BMS and Acceleron Announce Significant Phase 3 MEDALIST Trial Results for Reblozyl in Lower-Risk MDS-Related Anemia

January 11, 2020 /BioValleyBIOON/ -- Bristol-Myers Squibb (BMS) and Acceleron Pharma recently announced a joint evaluation of the erythroid maturation agent Reblozyl (luspatercept-aamt) for the treatment of patients with myelodysplastic syndromes (MDS)AnemiaThe results of the pivotal Phase III MEDALIST study (NCT02631070) have been published in The New England Journal of Medicine (NEJM), under the title:Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes。

MEDALIST was a randomized, double-blind, placebo-controlled, multicenter Phase 3 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 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 demonstrated 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 greater proportion of patients in the luspatercept group achieved 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 above results indicate that luspatercept treatment reduced the severity of anemia and significantly decreased transfusion burden in patients with very low- to intermediate-risk MDS who received regular red blood cell transfusions, had ring sideroblasts (RS+), were refractory or unlikely to respond to erythropoiesis-stimulating agents (ESAs), or discontinued such therapy due to adverse events.

Reblozyl is an erythroid maturation agent that was approved in the United States in November 2019FDAApproved 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 firstFDAA drug approved for the treatment of anemia associated with beta-thalassemia, it is also the first red blood cell maturation agent approved by the FDA. It represents a new class of therapies that help patients reduce their red blood cell transfusion burden by regulating the late stages of erythroid maturation. It should be noted that Reblozyl is not intended as a substitute for red blood cell transfusions in patients requiring immediate correction of anemia.

Currently, the Biologics License Application (BLA) for Reblozyl in the treatment of MDS-associated anemia is under reviewFDAThe BLA is under review for the approval of Reblozyl to treat anemia in adult patients with very low- to intermediate-risk MDS who have ring sideroblasts (RS+) on bone marrow smears and require regular red blood cell (RBC) transfusions, with a Prescription Drug User Fee Act (PDUFA) goal date of April 4, 2020. In Europe, the Marketing Authorization Application (MAA) for Reblozyl to treat anemia in adults with β-thalassemia and MDS is under review by the European Medicines Agency (EMA).

Mechanism of Action of Luspatercept

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 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 the treatment of 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 the 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, Jefferies, a prominent Wall Street investment bank, pointed out that if anemia associated with myelodysplastic syndromes (MDS) also receivedFDAApproved, Reblozyl’s annual peak sales are projected to reach $2 billion. (Bioon.com)

Original Source:New England Journal of Medicine Publishes Results of Pivotal Phase 3 Reblozyl® (luspatercept-aamt) MEDALIST Trial