U.S. Food and Drug Administration (FDA)-Approved Indications

Luspatercept-aamt is available as Reblozyl (Celgene Corporation). Luspatercept-aamt, an erythroid maturation agent, 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 models of β-thalassemia and MDS, luspatercept-aamt decreased abnormally elevated Smad2/3 signaling and improved hematology parameters associated with ineffective erythropoiesis in mice (Celgene, 2022).

The prescribing information includes the following warnings and precautions for Reblozyl: thrombosis/thromboembolism in patients with beta thalassemia, hypertension, and embryo-fetal toxicity. The most common adverse reactions (10% or more) include fatigue, headache, musculoskeletal pain, arthralgia, dizziness/vertigo, nausea, diarrhea, cough, abdominal pain, dyspnea, and hypersensitivity. Patients are advised not to breastfeed while on Reblozyl therapy.

Beta thalassemia, also called "Cooley’s anemia," is an inherited blood disorder that reduces the production of hemoglobin, an iron-containing protein in red blood cells that carries oxygen to cells throughout the body. In beta thalassemia, low levels of hemoglobin lead to a lack of oxygen in many parts of the body and anemia, causing pale skin, weakness, fatigue and more serious complications. People with beta thalassemia are also at an increased risk of developing abnormal blood clots. Supportive treatment for people with beta thalassemia often consists of lifelong regimens of chronic blood transfusions for survival and treatment for iron overload due to the transfusions.

On November 08, 2019, the FDA approved Reblozyl (luspatercept–aamt) for the treatment of anemia (lack of red blood cells) in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions. Reblozyl was approved by the FDA with both a fast track and orphan drug designations. Reblozyl was approved based on the results of a multicenter, randomized, double-blind, placebo-controlled trial in which (n = 336) patients with beta thalassemia requiring regular red blood cell transfusions (6 to 20 RBC units per 24 weeks) with no transfusion-free period greater than 35 days during that period were randomized 2:1 to Reblozyl (n = 224) or placebo (n = 112) (BELIEVE Trial; NCT02604433). 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 trial excluded patients with hemoglobin S/β-thalassemia or alpha-thalassemia, had major organ damage (liver disease, heart disease, lung disease, renal insufficiency), and patients with recent deep vein thrombosis or stroke and platelet counts greater than 1,000 x 10

/L

or recent use of ESA, immunosuppressant, or hydroxyurea therapy. The median age was 30 years (range of 18 to 66). The trial was comprised of patients who were 42 % male, 54.2 % white, 34.8 % Asian, and 0.3 % Black or African American. The percent of patients reporting their race as "other" was 7.7 %, and race was not collected or reported for 3 % of patients (Reblozyl prescribing information, 2019).

The primary efficacy endpoint of Reblozyl in adult patients with beta thalassemia was the proportion of patients achieving RBC transfusion burden reduction (greater than or equal to 33 % reduction from baseline) with a reduction of at least 2 units from Week 13 to Week 24. Twenty-one percent of the patients who received Reblozyl achieved at least a 33 % reduction in transfusions compared to 4.5 % of the patients who received a placebo (risk difference: 17; 95 % CI: 10.4 to 23.6); p < 0.0001) from Week 13 to Week 24. From Week 37 to Week 48, 19.6 % of patients who received Reblozyl achieved at least a 33 % reduction in transfusions compared to 3.6 % of patients who received placebo (risk difference: 16.1; 95 % CI: 9.8 to 22.4); p < 0.0001). The proportion of patients achieving RBC transfusion burden reduction (greater than or equal to 50 % reduction from baseline) with a reduction of at least 2 units for 12 consecutive weeks was also greater with Reblozyl (7.6 %) compared to placebo (1.8 %) from Week 13 to Week 24 (risk difference: 5.8; 95 % CI: 1.6 to 10.1; p = 0.0303) and from Week 37 to Week 48 (10.3 % with Reblozyl compared with 0.9 % with placebo; risk difference: 9.4; 95 % CI: 5 to 13,7; p = 0.0017). The transfusion reduction meant that the patient needed fewer transfusions over 12 consecutive weeks while taking Reblozyl

.

