BMS Announces FDA and EMA Acceptance of New sBLA/II Variation for Reblozyl (Luspatercept) as First-Line Treatment for Anemia in Lower-Risk MDS

May 02, 2023 09:16 CST Updated 09:16

Bristol-Myers Squibb

Biopharmaceutical and Nutritional Product R&D and Sales

FDA

U.S. Food and Drug Administration

European Medicines Agency

The European Medicines Agency (EMA) is a decentralized agency of the European Union (EU), located in London. It began operations in 1995. The agency is responsible for the scientific evaluation, supervision, and safety monitoring of medicines developed by pharmaceutical companies for use in the EU. By ensuring that all medicines available on the EU market are safe, effective, and of high quality, the EMA protects public and animal health in the 28 EU Member States and countries of the European Economic Area.

On May 1, Bristol-Myers Squibb (BMS) announced that the U.S. FDA has accepted the supplemental Biologics License Application (sBLA) for Reblozyl (luspatercept) for the treatment of anemia associated with very low- to intermediate-risk myelodysplastic syndromes (MDS) in adult patients who may require red blood cell (RBC) transfusions and are naïve to erythropoiesis-stimulating agents (ESA-naïve). The FDA has granted this sBLA a priority review, with a PDUFA date set for August 28, 2023. Meanwhile, the European Medicines Agency (EMA) has also validated the Type II variation application for Reblozyl, which will subsequently enter the centralized review process.

These applications are based on the results of the COMMANDS study, an open-label, randomized, active-controlled Phase III clinical trial that enrolled 347 patients. The study aimed to evaluate the efficacy and safety of luspatercept compared to epoetin alfa in treating anemia caused by very low- to intermediate-risk (assessed by the IPSS-R system) MDS patients who require regular red blood cell (RBC) transfusions and have not received prior ESA treatment.

The primary endpoint of the trial is the red blood cell transfusion independence (RBC-TI) at week 12, with an increase in average hemoglobin levels of ≥1.5g/dL. Key secondary endpoints include RBC-TI at week 24, RBC-TI for 12 weeks or more, and a red blood cell response for at least 8 weeks during the period from week 1 to week 24.

Interim analysis results showed that, in the first-line treatment of adult patients with anemia requiring red blood cell transfusions and very low-, low-, or intermediate-risk MDS, patients in the luspatercept group achieved a highly statistically significant and clinically meaningful improvement in RBC-TI, along with increased hemoglobin levels. Additionally, the safety profile of luspatercept was consistent with previous findings from the MEDALIST study, with no new safety signals reported.

MDS is a group of heterogeneous myeloid clonal disorders originating from hematopoietic stem cells, characterized by dysplasia in myeloid cell lines and clinically presenting as ineffective hematopoiesis and refractory cytopenia. Patients with MDS may experience symptoms such as infections, anemia, spontaneous bleeding, and easy bruising. MDS patients with anemia typically require regular blood transfusions to increase the number of healthy red blood cells in circulation. However, frequent transfusions increase the risk of iron overload, transfusion reactions, and infections. In the United States, approximately 10,000 new cases of MDS are diagnosed annually, with about 30% progressing to acute myeloid leukemia (AML). While MDS can occur at any age, it is most commonly seen in individuals aged 60 years and older.

Luspatercept, a fusion protein of activin receptor 2B (ACVR2B)-Fc jointly developed by Merck and Bristol-Myers Squibb (BMS), restores late-stage red blood cell maturation and enables the body to produce more normal red blood cells. It achieves this by binding to specific TGF-β superfamily ligands (key factors regulating red blood cell maturation) and reducing the overactivated Smad 2/3 signaling pathway. Luspatercept was initially developed by Acceleron Pharma. In August 2011, Celgene (which has since been acquired by BMS) partnered with Acceleron to co-lead the product’s development, manufacturing, and commercialization. In November 2021, Merck acquired Acceleron for $11.5 billion, thereby obtaining rights to luspatercept.

The Structure and Mechanism of Action of Luspatercept

In November 2019, Luspatercept was approved for the first time in the United States for the treatment of patients with transfusion-dependent β-thalassemia. In April 2020, Luspatercept was approved for a new indication to treat anemia in patients with very low- to intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts (MDS-RS), or MDS/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis. These patients had an inadequate response to erythropoiesis-stimulating agent (ESA) therapy, require regular red blood cell transfusions, and receive ≥2 units of red blood cells every 8 weeks.

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