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Red Cell Biology & its Disorders
Sotatercept, a novel transforming growth factor b ligand trap, improves anemia in b-thalassemia: a phase II, open-label, dose-finding study
Ferrata Storti Foundation
Haematologica 2019 Volume 104(3):477-484
Maria Domenica Cappellini,1 John Porter,2 Raffaella Origa,3 Gian Luca Forni,4 Ersi Voskaridou,5 Frédéric Galactéros,6 Ali T. Taher,7 Jean-Benoît Arlet,8,9,10 Jean- Antoine Ribeil,11 Maciej Garbowski,2 Giovanna Graziadei,1 Chantal Brouzes,11 Michaela Semeraro,11 Abderrahmane Laadem,12 Dimana Miteva,13 Jun Zou,12 Victoria Sung,14 Tatiana Zinger,13 Kenneth M. Attie15 and Olivier Hermine9,10,16
1Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Department of Clinical Sciences and Community Health, University of Milan, Italy; 2Department of Haematology, University College London, UK; 3Day Hospital Talassemia, Ospedale Pediatrico Microcitemico “A.Cao”, A.O. “G. Brotzu”, Cagliari, Italy; 4Centro della Microcitemia, Ospedali Galliera, Genova, Italy; 5Thalassemia Center, Laikon General Hospital, Athens, Greece; 6UMGGR, Hôpital Henri Mondor; Assistance Publique-Hôpitaux de Paris (APHP); UPEC, Créteil, France; 7Department of Internal Medicine, American University of Beirut Medical Center, Lebanon; 8Department of Internal Medicine, APHP, Hôpital Européen Georges- Pompidou, Paris, France; 9INSERM UMR1163, CNRS ERL 8254, Institut Imagine, Université Paris Descartes-Sorbonne Paris Cité, France; 10Laboratory of Excellence GR-Ex, Paris, France; 11Laboratory of Onco-hematology, Hôpital Necker-Enfants Malades, Paris, France;
12 13
bCelgene Corporation, Summit, NJ, USA; Celgene Corporation, Boudry, Switzerland;
14Celgene Corporation, San Francisco, CA, USA; 15Acceleron Pharma, Cambridge, MA, USA and 16Department of Hematology, APHP, Hôpital Necker, Paris, France
ABSTRACT
-thalassemia, a hereditary blood disorder caused by defective synthe- sis of hemoglobin b globin chains, leads to ineffective erythropoiesis and chronic anemia that may require blood transfusions. Sotatercept
(ACE-011) acts as a ligand trap to inhibit negative regulators of late-stage erythropoiesis in the transforming growth factor b superfamily, correcting ineffective erythropoiesis. In this phase II, open-label, dose-finding study, 16 patients with transfusion-dependent b-thalassemia and 30 patients with non-transfusion-dependent b-thalassemia were enrolled at seven centers in four countries between November 2012 and November 2014. Patients were treated with sotatercept at doses of 0.1, 0.3, 0.5, 0.75, or 1.0 mg/kg to deter- mine a safe and effective dose. Doses were administered by subcutaneous injection every 3 weeks. Patients were treated for ≤22 months. Response was assessed as a ≥20% reduction in transfusion burden sustained for 24 weeks in transfusion-dependent b-thalassemia patients, and an increase in hemoglobin level of ≥1.0 g/dL sustained for 12 weeks in non-transfusion- dependent b-thalassemia patients. Sotatercept was well tolerated. After a median treatment duration of 14.4 months (range 0.6-35.9), no severe life- threatening adverse events were observed. Thirteen percent of patients reported serious but manageable adverse events. The active dose of sotater- cept was ≥0.3 mg/kg for patients with non-transfusion-dependent b-tha- lassemia and ≥0.5 mg/kg for those with transfusion-dependent b-tha- lassemia. Of 30 non-transfusion-dependent b-thalassemia patients treated with ≥0.1 mg/kg sotatercept, 18 (60%) achieved a mean hemoglobin increase ≥1.0 g/dL, and 11 (37%) an increase ≥1.5 g/dL, sustained for ≥12 weeks. Four (100%) transfusion-dependent b-thalassemia patients treated with 1.0 mg/kg sotatercept achieved a transfusion-burden reduction of ≥20%. Sotatercept was effective and well tolerated in patients with b-tha- lassemia. Most patients with non-transfusion-dependent b-thalassemia treated with higher doses achieved sustained increases in hemoglobin level. Transfusion-dependent b-thalassemia patients treated with higher doses of sotatercept achieved notable reductions in transfusion requirements. This trial was registered at ClinicalTrials.gov with the number NCT01571635.
Correspondence:
MARIA DOMENICA CAPPELLINI
maria.cappellini@unimi.it
OLIVIER HERMINE
olivier.hermine@nck.aphp.fr
Received: May 30, 2018. Accepted: October 12, 2018. Pre-published: October 18, 2018.
doi:10.3324/haematol.2018.198887
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/3/477
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