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Sotatercept TGF-b ligand trap in β-thalassemia
Ineffective erythropoiesis in b-thalassemia is associated with increased iron absorption, and patients with TDT often require regular RBC transfusions, further increasing the risk of iron overload. Reducing ineffective erythro- poiesis and transfusion burden will decrease the rate of iron loading and associated complications such as heart, liver, and endocrine disorders. In this study, decreases in serum ferritin levels were observed in sotatercept-treated patients with NTDT and TDT, with the decreases occur- ring in a dose-dependent manner, regardless of concur- rent treatment with iron chelation therapy. Although these results suggest that sotatercept may reduce iron absorption by reducing ineffective erythropoiesis, other mechanisms such as removal or redistribution of iron from overloaded organs may also contribute to reduced iron levels. Further studies will be required to elucidate the mechanism of action; however, a reduction in iron overload with long-term use may translate into improved outcomes for patients.
Sotatercept treatment was associated with a reduction in the volume of extramedullary masses, as measured by magnetic resonance imaging, in two patients with record- ed data – one with NTDT and one with TDT. However, this change in extramedullary mass volume was not observed for all patients, and, due to technical difficulties, precise estimation of extramedullary mass volume was not always possible. Reductions in the volumes of these masses did not appear to correlate with response. Further study is needed to determine the effect of sotatercept on extramedullary masses.
In rodent models, sotatercept acts on ineffective ery- thropoiesis to reduce production of α-globin aggregates and apoptosis of late erythroid precursors, thereby increasing the efficiency of RBC production and hemo- globin levels.21,26 Although hemoglobin levels increased in NTDT patients during the study, no significant differ- ences in HbF or reticulocyte count were reported. In a small subset of patients, normalization of RBC morphol- ogy was reported and associated with increasing hemo- globin levels over time. These data suggest that sotater- cept may increase the lifespan of RBC in part by improv- ing reticulocyte quality. These changes are consistent with the mode of action of sotatercept as a ligand trap for TGF-b superfamily members, including GDF-11. Binding of sotatercept to GDF-11 inhibits SMAD2/3 signaling, reducing TGF-b superfamily ligand signaling and thereby promoting terminal differentiation of erythroblasts.20
There are some limitations to this study, notably the small number of patients enrolled, which limited the abil-
ity to draw comparisons between different sotatercept dose groups. The inclusion of both NTDT and TDT b- thalassemia patients also resulted in patients being grouped into smaller subgroups that further limited the scope of the study, especially as intrapatient dose escala- tion was allowed. The short duration of follow-up may be another limitation, and longer follow-up would pro- vide information on the long-term clinical efficacy and safety of sotatercept.
This study demonstrated the safety and efficacy of sotatercept in patients with b-thalassemia. An improve- ment in hemoglobin levels and reduction in transfusion burden with sotatercept treatment have also been demonstrated in a phase II study of anemia patients with lower-risk myelodysplastic syndromes.23 This suggests that sotatercept may work to decrease ineffective ery- thropoiesis in multiple disease states via a single underly- ing mode of action. Preliminary data with sotatercept led to the initiation of a similar phase II study in b-tha- lassemia of the related recombinant fusion protein, luspa- tercept. Luspatercept has more selective activity on GDF- 11, and is also safe and effective in the treatment of b-tha- lassemia (Piga A, et al. manuscript submitted) and myelodysplastic syndromes.27 Luspatercept comprises the modified extracellular domain of human ActRIIB linked to the human IgG Fc domain,26,28 and has a similar mode of action to sotatercept but does not bind to other mem- bers of the TGF-b superfamily, such as activin A.20,26 A double-blind, randomized, placebo-controlled phase III trial of luspatercept in patients who require regular RBC transfusions due to b-thalassemia has recently completed recruitment (BELIEVE; NCT02604433). Luspatercept is also being studied in a phase III trial of patients with very low-, low- and intermediate-risk myelodysplastic syn- dromes (MEDALIST; NCT02631070). While the decision was made not to advance trials of sotatercept in b-tha- lassemia due to binding of sotatercept to activin A, sotatercept represents the first drug developed in its class, functioning as a TGF-b superfamily inhibitor to correct ineffective erythropoiesis. TGF-b superfamily inhibition may provide an alternative or complementary treatment option for patients with b-thalassemia.
Acknowledgments
The authors would like to thank all the patients and their fam- ilies who participated in this study. The authors received editorial and writing support from Victoria Edwards, PhD, from Excerpta Medica, funded by Celgene Corporation. Celgene Corporation and Acceleron Pharma provided funding for this study.
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