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Sotatercept, a novel transforming growth factor ? ligand trap, improves anemia in ?-thalassemia: a phase II, open-label, dose-finding study.

ABSTRACT: ?-thalassemia, a hereditary blood disorder caused by defective synthesis of hemoglobin ? 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 ? superfamily, correcting ineffective erythropoiesis. In this phase II, open-label, dose-finding study, 16 patients with transfusion-dependent ? -thalassemia and 30 patients with non-transfusion-dependent ?-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 determine 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 ?-thalassemia patients, and an increase in hemoglobin level of ?1.0 g/dL sustained for 12 weeks in non-transfusion-dependent ?-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 sotatercept was ?0.3 mg/kg for patients with non-transfusion-dependent ?-thalassemia and ?0.5 mg/kg for those with transfusion-dependent ?-thalassemia. Of 30 non-transfusion-dependent ?-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 ?-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 ?-thalassemia. Most patients with non-transfusion-dependent ?-thalassemia treated with higher doses achieved sustained increases in hemoglobin level. Transfusion-dependent ?-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.

SUBMITTER: Cappellini MD

PROVIDER: S-EPMC6395345 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Sotatercept, a novel transforming growth factor β ligand trap, improves anemia in β-thalassemia: a phase II, open-label, dose-finding study.

Cappellini Maria Domenica MD Porter John J Origa Raffaella R Forni Gian Luca GL Voskaridou Ersi E Galactéros Frédéric F Taher Ali T AT Arlet Jean-Benoît JB Ribeil Jean-Antoine JA Garbowski Maciej M Graziadei Giovanna G Brouzes Chantal C Semeraro Michaela M Laadem Abderrahmane A Miteva Dimana D Zou Jun J Sung Victoria V Zinger Tatiana T Attie Kenneth M KM Hermine Olivier O

Haematologica 20181018 3

β-thalassemia, a hereditary blood disorder caused by defective synthesis of hemoglobin β 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 β superfamily, correcting ineffective erythropoiesis. In this phase II, open-label, dose-finding study, 16 patients with transfusion-dependent β -thalassemia and 30 p ...[more]

PMID: 30337358

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Project description:BackgroundPeginesatide is a peptide-based erythropoiesis-stimulating agent that was designed and engineered to stimulate specifically the erythropoietin receptor dimer that governs erythropoiesis. The primary objective of this phase 2 dose-finding study was to determine the once-monthly peginesatide dosing strategy that would maintain hemoglobin within ±1.0 g/dL of baseline values after conversion from epoetin alfa; the safety of peginesatide was evaluated concurrently.MethodsChronic hemodialysis patients on stable regimens of epoetin alfa were sequentially assigned to cohorts that differed on (1) how the peginesatide starting dose was determined (using a single epoetin alfa-to-peginesatide dose conversion ratio or a tiered, weight-based or absolute-dose conversion table) and on (2) whether or not a 1-week erythropoiesis-stimulating agent-free interval was used. Peginesatide doses were titrated to maintain hemoglobin levels within ±1.0 g/dL from baseline.ResultsA total of 164 patients were enrolled and received intravenous peginesatide every 4 weeks for up to 6 doses; the duration of the study including follow-up was ≤29 weeks. Overall, the proportion of patients with hemoglobin levels within ±1.0 g/dL of baseline increased over the course of the study from 39% (Weeks 2-13) to 54% (Weeks 18-25). Cohorts that used tiered dose conversion tables trended towards having more stable peginesatide doses than did those cohorts that used a single dose conversion ratio. Moreover, cohorts that used an erythropoiesis-stimulating agent-free interval did not have the substantial initial increase in hemoglobin levels that was seen in those cohorts that did not use such an interval. In this study, the safety profile of peginesatide was consistent with those of marketed erythropoiesis-stimulating agents.ConclusionsThe results of this study were used to guide the dosing regimens used subsequently in phase 3 studies. Once-monthly peginesatide is feasible in hemodialysis patients.Trial registrationClinicalTrials.gov registration: NCT00228449.

Project description:Lessons learnedPatients with hepatocellular carcinoma (HCC) often have limited therapeutic responses to the vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor sorafenib, which is standard of care in advanced HCC. Targeting the activin receptor-like kinase 1 (ALK1) and VEGF pathways simultaneously by combining the ALK1 ligand trap dalantercept with sorafenib may result in more effective angiogenic blockade and delay tumor progression in patients with advanced HCC.Although the combination was generally well tolerated, there was no additive antitumor activity with the combination of dalantercept plus sorafenib in patients with advanced HCC. No complete or partial responses were observed, and overall survival ranged from 1.9 to 23.3 months.These results suggest that, in this patient population, further development of the possible limited benefits of combination therapy with dalantercept plus sorafenib is not warranted.BackgroundTargeting the activin receptor-like kinase 1 (ALK1) and vascular endothelial growth factor (VEGF) pathways may result in more effective angiogenic blockade in patients with hepatocellular carcinoma (HCC).MethodsIn this phase Ib study, patients with advanced HCC were enrolled to dose-escalation cohorts, starting at 0.6 mg/kg dalantercept subcutaneously every 3 weeks plus 400 mg sorafenib orally once daily, or to a dose expansion cohort. The primary objective was to determine the safety and tolerability and the dalantercept maximum tolerated dose (MTD) level. Secondary objectives were to assess the preliminary activity and the association of pharmacodynamic biomarkers with tumor response.ResultsA total of 21 patients were enrolled in the study. Five patients received 0.6 mg/kg dalantercept in the first dose escalation cohort. Based on the initial safety results, the dose level was de-escalated to 0.4 mg/kg in the second cohort (n = 6). The MTD was identified as 0.4 mg/kg and used for the dose expansion cohort (n = 10). At this dose level, the combination was generally well tolerated. Overall survival ranged from 1.9 to 23.3 months, and the best overall response was stable disease.ConclusionThe addition of dalantercept to sorafenib did not improve antitumor activity in patients with HCC. The dalantercept program in this population was discontinued.

Dataset Information

Sotatercept, a novel transforming growth factor ? ligand trap, improves anemia in ?-thalassemia: a phase II, open-label, dose-finding study.

Publications

Sotatercept, a novel transforming growth factor β ligand trap, improves anemia in β-thalassemia: a phase II, open-label, dose-finding study.

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