Bristol Myers Squibb’s Reblozyl, the First-in-Class Erythroid Maturation Agent, Demonstrates Significant Hemoglobin Improvement in Non-Transfusion Dependent Beta Thalassemia Patients in Phase 2 BEYOND Study

β-thalassemiaAnemia(Image source: glowydowy.com)

June 15, 2021 /BioonBIOON/ -- Bristol-Myers Squibb (BMS) and Acceleron Pharma recently jointly announced the initial results from the Phase 2 BEYOND study. The study is evaluating the first-in-class erythroid maturation agent (EMA) Reblozyl (luspatercept) in combination with best supportive care (BSC) for the treatment of adult patients with non-transfusion-dependent (NTD) β-thalassemia. The results showed that,77.1% of patients in the Reblozyl + BSC treatment group achieved a hemoglobin increase of ≥1.0 g/dL, compared with 0% in the placebo + BSC group.Additionally,Compared with the placebo group, patient-reported outcomes in the Reblozyl group also showed improvement.NTD β-thalassemia is a term used to describe patients who do not require lifelong regular red blood cell (RBC) transfusions for survival, although they may require occasional or slightly more frequent transfusions, typically during specified periods.

Dr. Ali Taher of the American University of Beirut, an investigator for the BEYOND study, stated: “Patients with non-transfusion-dependent β-thalassemia experience chronic anemia and iron overload, which can lead to a range of clinical complications, creating an urgent need for treatment options. The results of the BEYOND study demonstrate that Reblozyl holds clinical potential to maintain elevated hemoglobin levels in the majority of adult patients with non-transfusion-dependent β-thalassemia, regardless of baseline hemoglobin levels, while also improving patients’ quality of life.”

Reblozyl is the first and only regulatory-approved erythroid maturation agent for the treatment of anemia associated with β-thalassemia and very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS).In the eligible patient population, Reblozyl represents an important therapeutic class. It should be noted that Reblozyl is not indicated as a substitute for red blood cell transfusions in patients who require immediate correction of anemia.

The efficacy and safety of Reblozyl in the treatment of β-thalassemia and MDS-associated anemia were confirmed in the pivotal Phase 3 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. Results showed that, compared with the placebo group, patients in the Reblozyl treatment group experienced a significant reduction in transfusion burden.

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

Luspatercept is globally co-developed by Celgene (acquired by Bristol-Myers Squibb) and Acceleron Pharma. Currently, both companies are also evaluating the therapeutic 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.

Mechanism of Action of Luspatercept

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

In the study, 145 patients were randomized in a 2:1 ratio to receive subcutaneous Reblozyl (1 mg/kg [titrated to 1.25 mg/kg]) or placebo every 3 weeks for ≥48 weeks. Both groups continued to receive best supportive care (BSC), including RBC transfusions and iron chelation therapy. The primary endpoint was a mean hemoglobin increase of 1.0 g/dL from baseline without RBC transfusion for 12 consecutive weeks starting from weeks 13–24. Secondary endpoints included the proportion of patients remaining transfusion-free during weeks 1–24, the proportion of patients with a mean hemoglobin increase of ≥1.5 g/dL from baseline through weeks 13–24, and the mean change in the non-transfusion-dependent β-thalassemia patient-reported outcomes fatigue and weakness (NTDT-PRO T/W) score (higher scores reflect worse quality of life [QoL]).

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

Regarding key secondary endpoints: (1) In the Reblozyl treatment group, 52.1% (n=50/96) of patients achieved an increase in mean Hb level of ≥1.5 g/dL from baseline during weeks 13–24, compared with 0% in the placebo group (p < 0.0001). (2) During weeks 1–24, 89.6% of patients in the Reblozyl group remained transfusion-independent, compared with 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.

Regarding 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%). Among patients treated with Reblozyl, no malignantTumoror thromboembolic events. (Bioon.com)

Source:Bristol Myers Squibb and Acceleron Present First Results from Phase 2 BEYOND Study of Reblozyl® (luspatercept-aamt) in Adults with Non-Transfusion Dependent(NTD)Beta Thalassemia