Contributions
Type: Oral Presentation
Presentation during EHA20: From 12.06.2015 11:30 to 12.06.2015 11:45
Location: Room Strauss 1
Background
Luspatercept, a fusion protein containing modified activin receptor, is being developed for the treatment of beta-thalassemia (β-thal). Luspatercept binds to GDF11 and other ligands in the TGF-β superfamily to promote late-stage erythroid differentiation. Luspatercept corrected the effects of ineffective erythropoiesis in a thalassemia mouse model (Suragani R, Blood 2014) and was well tolerated and increased hemoglobin (Hb) in a phase 1 clinical study (Attie K, Am J Hematol 2014).
Aims
This is an ongoing, phase 2, multicenter, open-label, dose-finding study to evaluate luspatercept in adults with transfusion-dependent (TD) or non-transfusion dependent (NTD) β-thal. Efficacy outcomes include Hb increase in NTD patients, reduced RBC transfusion burden in TD patients, and liver iron concentration (LIC) by MRI.
Methods
Inclusion criteria included age ≥18 yr and either being TD or NTD β-thal with baseline Hb <10.0 g/dL. Luspatercept was administered SC every 3 wks for up to 5 doses with a 2-month follow-up. Six sequential cohorts (n=up to 6 each) were treated at escalating doses from 0.2 to 1.25 mg/kg. An expansion cohort (n=30) is ongoing; patients who complete the core study may be eligible to enroll in a 12-month extension study.
Results
Preliminary data (as of 16-Jan-2015) were available for 35 patients treated for 3 months. Median age was 35 yr, ranging from 20-57 yr, and 86% had prior splenectomy.
TD β-thal patients (n=11). Transfusion burden prior to treatment ranged from 4 to 8 units/12 weeks. All 10 (100%) evaluable patients achieved the primary endpoint of >20% decrease in transfusion burden over 12 weeks (includes 1 patient with only 8 weeks) compared with the 12 weeks prior to treatment (median 67%, ranging from 43 to 100%). The 5 TD β-thal patients in the higher dose groups with baseline LIC ≥5 mg/g dw who were on chronic iron chelation therapy (mean duration 2.5 yr) had a mean LIC decrease of 17% by week 16; this decrease in LIC correlated with a decrease in transfusion burden.
NTD β-thal patients (n=24). Mean baseline Hb was 8.3 g/dL, ranging from 6.5 to 9.6 g/dL. Three of 7 (43%) patients in the higher dose groups achieved the primary endpoint of increase in Hb >1.5 g/dL sustained for ≥2 weeks (mean duration 9 weeks) compared with 0 of 17 (0%) patients in the lower dose groups. The 5 NTD β-thal patients in the higher dose groups with baseline LIC ≥5 mg/g dw (includes 3 patients on iron chelation therapy) had a mean LIC decrease of 18%; this decrease in LIC correlated with an increase in hemoglobin.
All 3 β-thal patients with chronic leg ulcers at baseline (2 NTD, 1 TD) had substantial, rapid healing, beginning 4-6 weeks after the first dose of luspatercept. Luspatercept was generally well tolerated, with no related serious adverse events reported to date. Adverse events were mostly mild-moderate and the most frequent related adverse events (>10% patients) were bone pain, headache, myalgia, and pain in extremity.
Summary
Luspatercept treatment for up to 3 months was well-tolerated, increased Hb levels in NTD patients, and decreased transfusion requirement in TD patients with β-thalassemia. Both TD and NTD β-thal patients had decreases in LIC at therapeutic doses, and healing of leg ulcers occurred in 3 of 3 patients. These changes represent a significant reduction in disease burden for patients with β-thalassemia. Phase 3 studies of luspatercept in β-thalassemia are planned.
Keyword(s): Anemia, Clinical trial, Phase II, Thalassemia
Session topic: Red cells: Novel clinical aspects
Type: Oral Presentation
Presentation during EHA20: From 12.06.2015 11:30 to 12.06.2015 11:45
Location: Room Strauss 1
Background
Luspatercept, a fusion protein containing modified activin receptor, is being developed for the treatment of beta-thalassemia (β-thal). Luspatercept binds to GDF11 and other ligands in the TGF-β superfamily to promote late-stage erythroid differentiation. Luspatercept corrected the effects of ineffective erythropoiesis in a thalassemia mouse model (Suragani R, Blood 2014) and was well tolerated and increased hemoglobin (Hb) in a phase 1 clinical study (Attie K, Am J Hematol 2014).
Aims
This is an ongoing, phase 2, multicenter, open-label, dose-finding study to evaluate luspatercept in adults with transfusion-dependent (TD) or non-transfusion dependent (NTD) β-thal. Efficacy outcomes include Hb increase in NTD patients, reduced RBC transfusion burden in TD patients, and liver iron concentration (LIC) by MRI.
Methods
Inclusion criteria included age ≥18 yr and either being TD or NTD β-thal with baseline Hb <10.0 g/dL. Luspatercept was administered SC every 3 wks for up to 5 doses with a 2-month follow-up. Six sequential cohorts (n=up to 6 each) were treated at escalating doses from 0.2 to 1.25 mg/kg. An expansion cohort (n=30) is ongoing; patients who complete the core study may be eligible to enroll in a 12-month extension study.
Results
Preliminary data (as of 16-Jan-2015) were available for 35 patients treated for 3 months. Median age was 35 yr, ranging from 20-57 yr, and 86% had prior splenectomy.
TD β-thal patients (n=11). Transfusion burden prior to treatment ranged from 4 to 8 units/12 weeks. All 10 (100%) evaluable patients achieved the primary endpoint of >20% decrease in transfusion burden over 12 weeks (includes 1 patient with only 8 weeks) compared with the 12 weeks prior to treatment (median 67%, ranging from 43 to 100%). The 5 TD β-thal patients in the higher dose groups with baseline LIC ≥5 mg/g dw who were on chronic iron chelation therapy (mean duration 2.5 yr) had a mean LIC decrease of 17% by week 16; this decrease in LIC correlated with a decrease in transfusion burden.
NTD β-thal patients (n=24). Mean baseline Hb was 8.3 g/dL, ranging from 6.5 to 9.6 g/dL. Three of 7 (43%) patients in the higher dose groups achieved the primary endpoint of increase in Hb >1.5 g/dL sustained for ≥2 weeks (mean duration 9 weeks) compared with 0 of 17 (0%) patients in the lower dose groups. The 5 NTD β-thal patients in the higher dose groups with baseline LIC ≥5 mg/g dw (includes 3 patients on iron chelation therapy) had a mean LIC decrease of 18%; this decrease in LIC correlated with an increase in hemoglobin.
All 3 β-thal patients with chronic leg ulcers at baseline (2 NTD, 1 TD) had substantial, rapid healing, beginning 4-6 weeks after the first dose of luspatercept. Luspatercept was generally well tolerated, with no related serious adverse events reported to date. Adverse events were mostly mild-moderate and the most frequent related adverse events (>10% patients) were bone pain, headache, myalgia, and pain in extremity.
Summary
Luspatercept treatment for up to 3 months was well-tolerated, increased Hb levels in NTD patients, and decreased transfusion requirement in TD patients with β-thalassemia. Both TD and NTD β-thal patients had decreases in LIC at therapeutic doses, and healing of leg ulcers occurred in 3 of 3 patients. These changes represent a significant reduction in disease burden for patients with β-thalassemia. Phase 3 studies of luspatercept in β-thalassemia are planned.
Keyword(s): Anemia, Clinical trial, Phase II, Thalassemia
Session topic: Red cells: Novel clinical aspects