Contributions
Abstract: S129
Type: Oral Presentation
Presentation during EHA22: On Friday, June 23, 2017 from 11:45 - 12:00
Location: Room N105
Background
Luspatercept (ACE-536), a fusion protein containing a modified activin receptor type IIB, is being developed for the treatment of β-thalassemia. Luspatercept binds to select TGF-β superfamily ligands (such as GDF11) reducing aberrant Smad2/3 signaling and promoting late-stage erythroid differentiation and increased hemoglobin (Hgb). Luspatercept corrected the effects of ineffective erythropoiesis in a mouse model of thalassemia (Suragani R, Blood, 2014) and increased Hgb and was well tolerated in a phase 1 study in healthy volunteers (Attie K, Am J Hematol, 2014).
Aims
This ongoing, phase 2, multicenter, open-label study followed by a long-term extension (ext) study evaluates the effects of luspatercept in patients (pts) with either transfusion-dependent (TD) or non-transfusion dependent (NTD) β-thalassemia with key endpoints of erythroid response (including Hgb increase) and pt-reported quality-of-life (QoL) in NTD patients, and reductions in RBC transfusion burden in TD patients.
Methods
Inclusion criteria: age ≥18 yr and either TD (≥4 RBC U/8 weeks prior to first dose, confirmed over 6 months) or NTD (<4 RBC U/8 weeks prior to first dose with baseline Hgb <10 g/dL). Pts were treated every 3 weeks subcutaneously for up to 5 doses; 6 cohorts were treated at dose levels from 0.2-1.25 mg/kg. Pts in the expansion cohort and those who rolled over to the ext study were treated at ≥0.8 mg/kg with titration up to 1.25 mg/kg (base completed NCT01749540; ext ongoing NCT02268409).
Results
As of 02Sept2016, a total of 64 pts enrolled in the base study (31 TD, 33 NTD) and, of those, 51 enrolled in the ext study (24 TD, 27 NTD). Median (range) age (yr) was 38.5 (20-62); 67% had prior splenectomy. For TD pts, at baseline, median (range) transfusion burden was 8 U/12 weeks (4-18 U); mean (SD) liver iron concentration (LIC, mg/g dw) was 5.0 (5.3). For NTD pts, at baseline, median (range) Hgb (g/dL) 8.5 (6.5-9.8); mean (SD) LIC (mg/g dw) was 5.4 (3.8).
Conclusion
Long-term luspatercept treatment in pts with β-thalassemia was generally safe and well tolerated. Efficacy was clinically relevant in both TD pts (decreased transfusion burden) and NTD pts (increased Hgb levels, improved QoL). A Phase 3, double-blind, placebo-controlled study of luspatercept in regularly transfused adults with β-thalassemia is ongoing (NCT02604433).
Session topic: 26. Thalassemias
Keyword(s): Thalassemia, TGF-, Erythropoieisis, Clinical Trial
Abstract: S129
Type: Oral Presentation
Presentation during EHA22: On Friday, June 23, 2017 from 11:45 - 12:00
Location: Room N105
Background
Luspatercept (ACE-536), a fusion protein containing a modified activin receptor type IIB, is being developed for the treatment of β-thalassemia. Luspatercept binds to select TGF-β superfamily ligands (such as GDF11) reducing aberrant Smad2/3 signaling and promoting late-stage erythroid differentiation and increased hemoglobin (Hgb). Luspatercept corrected the effects of ineffective erythropoiesis in a mouse model of thalassemia (Suragani R, Blood, 2014) and increased Hgb and was well tolerated in a phase 1 study in healthy volunteers (Attie K, Am J Hematol, 2014).
Aims
This ongoing, phase 2, multicenter, open-label study followed by a long-term extension (ext) study evaluates the effects of luspatercept in patients (pts) with either transfusion-dependent (TD) or non-transfusion dependent (NTD) β-thalassemia with key endpoints of erythroid response (including Hgb increase) and pt-reported quality-of-life (QoL) in NTD patients, and reductions in RBC transfusion burden in TD patients.
Methods
Inclusion criteria: age ≥18 yr and either TD (≥4 RBC U/8 weeks prior to first dose, confirmed over 6 months) or NTD (<4 RBC U/8 weeks prior to first dose with baseline Hgb <10 g/dL). Pts were treated every 3 weeks subcutaneously for up to 5 doses; 6 cohorts were treated at dose levels from 0.2-1.25 mg/kg. Pts in the expansion cohort and those who rolled over to the ext study were treated at ≥0.8 mg/kg with titration up to 1.25 mg/kg (base completed NCT01749540; ext ongoing NCT02268409).
Results
As of 02Sept2016, a total of 64 pts enrolled in the base study (31 TD, 33 NTD) and, of those, 51 enrolled in the ext study (24 TD, 27 NTD). Median (range) age (yr) was 38.5 (20-62); 67% had prior splenectomy. For TD pts, at baseline, median (range) transfusion burden was 8 U/12 weeks (4-18 U); mean (SD) liver iron concentration (LIC, mg/g dw) was 5.0 (5.3). For NTD pts, at baseline, median (range) Hgb (g/dL) 8.5 (6.5-9.8); mean (SD) LIC (mg/g dw) was 5.4 (3.8).
Conclusion
Long-term luspatercept treatment in pts with β-thalassemia was generally safe and well tolerated. Efficacy was clinically relevant in both TD pts (decreased transfusion burden) and NTD pts (increased Hgb levels, improved QoL). A Phase 3, double-blind, placebo-controlled study of luspatercept in regularly transfused adults with β-thalassemia is ongoing (NCT02604433).
Session topic: 26. Thalassemias
Keyword(s): Thalassemia, TGF-, Erythropoieisis, Clinical Trial