Luspatercept-aamt approved to treat anemia in adult patients with beta thalassemia who require regular red blood cell transfusions.
A recombinant fusion protein that consists of a modified extracellular domain of the human activin receptor type IIB (ActRIIB) linked to the human immunoglobulin IgI Fc domain.
ActRIIB Receptor and its ligand are part of the transforming growth factor-beta super family which modulate erythrocyte differentiation in the bone marrow.
Luspatercept is a recombinant fusion proteins that bind transforming growth factor B super family ligands to reduce SMAD2 and SMAD3 and signaling in late stages of erythropoiesis.
Luspatercept has shown the most promise for patients with ringed sideroblasts (RS), particularly those harboring mutant SF3B1.
Luspatercept is a Recombinant fusion protein that binds transforming growth factor beta super family ligands to enhance late stage erythropoiesis.
In patients with ring sideroblasts luspatercept results in transfusion independence in 38 cases 38% of cases.
Smad 2/3 signaling pathway negatively regulates erythroid differentiation in beta thalassemia.
This drug prevents activin binding and subsequently decreases aberrant Smad 2/3 signaling increasing erythroid maturation.
Luspatercept is a modified activin receptor IIB-IgG Fc fusion protein that targets transforming growth factor beta (TGF-B) signaling and differentiation factor 11 enhancing g late-stage red blood cell (RBC) maturation.
In patients with lower risk myelodysplastic syndrome, this agent was developed for transfusion-dependent, anemic patients who do not meet criteria for erythropoiesis stimulating agents (ESA) therapy or who have failed to respond to such treatment.
This agent has shown the most promise for patients with ringed sideroblasts (RS), particularly those harboring mutant SF3B1.
Reblozyl is tradename.
It the first and only approved erythroid maturation agent.
It is a modified activin receptor IIB-IgG Fc fusion protein that targets transforming growth factor beta (TGF-B) signaling via Smad2/3 and growth and differentiation factor 11 (GDF-11) enhances late-stage red blood cell (RBC) maturation.
Phase 3, randomized, double-blind, placebo-controlled, multicenter BELIEVE trial – designed to evaluate the safety and efficacy of luspatercept, which works by regulating late-stage red blood cell maturation to help patients reduce their red blood cell transfusion burden, for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell transfusions.
Patients were randomized 2:1 to receive either luspatercept administered subcutaneously once every 3 weeks as long as a reduction in transfusion requirement was observed or until unacceptable toxicity, or placebo.
Patients treated with luspatercept significant improvement in the reduction of red blood cell transfusion burden.
Approved for the treatment of anemia in patients with beta cells same year based on the BELIVE trial, a phase III Multi Center, randomized, double blind, placebo controlled trial in adults requiring regular red cell blood transfusions.
Overall, 21.4% of patients achieved a ≥33% reduction during weeks 13-24 after randomization of treatment, compared to 4.5% of patients in the placebo arm.
In addition, 19.6% of patients in the luspatercept arm and 3.6% in the placebo arm experienced a transfusion burden reduction of at least 33% during weeks 37-48.
There was a ≥50% reduction in transfusion burden in 7.6% of patients who received luspatercept, compared with 1.8% of patients (n = 2) in the placebo arm at weeks 13-24 (risk difference, 5.8; 95% CI, 1.6-10.1; P =.0303); and 10.3% of patients (n = 23), compared with 0.9% of patients (n = 1), respectively, at weeks 37-48 (risk difference, 9.4; 95% CI, 5-13.7; P =.0017).
In a double blind placebo controlled phase 3 trial reduced the severity of anemia in patients with very low risk myelodysplastic syndrome with ring sideroblasts who is receiving regular red cell transfusions and who had disease that was refractory to or unlikely to respond to a erythropoiesis stimulating agents or who had discontinued such agents due to an adverse event ( Fenaux P).
Approved luspatercept-aamt (Reblozyl) for the treatment of anemia failing an erythropoiesis stimulating agent (ESA) and requiring 2 or more red blood cell (RBC) units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis
Thromboembolic events, which occurred in 3.6% of patients treated with luspatercept, included deep vein thromboses, pulmonary embolus, portal vein thrombosis, and ischemic stroke.
Serious adverse events (AEs) occurred in 3.6% of patients. One patient died due to an unconfirmed case of acute myeloid leukemia.
The most common AEs in the luspatercept and placebo arms were headache (26% vs 24%, respectively), bone pain (20% vs 8%), arthralgia (19% vs 12%), fatigue (14% vs 13%), cough (14% vs 11%), abdominal pain (14% vs 12%), diarrhea (12% vs 10%), and dizziness (11% vs 5%).
Permanent discontinuation due to an AE occurred in 5.4% of patients who received luspatercept, which included arthralgia (1%), back pain (1%), bone pain (<1%), and headache (<1%), and dose reductions occurred in 2.7% of patients.
Lastly, Celgene noted that the agent is not indicated for use as a substitute for red blood cell transfusions in patients who require immediate correction of anemia.
The FDA recommended a starting dose of 1 mg/kg once every 3 weeks by subcutaneous injection.
Most common adverse events are headache, increased serum bilirubin, bone pain, and muscle pain.