Reblozyl (luspatercept-aamt) - 3 indications

Scroll down for information on each indication:

• for the treatment of anemia in adults with beta thalassemia requiring regular RBC transfusion; approved November 2019
• for the treatment of anemia failing an erythropoiesis stimulating agent and requiring 2 or more red blood cell units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndromes or with myelodysplastic/ myeloproliferative neoplasm; approved April 2020
• for the treatment of anemia without previous erythropoiesis stimulating agent use (ESA-naïve) in adult patients with very low- to intermediate-risk myelodysplastic syndromes who may require regular red blood cell transfusions; approved August 2023

General Information

Reblozyl (luspatercept-aamt) is an erythroid maturation agent.

Reblozyl is specifically indicated for the following conditions:

• the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions.
• the treatment of anemia failing an erythropoiesis stimulating agent and requiring 2 or more red blood cell 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.
• for the treatment of anemia without previous erythropoiesis stimulating agent use (ESA-naïve) in adult patients with very low- to intermediate-risk myelodysplastic syndromes who may require regular red blood cell transfusions

Reblozyl is supplied as an injection for subcutaneous administration. The recommended starting dose of Reblozyl is 1 mg/kg once every 3 weeks by subcutaneous injection.
 
If a planned administration of Reblozyl is delayed or missed, administer Reblozyl as soon as possible and continue dosing as prescribed, with at least 3 weeks between doses. Assess and review hemoglobin (Hgb) results prior to each administration. If an RBC transfusion occurred prior to dosing, the pretransfusion Hgb must be considered for dosing purposes.
 
If the pre-dose Hgb is greater than or equal to 11.5 g/dL and the Hgb level is not influenced by recent transfusion, delay dosing until the Hgb is less than or equal to 11 g/dL.

If a patient does not achieve a reduction in RBC transfusion burden after at least 2 consecutive doses (6 weeks) at the 1 mg/kg starting dose, increase the Reblozyl dose to 1.25 mg/kg. Do not increase the dose beyond the maximum dose of 1.25 mg/kg.  

Mechanism of Action

Reblozyl (Luspatercept-aamt) is a recombinant fusion protein that binds several endogenous TGF-β superfamily ligands, thereby diminishing Smad2/3 signaling. Luspatercept-aamt promoted erythroid maturation through differentiation of late-stage erythroid precursors (normoblasts) in mice. In a model of β-thalassemia, luspatercept-aamt decreased abnormally elevated Smad2/3 signaling and improved hematology parameters associated with ineffective erythropoiesis in mice.

Side Effects

Adverse effects associated with the use of Reblozyl may include, but are not limited to, the following:

• headache
• bone pain
• arthralgia
• fatigue
• cough
• abdominal pain
• diarrhea
• dizziness
• musculoskeletal pain
• dyspnea
• nausea
• hypersensitivity reactions
• upper respiratory tract infection

Indication 1 - for the treatment of anemia in adults with beta thalassemia requiring regular RBC transfusion

approved November 2019

Clinical Trial Results

The FDA approval of Reblozyl was based on the phase 3 BELIEVE trial. The multicenter, randomized, double-blind, placebo-controlled trial enrolled 336 patients with beta thalassemia requiring regular red blood cell transfusions (6-20 RBC units per 24 weeks) with no transfusion-free period greater than 35 days during that period who were randomized 2:1 to Reblozyl (n=224) or placebo (n=112). Reblozyl was administered subcutaneously once every 3 weeks as long as a reduction in transfusion requirement was observed or until unacceptable toxicity. All patients were eligible to receive best supportive care, which included RBC transfusions; iron-chelating agents; use of antibiotic, antiviral, and antifungal therapy; and/or nutritional support, as needed. The BELIEVE trial showed a highly statistically significant improvement in the primary endpoint of erythroid response, defined as at least a 33 percent cut from baseline in red blood cell (RBC) transfusion burden with a reduction of at least two units during a defined period of 12 consecutive weeks, from weeks 13 to 24, compared to placebo. The drug also met all key secondary endpoints of statistically significant improvements in RBC transfusion burden from baseline of at least 33 percent decrease during the weeks 37 to 48 period, and at least a 50 percent reduction from week 13 to week 24, at least a 50 percent decrease from weeks 37 to 48, and a mean change in transfusion burden from weeks 13 to 24.

