Luspatercept (ACE-536) Reduces Disease Burden, Including Anemia, Iron Overload, and Leg Ulcers, in Adults with Beta-Thalassemia: Results from a Phase 2 Study

Background. Luspatercept is a fusion protein (modified activin receptor IIB-IgG Fc) being investigated for the treatment of anemias with ineffective erythropoiesis. In beta-thalassemia, imbalanced production of alpha and beta globin chains in erythroid precursors inhibits late-stage erythroid differentiation, leading to anemia, ineffective erythropoiesis (IE), and dysregulated iron homeostasis.  Luspatercept promotes late-stage erythroid differentiation, corrects ineffective erythropoiesis, and reduces alpha globin aggregates, hemolysis, and disease complications including iron overload in a beta-thalassemia mouse model (Suragani R, Blood 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) beta-thalassemia. Efficacy outcomes include erythroid response including Hb increase in NTD patients and reduction in RBC transfusion burden in TD patients, and reduction in liver iron concentration (LIC) by MRI in both TD and NTD patients.

Methods. Inclusion criteria included age ≥ 18 yr and either TD (defined as ≥4 RBC units transfused in the 8 weeks prior to first dose, confirmed over 6 months) or NTD (defined as <4 RBC units transfused in the 8 weeks prior to first dose) with baseline Hb <10.0 g/dL. Luspatercept was administered SC every 3 weeks for up to 5 doses (12 weeks) with an 8-week follow-up (20 weeks total). Six sequential cohorts (n=up to 6 each) were treated at escalating dose levels from 0.2 to 1.25 mg/kg and an expansion cohort (n=30) is ongoing with starting dose level 0.8 mg/kg and individual dose titration.  Patients who completed the core study may have been eligible to enroll in an ongoing 24-month extension study.

Results. Preliminary data (as of 10-Apr-2015) were available for 39 patients, 35 patients from dose escalation, and 4 patients from the expansion. Median age was 40 yr, ranging from 20-57 yr, and 82% had prior splenectomy.

TD patients (n=14).  Transfusion burden prior to treatment ranged from 4 to 12 units/12 weeks.  Ten of 14 (71%) patients were treated for ≥12 weeks and were evaluable for the primary endpoint of ≥20% reduction in transfusion burden. All 10 of these patients responded with >40% reduction in transfusion burden over any 12-week period during the study. Reduction in transfusion burden correlated with reduction in LIC. Two of the 3 TD patients with baseline LIC ≥7 mg/g dw (all on iron chelation therapy) had a reduction in LIC at 16 weeks (-2.0 and -4.7 mg/g dw).

NTD patients (n=25).  Median baseline Hb was 8.4 g/dL (range 6.5-9.6 g/dL). Four of 8 (50%) patients in the 0.8-1.25 mg/kg dose groups achieved the primary endpoint of increase in Hb ≥1.5 g/dL sustained for ≥2 weeks, compared with 0 of 17 (0%) patients in the 0.2-0.6 mg/kg dose groups.  Four of eight (50%) patients in the 0.8-1.25 mg/kg dose groups had a mean increase in Hb ≥1.0 g/dL sustained for ≥12 weeks, compared with 5 of 17 (29%) patients in the 0.2-0.6 mg/kg dose groups. Eight of 12 (67%) NTD patients with baseline LIC ≥5 mg/g dw (including 6 patients on iron chelation therapy) had a reduction of at least 1 mg/g dw in LIC at 16 weeks; reduction in LIC correlated with increase in hemoglobin.

All 3 patients with chronic leg ulcers at baseline (2 NTD, 1 TD) had substantial, rapid healing, evident within 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; most frequent related adverse events (>10% patients) were bone pain, myalgia, headache and asthenia.

Longer-term treatment data from the extension study for TD and NTD patients will be presented.

Conclusions.  Luspatercept treatment for up to 3 months was well-tolerated, increased Hb levels in NTD patients, and decreased transfusion requirement in TD patients with beta-thalassemia.  Both TD and NTD patients also had decreases in LIC, and healing of leg ulcers occurred in 3 of 3 patients. These treatment effects represent a significant reduction in disease burden for patients with beta-thalassemia.  Phase 3 studies of luspatercept in beta-thalassemia are planned.