In their open-label, nonrandomized, uncontrolled study, Piga et al (2019; NCT01749540 and NCT02268409) aimed to determine whether

could improve anemia and disease complications in patients with β-thalassemia. This study consisted of a 24-week dose-finding and expansion stage (initial stage) and a 5-year extension stage, currently ongoing. Sixty-four patients were enrolled; 33 were non-transfusion dependent (mean hemoglobin, less than 10.0 g/dL; less than 4 RBC units transfused per 8 weeks), and 31 were transfusion dependent (greater than or equal to 4 RBC units per 8 weeks). Patients received 0.2 to 1.25 mg/kg

subcutaneously every 21 days for greater than or equal to 5 cycles (dose-finding stage) and 0.8 to 1.25 mg/kg (expansion cohort and 5-year extension). The primary end point was erythroid response, defined as hemoglobin increase of greater than or equal to 1.5 g/dL from baseline for greater than or equal to 14 consecutive days (without RBC transfusions) for non-transfusion-dependent patients or RBC transfusion burden reduction greater than or equal to 20 % over a 12-week period versus the 12 weeks before treatment for transfusion-dependent patients. Eighteen non-transfusion-dependent patients (58 %) receiving higher dose levels of

(0.6 to 1.25 mg/kg) achieved mean hemoglobin increase greate than or equal to 1.5 g/dL over greater than or equal to 14 days versus baseline. Twenty-six (81 %) transfusion-dependent patients achieved greater than or equal to 20 % reduction in RBC transfusion burden. The most common grade 1 to 2 adverse events were bone pain, headache, and myalgia. As of the cut-off, 33 patients remain on study. In this study, a high percentage of β-thalassemia patients receiving

had hemoglobin or transfusion burden improvements. The authors concluded that these findings support a randomized clinical trial to assess efficacy and safety.

Myelodysplastic Syndromes

On April 3, 2020, the FDA approved Reblozyl (luspatercept-aamt) for the treatment of anemia failing an erythropoiesis stimulating agent and requiring 2 or more 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 (MDS/MPN-RS-T). Efficacy was demonstrated in the MEDALIST trial by Fenaux et al (NCT02631070). Fenaux et al (2020; NCT02631070;) stated patients with anemia and lower-risk myelodysplastic syndromes in whom erythropoiesis-stimulating agent therapy is not effective generally become dependent on red-cell transfusions. Luspatercept, a recombinant fusion protein that binds transforming growth factor β superfamily ligands to reduce SMAD2 and SMAD3 signaling, showed promising results in a phase 2 study. This double-blind, placebo-controlled, phase 3 trial randomly assigned patients with very-low-risk, low-risk, or intermediate-risk myelodysplastic syndromes (defined according to the Revised International Prognostic Scoring System) with ring sideroblasts who had been receiving regular red-cell transfusions to receive either luspatercept (at a dose of 1.0 up to 1.75 mg per kilogram of body weight) or placebo, administered subcutaneously every 3 weeks. The primary end point was transfusion independence for 8 weeks or longer during weeks 1 through 24, and the key secondary end point was transfusion independence for 12 weeks or longer, assessed during both weeks 1 through 24 and weeks 1 through 48. Of the 229 patients enrolled, 153 were randomly assigned to receive luspatercept and 76 to receive placebo; the baseline characteristics of the patients were balanced. Transfusion independence for 8 weeks or longer was observed in 38 % of the patients in the luspatercept group, as compared with 13 % of those in the placebo group (p < 0.001). A higher percentage of patients in the luspatercept group than in the placebo group met the key secondary end point (28 % versus 8 % for weeks 1 through 24, and 33 % versus 12 % for weeks 1 through 48; p < 0.001 for both comparisons). The most common luspatercept-associated adverse events (of any grade) included fatigue, diarrhea, asthenia, nausea, and dizziness. The incidence of adverse events decreased over time. The authors concluded that luspatercept reduced the severity of anemia in patients with lower-risk myelodysplastic syndromes with ring sideroblasts who had been receiving regular red-cell transfusions and who had disease that was refractory to or unlikely to respond to erythropoiesis-stimulating agents or who had discontinued such agents owing to an adverse event.

: Requires Precertification:

Precertification of luspatercept-aamt (Reblozyl) is required of all Aetna participating providers and members in applicable plan designs. For precertification of luspatercept–aamt, call (866) 752-7021 (Commercial), or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see

Criteria for Initial Approval

The member required at least 6 red blood cell (RBC) units transfused in the previous 24 weeks.

: If a red blood cell (RBC) transfusion occurred prior to dosing, the pretransfusion hemoglobin (Hgb) level must be considered for dosing purposes.

Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

Continuation of Therapy

Dosage and Administration

Reblozyl is supplied for injection as 25 mg and 75 mg lyophilized powder in single-dose vials for reconstitution. Reblozyl should be reconstituted and administered by a healthcare professional.

The recommended starting dose is 1 mg/kg once every 3 weeks by subcutaneous injection. Review hemoglobin (Hgb) results prior to each administration.

See full prescribing information for dosing titration and dosing modification information,

.

Source: Celgene, 2022

Experimental and Investigational

Aetna considers luspatercept–aamt (Reblozyl) therapy experimental and investigational for the treatment of hemoglobin S/β-thalassemia or alpha-thalassemia because the safety and efficacy has not been established in the peer-reviewed published literature.