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M.D. Cappellini et al.
Introduction
tolerable, and effective dose of sotatercept to increase hemoglobin levels and reduce blood transfusion burden in adults with TDT and NTDT b-thalassemia.
Methods
In this phase II, open-label, dose-finding study, patients were enrolled at seven centers in France, Greece, Italy, and the United Kingdom (listed in the Online Supplementary Data) between November 2012 and November 2014. The study was approved by individual institutional review boards at participating centers and, where appropriate, national health authorities, and was conducted in compliance with the Declaration of Helsinki. All patients pro- vided written informed consent. ClinicalTrials.gov registration num- ber: NCT01571635.
Inclusion criteria
b-thalassemia is a hereditary blood disorder caused by defective synthesis of the b globin chains of hemoglobin1 characterized by ineffective erythropoiesis.2-4 Mutations in the b-globin genes lead to reduced or absent b-globin chain synthesis, increasing the ratio of α-globin to non-α- globin chains. Due to the relative excess of α-globin chains, α-globin precipitates within erythroblasts as hemichromes, leading to oxidative stress, maturation arrest, membrane damage and apoptosis of late-stage ery- throid precursors, and reduced red blood cell (RBC) life span.4-6 Although erythropoiesis-stimulating agents have been used in patients with b-thalassemia, ineffective ery- thropoiesis is not corrected.7 Use of erythropoiesis-stimu- lating agents is, therefore, not recommended for the treat- ment of b-thalassemia.7,8
b-thalassemia phenotypes vary in severity, ranging from asymptomatic thalassemia minor to non-transfusion- dependent thalassemia (NTDT) (including thalassemia intermedia and hemoglobin E - b-thalassemia) to transfu- sion-dependent thalassemia (TDT) (thalassemia major). Treatment of TDT involves regular and lifelong blood transfusions leading to iron overload; long-term manage- ment of iron overload requires regular iron chelation ther- apy.9,10 However, iron chelation therapy is associated with significant toxicities and requires a high level of treatment adherence and monitoring that can be difficult to manage and may have a negative impact on patients’ quality of life.11,12 Bone marrow transplantation offers potentially cur- ative treatment,13 but is not possible in all patients,14 and is associated with significant morbidity and mortality.15 Gene therapy has shown early promise but is still under investigation.16 The treatment of NTDT is based on man- aging the long-term complications of ineffective erythro- poiesis, including chronic anemia and iron overload,17 using iron chelation therapy and occasional RBC transfu- sion.18,19
Eligible patients were aged ≥18 years with a diagnosis of TDT or NTDT, and an Eastern Cooperative Oncology Group Performance Status of 0 to 1. Transfusion dependence was defined as receiving ≥2 RBC units every 30 days for ≥168 days prior to study enrollment, with no transfusion-free period of >45 consecu- tive days during this period. The mean hemoglobin level before transfusion was ≤10.5 g/dL in the 168 days prior to enrollment, with the last pretransfusion hemoglobin level preceding enroll- ment being ≤10.5 g/dL.
Sotatercept is a ligand trap that inhibits transforming growth factor beta (TGF-b) superfamily members includ- ing growth differentiation factor 11 (GDF-11) and activin B.20,21 GDF-11 is overexpressed in immature erythroblasts in b-thalassemia.21 Aberrant GDF-11 production may induce expansion of erythroid progenitors and increase oxidative stress, leading to maturation arrest of late ery- throid precursors and ineffective erythropoiesis.21 Preclinical work has shown that administration of an activin receptor IIA (ActRIIA) ligand trap decreases GDF- 11 concentration, reduces reactive oxidative stress levels, and promotes terminal maturation in immature erythro- blasts.21 Sotatercept is a novel recombinant fusion protein consisting of the extracellular domain of the human ActRIIA (ACVR2A) linked to the human immunoglobulin G1 Fc domain.20 When administered subcutaneously, sotatercept increased hemoglobin levels and RBC count in healthy, postmenopausal women.22 In a phase II trial of patients with lower-risk myelodysplastic syndromes and anemia, sotatercept reduced transfusion burden in 47% of patients with a high transfusion burden, and increased hemoglobin levels in 58% of patients with a low transfu- sion burden.23 In a b-thalassemia mouse model, RAP-011 (a murine analog of sotatercept) improved hematologic parameters including RBC count, total hemoglobin, hema- tocrit, and mean corpuscular volume.21
The aim of this phase II study was to determine a safe,
Study design
To determine a safe and tolerable dose of sotatercept, a dose- escalation study was carried out. Patients were initially enrolled in two cohorts, receiving doses of 0.1 mg/kg and 0.3 mg/kg, admin- istered by subcutaneous injection every 3 weeks. Four dose-esca- lation cohorts, with doses of 0.5, 0.75, 1.0, and 1.5 mg/kg, were subsequently opened to enrollment. Details of the study design are included in the Online Supplementary Data.
Study endpoints
Primary efficacy endpoints were a reduction in transfusion bur- den of ≥20% from pretreatment levels, sustained for 24 weeks in TDT patients, and an increase in hemoglobin level of ≥1.0 g/dL sus- tained for 12 weeks from mean pretreatment hemoglobin levels in NTDT patients. Hematologic parameters, including hemoglobin levels and RBC counts, were measured on days 1, 8, and 15 (±3 days) of each 3-week sotatercept dose period. Secondary endpoints included reduction in RBC transfusion burden in TDT patients, hemoglobin level increase from baseline in NTDT patients, and safety. Exploratory endpoints included iron metabolism markers (including serum ferritin and hepcidin), and clinical symptoms asso- ciated with ineffective erythropoiesis and anemia (including extramedullary hematopoiesis, leg ulcers, and bilirubin levels).
Statistical analysis
Efficacy analyses were carried out on the intent-to-treat popula- tion, which included all patients enrolled for treatment. Efficacy data are presented by assigned dose group. Safety analyses were conducted on the safety population, defined as those patients who received one or more dose of sotatercept. Safety data are present- ed prior to intrapatient dose escalation for sotatercept dose groups and presented post-intrapatient dose escalation for patients over-
Non-transfusion dependence was defined as ≤1 episode of transfusion during the 168 days prior to enrollment; an episode of transfusion was defined as ≤4 RBC units received during the 168 days prior to enrollment. Exclusion criteria are listed in the Online Supplementary Data.
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haematologica | 2019; 104(3)