Indication 2 - for the treatment of anemia failing an erythropoiesis stimulating agent and requiring 2 or more red blood cell units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndromes or with myelodysplastic/ myeloproliferative neoplasm

Approved April of 2020

Clinical Trial Results

The FDA approval of Reblozyl for patients with very low- to intermediate-risk myelodysplastic syndromes was based on MEDALIST, a Phase 3, randomized, double blind, placebo-controlled, multi-center study evaluating the efficacy and safety of Reblozyl in patients with IPSS-R-defined very low-, low- and intermediate-risk non-del(5q) myelodysplastic syndromes (MDS) with ring sideroblasts. All patients were red blood cell (RBC) transfusion-dependent and were either refractory or intolerant to prior erythropoiesis-stimulating agent (ESA) therapy or were ESA naïve and unlikely to respond due to endogenous serum erythropoietin ≥200 U/L, and had no prior treatment with disease modifying agents. In the trial, a significantly greater proportion of patients receiving Reblozyl achieved independence from RBC transfusions for at least eight weeks during the first 24 weeks of the trial compared with those receiving placebo, meeting the study’s primary endpoint. Additionally, a significantly greater proportion of patients receiving Reblozyl vs. placebo achieved at least 12 weeks of independence from transfusions within the first 24 and 48 weeks of the study.

Indication 3 -  for the treatment of anemia without previous erythropoiesis stimulating agent use (ESA-naïve) in adult patients with very low- to intermediate-risk myelodysplastic syndromes who may require regular red blood cell transfusions

Approved August of 2023

Clinical Trial Results

The FDA approval of Reblozyl for the treatment of anemia without previous erythropoiesis stimulating agent use (ESA-naïve) in adult patients with very low- to intermediate-risk myelodysplastic syndromes who may require regular red blood cell transfusions was based on interim results from the pivotal Phase 3 COMMANDS trial. The open-label, randomized study randomized patients 1:1 to receive subcutaneous Reblozyl (starting dose 1.0 mg/kg, titration up to 1.75 mg/kg) once every 3 weeks or epoetin alfa (starting dose 450 IU/kg, titration up to 1050 IU/kg) weekly for ≥24 weeks. The primary endpoint evaluated in this study is RBC transfusion independence (RBC-TI) for 12 weeks with a mean hemoglobin (Hb) increase ≥1.5 g/dL. At the time of the planned interim analysis (October 31, 2022), 147 evaluable patients received Reblozyl and 154 evaluable patients received epoetin alfa, with median treatment durations of 41.6 and 27 weeks, respectively. 

• 58.5% (n=86) of patients receiving Reblozyl vs. 31.2% (n=48) of patients receiving epoetin alfa achieved the primary endpoint of RBC-TI of at least 12 weeks with concurrent mean Hb increase of at least 1.5 g/dL within the first 24 weeks (p<0.0001).

Key secondary endpoints include erythroid response (HI-E) of at least 8 weeks during weeks 1-24 of the study, RBC-TI ≥12 weeks and RBC-TI for 24 weeks. 

• HI-E increase of at least 8 weeks was achieved by 74.1% (n=109) of Reblozyl patients vs. 51.3% (n=79) of epoetin alfa patients (p<0.0001).
• Within the first 24 weeks of treatment, RBC-TI of at least 24 weeks was achieved by 47.6% (n=70) of Reblozyl patients vs. 29.2% (n=45) of epoetin alfa patients (p=0.0012).
• RBC-TI of at least 12 weeks was achieved by 66.7% (n=98) of Reblozyl patients vs. 46.1% (n=71) of epoetin alfa patients (p=0.0003).

Patients treated with Reblozyl demonstrated durable responses with nearly 2.5 years of median RBC-TI ≥12 weeks (126.6 weeks, week 1 to end of treatment).