BMS Submits sBLA and Type II Variation for Reblozyl to Expand Indication to Non-Transfusion Dependent Beta Thalassemia in the US and EU

β ThalassemiaAnemia(Image Source: glowydowy.com)

December 14, 2021 /BioValleyBIOON/ -- Bristol-Myers Squibb (BMS) recently announced that the U.S. Food and Drug Administration (FDA) has accepted the supplemental Biologics License Application (sBLA) for Reblozyl (luspatercept-aamt) and granted priority review:This drug is a first-in-class erythroid maturation agent (EMA), used to treat anemia in non-transfusion-dependent (NTD) adult patients with β-thalassemia.。FDAThe Prescription Drug User Fee Act (PDUFA) target date for this sBLA has been set for March 27, 2022. Additionally, the European Medicines Agency (EMA) has accepted the Type II variation application for Reblozyl for the treatment of anemia in adult patients with NTDβ thalassemia.

NTD β-Thalassemia is a term used to describe patients who do not require lifelong regular red blood cell (RBC) transfusions to sustain life, although they may need occasional or slightly more frequent transfusions, usually within a specified period. Patients with NTD β-thalassemia experience chronic anemia and iron overload, which can lead to a range of clinical complications and an urgent need for treatment options.Clinical TrialData show,In adult patients with NTD β-thalassemia, regardless of baseline hemoglobin levels, Reblozyl can increase hemoglobin levels and improve patients' quality of life.

Reblozyl was originally co-developed by BMS and Acceleron Pharma. Following Merck's recent completion of the $11.5 billion acquisition of Acceleron, Reblozyl is now jointly developed and commercialized by BMS and Merck.Reblozyl is the first erythroid maturation agent (EMA) to receive regulatory approval for the treatment of β-thalassemia and anemia associated with very low/low/intermediate-risk myelodysplastic syndromes (MDS).。In the eligible patient population, Reblozyl represents an important treatment category. It should be noted that in patients requiring immediate correction of anemia, Reblozyl is not suitable as a substitute for red blood cell transfusion.

The active pharmaceutical ingredient of Reblozyl is luspatercept, a first-in-class erythroid maturation agent (EMA) that regulates the maturation of late-stage red blood cells. Luspatercept is a soluble fusion protein consisting of the Fc domain of human IgG1 fused to the extracellular domain of the activin IIB receptor (ActRIIB). It acts as a ligand trap by targeting and binding to specific ligands of the transforming growth factor (TGF)-β superfamily that regulate late-stage red blood cell maturation, thereby reducing the activation of the Smad2/3 signaling pathway, improving ineffective red blood cell production, promoting the maturation of late-stage red blood cells, and increasing hemoglobin levels.

Reblozyl sBLA and Type II Variation Application, Based on Safety and Efficacy Results from the Pivotal Phase 2 BEYOND Study. The study was conducted in adult patients with NTD β-thalassemia, evaluating Reblozyl in combination with Best Supportive Care (BSC). Data published in June 2021 showed,77.1% of patients in the Reblozyl+BSC treatment group achieved an increase in hemoglobin levels (≥1.0g/dL), compared to 0% in the placebo+BSC group. Additionally, patient-reported outcomes in the Reblozyl group showed improvement compared to the placebo group.

Noah Berkowitz, M.D., Ph.D., Senior Vice President of Hematology Development at Bristol-Myers Squibb, stated: "Patients with non-transfusion-dependent β-thalassemia may not require lifelong transfusions to sustain life, but they do need effective treatment options as they face a range of chronic anemia and iron overload-related clinical complications. Reblozyl is a significant therapy approved in multiple countries, including the United States and the European Union, for treating anemia associated with β-thalassemia and low-risk myelodysplastic syndromes. Together with Merck, we are committed to advancing the Reblozyl clinical program and look forward to engaging with regulatory authorities throughout the review process."FDA"Close collaboration and communication to bring a new treatment option to this underserved patient population."

Mechanism of Action of Luspatercept

BEYOND is a randomized, double-blind, placebo-controlled, multicenter Phase 2 study conducted in non-transfusion-dependent (NTD) adult patients with β-thalassemia, aiming to evaluate the efficacy and safety of Reblozyl compared to placebo. Enrolled patients were: aged ≥18 years, diagnosed with β-thalassemia or hemoglobin (Hb) E β-thalassemia, received ≤5 units of red blood cell (RBC) transfusions within 24 weeks prior to randomization, and had an average baseline Hb ≤10.0 grams/deciliter (g/dL).

In the study, 145 patients were randomly assigned in a 2:1 ratio to receive either Reblozyl (1 mg/kg [titrated to 1.25 mg/kg]) or placebo via subcutaneous injection every 3 weeks for a treatment duration of ≥48 weeks. Patients in both groups continued to receive best supportive care (BSC), including RBC transfusions and iron chelation therapy. The primary endpoint was the mean increase in hemoglobin by ≥1.0 g/dL from baseline during a consecutive 12-week period from Weeks 13–24 without RBC transfusion. Secondary endpoints included: the proportion of patients remaining transfusion-free during Weeks 1–24, the proportion of patients with a mean increase in hemoglobin levels of ≥1.5 g/dL from baseline to Weeks 13–24, and the mean change in patient-reported fatigue and weakness scores on the NTDT-PRO T/W scale (higher scores reflect worse quality of life [QoL]).

The primary endpoint results showed that 77.1% (n=74/96) of patients in the Reblozyl treatment group reached the primary endpoint, compared to 0% (n=0/49) in the placebo group, with a statistically significant difference (p<0.0001). Among patients with an average baseline Hb <8.5g/dL, 72.7% (n=40/55) in the Reblozyl treatment group reached the primary endpoint, compared to 0% in the placebo group (p<0.0001); among patients with an average baseline Hb ≥8.5g/dL, 82.9% (n=34/41) in the Reblozyl treatment group reached the primary endpoint, compared to 0% in the placebo group (p<0.0001).

For key secondary endpoints: (1) 52.1% (n=50/96) of patients in the Reblozyl treatment group achieved an average Hb increase ≥1.5g/dL from baseline during weeks 13-24, compared to 0% in the placebo group (p<0.0001). (2) During weeks 1-24, 89.6% of patients in the Reblozyl treatment group remained transfusion-free, compared to 67.3% in the placebo group (p=0.0013). (3) Improvements in patient-reported quality of life outcomes (fatigue and weakness) were also associated with increases in hemoglobin.

In terms of safety, the most common treatment-emergent adverse events (TEAEs) of any grade occurring in ≥5% of patients were bone pain (Reblozyl group vs placebo group: 36.5% vs 6.1%), headache (30.2% vs 20.4%), and arthralgia (29.2% vs 14.3%). No malignancies were reported in patients receiving Reblozyl.TumorOr thromboembolic events.

The latest analysis of the BEYOND study will be presented at the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition, to be held from December 11 to 14. (Bioon.com)

Source of the original text:U.S. Food and Drug Administration Accepts for Priority Review supplemental Biologics License Application for Reblozyl (luspatercept-aamt) in Adults with Non-Transfusion Dependent (NTD) Beta Thalassemia