BMS and Acceleron Announce FDA Approval of Reblozyl (Luspatercept), the First Erythroid Maturation Agent, for Anemia in Lower-Risk MDS Patients

April 06, 2020 News /BioonBIOON/ -- Bristol-Myers Squibb (BMS) and Acceleron Pharma recently jointly announced that the U.S. Food and Drug Administration (FDA) has approved Reblozyl (luspatercept) for the treatment of adult patients with low-risk myelodysplastic syndromes (MDS)Anemia. The specific indications for this drug are: adult patients with very low-risk to intermediate-risk myelodysplastic syndrome with ring sideroblasts (MDS-RS) who have failed treatment with one erythropoiesis-stimulating agent, require transfusion of ≥2 red blood cell (RBC) units within 8 weeks, and have ring sideroblasts present in bone marrow smears; or patients with myelodysplastic syndrome/myeloproliferativeTumor(MDS/MPN-RS-T) Adult patients, treatment of anemia.

Reblozyl is the first and onlyFDAApproved Erythroid Maturation Agents, representing a new class of therapies that help reduce the burden of red blood cell transfusions in patients by modulating the late stages of erythroid maturation. This approval marks the second indication for Reblozyl approved in the United States. In the U.S., Reblozyl was first approved in November 2019 for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell transfusions.

It is worth mentioning that,Reblozyl is the first drug approved by the FDA for the treatment of anemia associated with beta-thalassemia, and also the first in over a decade to beFDAApproval of a New Treatment Regimen for MDS Patients Requiring Red Blood Cell (RBC) Transfusions and Who Have Failed Treatment with an Erythropoiesis-Stimulating AgentIt should be noted that Reblozyl is not indicated as a substitute for red blood cell transfusion in patients who require immediate correction of anemia.

The University of Texas MD Anderson Cancer CenterLeukemiaGuillermo Garcia-Manero, M.D., professor in the Department of Myelodysplastic Syndromes, said: “InClinical TrialReblozyl demonstrated significant therapeutic benefits for anemia in patients with myelodysplastic syndromes (MDS) with ring sideroblasts. Anemia is a serious complication of MDS, requiring most patients to undergo regular red blood cell transfusions, which can lead to additional complications such as iron overload, transfusion site reactions, and infections. In our current landscape, we must recognize the substantial burden that frequent transfusions may impose on both individuals and the healthcare system. The approval of Reblozyl represents an important milestone for the majority of patients with myelodysplastic syndromes who have limited treatment options for disease-related anemia.”

The approval of this indication for MDS is based on the results of the Phase III MEDALIST study (NCT02631070). This was a randomized, double-blind, placebo-controlled, multicenter study evaluating Reblozyl inipsEfficacy and Safety of S-R in Adult Patients with Very Low-, Low-, or Intermediate-Risk Non-del(5q) Myelodysplastic Syndromes (MDS) and Ring Sideroblasts (RS) in Bone Marrow Smears. All patients were red blood cell (RBC) transfusion-dependent, refractory or intolerant to prior erythropoiesis-stimulating agent (ESA) therapy, or ESA-naïve with a low likelihood of response due to endogenous serum erythropoietin levels ≥200 U/L, and had not previously received disease-modifying therapy.

The findings of this study were published in January 2020 in the New England Journal of Medicine (NEJM), a premier international medical journal. The article is titled:Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes。

The results showed that during the first 24 weeks of the study, a significantly higher proportion of patients in the Reblozyl group achieved freedom from transfusion dependence for ≥8 weeks compared with the placebo group (38% vs. 13%, p<0.001), thereby meeting the primary endpoint of the study. Furthermore, during the first 24 and 48 weeks of the study, a significantly higher proportion of patients in the Reblozyl group achieved freedom from transfusion dependence for ≥12 weeks compared with the placebo group (weeks 1–24: 28% vs. 8%, p<0.001; weeks 1–48: 33% vs. 12%, p<0.001).

Regarding safety, most treatment-emergent adverse events (TEAEs) were Grade 1–2. Grade 3 or 4 TEAEs were reported in 42.5% of patients in the Reblozyl group and 44.7% of patients in the placebo group. The most common (＞10%) all-gradeAdverse ReactionsIncluding: fatigue, musculoskeletal pain, dizziness, diarrhea, dyspnea, nausea, allergic reactions, headache, and upper respiratory tract infection.

The above results indicate that in patients with very low- to intermediate-risk MDS who receive regular red blood cell transfusions, have ring sideroblasts (RS+), are refractory to erythropoiesis-stimulating agents (ESAs) or are unlikely to achieve a therapeutic response, or who have discontinued such agents due to adverse events, treatment with Reblozyl reduced the severity of anemia and significantly decreased the transfusion burden.

Mechanism of Action of Luspatercept

Myelodysplastic Syndromes (MDS) are a group of blood cancers closely associated with abnormal bone marrow proliferation, characterized by ineffective hematopoiesis and reduced production of healthy red blood cells, white blood cells, and platelets, leading to anemia and frequent or severe infections. MDS patients who develop anemia often require regular blood transfusions to increase the number of healthy red blood cells in the circulatory system. Frequent transfusions increase the risk of iron overload, transfusion reactions, and infections.

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 selectively binds specific 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 RBC 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 optimistic views on the commercial prospects of luspatercept. Late last year, EvaluatePharma released the report “Vantage 2019 Preview,” which reviewed 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 pointed out that if anemia associated with myelodysplastic syndromes (MDS) also receivesFDAApproved, Reblozyl’s annual peak sales are projected to reach $2 billion. (Bioon.com)

Original Source:U.S. Food and Drug Administration (FDA) Approves Reblozyl® (luspatercept-aamt) , the First and Only Erythroid Maturation Agent, to Treat Anemia in Adults with Lower-Risk Myelodysplastic Syndromes (MDS)