Bristol Myers Squibb and Acceleron Announce European Commission Approval of Reblozyl (Luspatercept) for Transfusion-Dependent Anemia in Adult Patients with Beta Thalassemia or Myelodysplastic Syndromes

June 25, 2020 /BioonBIOON/ -- Bristol-Myers Squibb (BMS) and Acceleron Pharma recently announced jointly that the European Commission (EC) has approved Reblozyl (luspatercept) for the treatment of adult patients with beta-thalassemiaAnemia(β-thalassemia) and anemia associated with myelodysplastic syndromes (MDS). Specifically: (1) for the treatment of transfusion-dependent anemia associated with β-thalassemia in adult patients; (2) for the treatment of transfusion-dependent anemia caused by MDS in adult patients with very low-, low-, or intermediate-risk MDS who have ring sideroblasts (RS) in bone marrow smears and are unsuitable for or have an inadequate response to erythropoietin (EPO).

It is worth noting that Reblozyl is the first and only erythroid maturation agent approved in the United States and the European Union, representing a novel class of therapies that reduce or eliminate the burden of regular red blood cell transfusions by modulating the late stages of erythroid maturation. It should be noted that Reblozyl is not indicated as a substitute for red blood cell transfusion in patients requiring immediate correction of anemia.

The efficacy and safety of Reblozyl in the treatment of β-thalassemia and MDS-related anemia were confirmed in the pivotal Phase III BELIEVE and MEDALIST studies, respectively. The BELIEVE study was conducted in patients with transfusion-dependent β-thalassemia, while the MEDALIST study was conducted in patients with very low- to intermediate-risk MDS. Both studies met their primary endpoints and all key secondary endpoints. The results demonstrated that, compared with the placebo group, patients treated with luspatercept experienced a significant reduction in transfusion burden.

——BELIEVE：This is a randomized, double-blind, placebo-controlled, multicenter study conducted in adult patients with transfusion-dependent β-thalassemia who require regular red blood cell (RBC) transfusions (6–20 units of RBCs every 24 weeks, with no transfusion-free interval exceeding 35 days during this period). In the study, patients were randomly assigned to receive either Reblozyl plus best supportive care (BSC) or placebo plus BSC. In this study, BSC included: RBC transfusions, iron chelation therapy, use ofAntibiotics, antiviral and antifungal therapy, and/or nutritional support as needed.

The results showed that the proportion of patients with a reduction in red blood cell (RBC) transfusion burden of >33% (a reduction of at least 2 units) from baseline during Weeks 13–24 was significantly higher in the Reblozyl treatment group than in the placebo group, thereby meeting the primary endpoint of the study. Furthermore, the study also met all key secondary endpoints: the proportions of patients with a >33% reduction in RBC transfusion burden during Weeks 37–49, and those with a >50% reduction during Weeks 13–24 or Weeks 37–48, were all significantly higher in the Reblozyl treatment group than in the placebo group. In this study, the most common adverse events (any grade) with an incidence rate more than 5% higher in the Reblozyl treatment group than in the placebo group included: bone pain (19.7% vs 8.3%), dizziness (11.2% vs 4.6%),Hypertension(8.1% vs. 2.8%), hyperuricemia (7.2% vs. 0%).

——MEDALIST：This was a randomized, double-blind, placebo-controlled, multicenter Phase III study conducted in 229 patients with very low- to intermediate-risk myelodysplastic syndromes (MDS) to evaluate the efficacy and safety of luspatercept versus placebo for the treatment of anemia. These patients had ring sideroblasts (RS+), required red blood cell (RBC) transfusions, and had failed prior erythropoiesis-stimulating agent (ESA) therapy, were intolerant to ESAs, or were ineligible/unlikely to respond to ESA treatment. In the study, patients were randomized in a 2:1 ratio to receive either luspatercept (n=153; subcutaneous injection at 1.0–1.75 mg/kg body weight every 3 weeks) or placebo (n=76). The primary endpoint was achieving RBC transfusion independence (RBC-TI) for ≥8 consecutive weeks during Weeks 1–24 of the study. Key secondary endpoints included achieving RBC-TI for ≥12 consecutive weeks during Weeks 1–24 and during Weeks 1–48 of the study.

The results showed that the study met its primary endpoint: a statistically significant higher proportion of patients in the luspatercept group achieved red blood cell transfusion independence (RBC-TI) for ≥8 weeks during the first 24 weeks (Weeks 1–24) compared with the placebo group (38% vs. 18%, p<0.001). Furthermore, a higher proportion of patients in the luspatercept group achieved the key secondary endpoints compared with the placebo group (RBC-TI for ≥12 weeks during Weeks 1–24: 28% vs. 8%; RBC-TI for ≥12 weeks during Weeks 1–48: 33% vs. 12%; p<0.001 for both comparisons). The most common adverse events (any grade) associated with luspatercept in this study included fatigue, diarrhea, asthenia, nausea, and dizziness. The incidence of adverse events decreased over time.

The active pharmaceutical ingredient of Reblozyl is luspatercept, a first-in-class erythroid maturation agent (EMA) that modulates late-stage erythrocyte maturation. This drug is a soluble fusion protein composed of the Fc domain of human IgG1 fused to the extracellular domain of the activin receptor type IIB (ActRIIB). Acting as a ligand trap, it specifically binds to certain ligands of the transforming growth factor (TGF)-β superfamily that regulate late-stage red blood cell (RBC) maturation, thereby reducing activation of the Smad2/3 signaling pathway, ameliorating ineffective erythropoiesis, promoting late-stage erythrocyte maturation, and increasing hemoglobin levels.

Luspatercept is being developed globally through a collaboration between Celgene (acquired by BMS) and Acceleron Pharma. Currently, both parties are also evaluating the potential of luspatercept for treating erythropoiesis-stimulating agent (ESA)-naïve patients with lower-risk myelodysplastic syndromes (MDS) (Phase III COMMANDS study), non-transfusion-dependent β-thalassemia (Phase II BEYOND study), and myelofibrosis. The industry holds strong optimism regarding the commercial prospects of luspatercept. Late last year, EvaluatePharma released its report “Vantage 2019 Preview,” which highlighted the top 20 most valuable R&D projects worldwide, with luspatercept ranking 18th with a net present value (NPV) of $3.1 billion.

Previously, analysts at the prominent Wall Street investment bank Jefferies predicted that Reblozyl’s annual peak sales would reach $2 billion. (Bioon.com)

Original Source: European Commissionapproves Reblozyl (luspatercept) for the Treatment of Transfusion-Dependent Anemia in Adult Patients with Myelodysplastic Syndromes or Beta Thalassemia