequent multiorgan morbidity, even in NTDT patients who never received transfusion therapy. Patients with NTDT accumulate iron from increased intestinal iron absorption and release from the reticuloendothelial system, signaled by low hepcidin levels attributed to ineffective erythropoiesis. Although this milestone in disease management addressed a key morbidity risk factor, there are currently no approved therapies specifically targeting the underlying ineffective erythropoiesis and anemia, which are not only the drivers for primary iron overload, but are also linked with a variety of clinical complications stemming from chronic tissue hypoxia, hemolysis, and hypercoagulability. There is evidence that transfusion therapy may be associated with lower morbidity rates in NTDT, but physicians are understandably hesitant to start these patients on regular transfusion programs which would open the door to transfusional siderosis and progressive organ dysfunction. In this context, several agents are currently being evaluated in clinical trials with the aim of targeting ineffective erythropoiesis or iron dysregulation in NTDT, with the expectation that addressing one pathophysiologic mechanism will ameliorate the other; since a bidirectional relationship between both anomalies has been confirmed. Clinically, this would translate to improvement in anemia and prevention of iron overload. Luspatercept (ACE-536) is a recombinant fusion protein that binds to select transforming growth factor β superfamily ligands and enhances late-stage erythropoiesis. Luspatercept showed encouraging data in a single-arm, open-label, phase two study including improvement in hemoglobin level in NTDT and reduction in transfusion burden in transfusion-dependent β-thalassemia (TDT). A phase three trial (BELIEVE) confirmed these findings in TDT patients and led to product approval in this subset of patients. The ongoing randomized (2:1), double-blind, placebo-controlled, phase two BEYOND trial (NCT03342404) is evaluating the efficacy of subcutaneous luspatercept (every 3 weeks) in increasing hemoglobin level (by ≥ 1.0 g/dL) in adult patients with NTDT and a baseline hemoglobin ≤ 10 g/dL. Assessment of effects on tiredness, weakness, and shortness of breath is also being undertaken to confirm clinical benefit. The impact of therapy on iron indices and use of iron chelation will also be reported. Mitapivat (AG-348) is an oral, small-molecule, allosteric activator of the red blood cell (RBC)-specific form of pyruvate kinase (PK-R). Adenosine triphosphate (ATP) supply appears to be insufficient in thalassemic RBCs to maintain RBC membrane fitness and clearance of globin precipitates. In β-thalassemia mouse models, mitapivat increased ATP levels, reduced markers of ineffective erythropoiesis, and improved anemia, RBC survival, and indices of iron overload. An open-label, phase two trial (NCT03692052) in adults with NTDT and a baseline hemoglobin of ≤ 10 g/dL is evaluating the efficacy of mitapivat in improving hemoglobin level (by ≥ 1.0 g/dL) as well as markers of hemolysis and ineffective erythropoiesis. Interim data showed response in eight of nine patients following 12 weeks of therapy. Anti-sense oligonucleotides (ASO) downregulating TMPRSS6, a metalloprotease which plays a key role in hepcidin expression, stimulated hepcidin, reduced iron burden, and improved ineffective erythropoiesis and RBC survival in β-thalassemia mouse models. TMPRSS6-LRx is a generation 2+ ligand-conjugated ASO subcutaneous drug (given every 4 weeks) that is now being evaluated in a randomized, open-label, phase two trial (NCT04059406) in adults with NTDT and baseline hemoglobin ≤ 10 g/dL. The main endpoints include increasing hemoglobin level (by ≥ 1.0 g/dL) and decreasing LIC. Finally, VIT-2763 is an oral ferroportin inhibitor which restricted iron availability, ameliorated anemia, and reversed the dysregulated iron homeostasis in β-thalassemia mouse models. VITHAL (NCT04364269) is a randomized, double-blind, placebo-controlled, phase two trial evaluating the efficacy of VIT-2763 in improving hemoglobin and iron indices in NTDT patients aged ≥ 12 years with a baseline hemoglobin ≤ 11 g/dL. All novel agents primarily aim to ameliorate anemia and iron overload in patients with NTDT, and final data from ongoing and subsequent registration trials are awaited. Considering multiple agents may become available not long from today; it is imperative to think ahead and try to visualize the outlook for overall disease management (Figure 1), so gaps in knowledge can be promptly identified and addressed alongside clinical development. Realizing the impact of improvement in anemia in the context of clinical trials may be challenging, since the aim of such improvement is to prevent the Received: 27 October 2020 Revised: 10 November 2020 Accepted: 18 November 2020