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THE NEED FOR REBLOZYL: MECHANISM OF ACTION

REBLOZYL helps address ineffective erythropoiesis1

Impaired erythroid maturation contributes to ineffective erythropoiesis, resulting in low production of red blood cells and anemia2,3

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Beta-Thal Mechanism of Action Image. Tap over to Text View tab for details.

For illustrative purposes only.

Early-stage erythropoiesis
Endogenous erythropoietin regulates proliferaton.4
Hematopoietic stem cell progresses to burst-forming unit erythroid, which progresses to colony-forming unit erythroid, which progresses to proerythroblast.

Impaired erythroid maturation in late-stage erythropoiesis
Basophilic erythroblast progresses to polychromatic erythroblast, which progresses to orthochromatic erythroblast, which progresses to erticulocyte, which progresses to red blood cell.

In late-stage erythropoiesis, select transforming growth (TGF-β) superfamily ligands help regulate maturation. TGF-β superfamily signaling through Smad2/3 is abnormally high in diseases characterized by ineffective erythropoiesis, which leads to impaired erythroid maturation of red blood cells.5-7

REBLOZYL restores erythropoiesis by increasing the number and improving the quality of mature RBCs as observed in preclinical studies1

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Impaired erythroid maturation graphic. Tap over to Text View tab for details.

EARLY-STAGE ERYTHROPOIESIS
Endogenous erythropoietin regulates proliferation4

LATE-STAGE ERYTHROPOIESIS
REBLOZYL regulates erythroid maturation REBLOZYL binds several TGF-β superfamily ligands, thereby diminishing Smad2/3 signaling and increasing the number of mature RBCs1,6,7

For illustrative purposes only.

EARLY-STAGE ERYTHROPOIESIS
Endogenous erythropoietin regulates proliferation4

LATE-STAGE ERYTHROPOIESIS

REBLOZYL regulates erythroid maturation

REBLOZYL binds several TGF-β superfamily ligands, thereby diminishing Smad 2/3 signaling and increasing the number of mature RBCs1,6,7

In preclinical models, REBLOZYL improved Hgb levels, RBC morphology, and other hematology parameters* associated with ineffective erythropoiesis1,6

*Other hematology parameters include reducing oxidative stress in erythrocytes, reducing accumulation of α-globin aggregates in erythrocyte membranes, and improving RBC lifespan.

BFU-E=burst-forming unit erythroid; CFU-E=colony-forming unit erythroid; Hgb=hemoglobin; HSC=hematopoietic stem cell; RBC=red blood cell; TGF-β=transforming growth factor beta.

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References: 1. REBLOZYL [US Prescribing Information]. Summit, NJ: Celgene Corporation; 2023. 2. Liang R, Ghaffari S. Advances in understanding the mechanisms of erythropoiesis in homeostasis and disease. Br J Haematol. 2016;174(5):661-673. 3. Ponka P, Koury MJ, Sheftel AD. Erythropoiesis, hemoglobin synthesis, and erythroid mitochondrial iron homeostasis. In: Ferreira GC, ed. Handbook of Porphyrin Science: With Applications to Chemistry, Physics, Materials Science, Engineering, Biology and Medicine. Vol 27. Singapore: World Scientific Publishing Co.; 2014. 4. Lodish H, Flygare J, Chou S. From stem cell to erythroblast: regulation of red cell production at multiple levels by multiple hormones. IUBMB Life. 2010;62(7):492-496. 5. Fortunel NO, Hatzfeld A, Hatzfeld JA. Transforming growth factor-β: pleiotropic role in the regulation of hematopoiesis. Blood. 2000;96(6):2022-2036. 6. Suragani RN, Cadena SM, Cawley SM, et al. Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med. 2014;20(4):408-414. 7. Attie KM, Allison MJ, McClure T, et al. A phase 1 study of ACE-536, a regulator of erythroid differentiation, in healthy volunteers. Am J Hematol. 2014;89(7):766-770.

INDICATIONS

REBLOZYL® (luspatercept-aamt) is indicated for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions.

REBLOZYL® (luspatercept-aamt) is indicated for the treatment of anemia without previous erythropoiesis stimulating agent use (ESA-naïve) in adult patients with very low- to intermediate-risk myelodysplastic syndromes (MDS) who may require regular red blood cell (RBC) transfusions.

REBLOZYL® (luspatercept-aamt) is indicated for the treatment of anemia failing an erythropoiesis stimulating agent 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 (MDS/MPN-RS-T).

REBLOZYL is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Thrombosis/Thromboembolism

In adult patients with beta thalassemia, thromboembolic events (TEE) were reported in 8/223 (3.6%) of REBLOZYL-treated patients. TEEs included deep vein thrombosis, pulmonary embolus, portal vein thrombosis, and ischemic stroke. Patients with known risk factors for thromboembolism (splenectomy or concomitant use of hormone replacement therapy) may be at further increased risk of thromboembolic conditions. Consider thromboprophylaxis in patients at increased risk of TEE. Monitor patients for signs and symptoms of thromboembolic events and institute treatment promptly.

Hypertension

Hypertension was reported in 11.4% (63/554) of REBLOZYL-treated patients. Across clinical studies, the incidence of Grade 3 to 4 hypertension ranged from 2% to 9.6%. In patients with beta thalassemia with normal baseline blood pressure, 13 (6.2%) patients developed systolic blood pressure (SBP) ≥130 mm Hg and 33 (16.6%) patients developed diastolic blood pressure (DBP) ≥80 mm Hg. In ESA-refractory or -intolerant adult patients with MDS with normal baseline blood pressure, 26 (30%) patients developed SBP ≥130 mm Hg and 23 (16%) patients developed DBP ≥80 mm Hg. In ESA-naïve adult patients with MDS with normal baseline blood pressure, 23 (36%) patients developed SBP ≥140 mm Hg and 11 (6%) patients developed DBP ≥80 mm Hg. Monitor blood pressure prior to each administration. Manage new or exacerbations of preexisting hypertension using anti-hypertensive agents.

Extramedullary Hematopoietic (EMH) Masses

In adult patients with transfusion-dependent beta thalassemia, EMH masses were observed in 3.2% of REBLOZYL-treated patients, with spinal cord compression symptoms due to EMH masses occurring in 1.9% of patients (BELIEVE and REBLOZYL long-term follow-up study).

In a study of adult patients with non-transfusion-dependent beta thalassemia, a higher incidence of EMH masses was observed in 6.3% of REBLOZYL-treated patients vs. 2% of placebo-treated patients in the double-blind phase of the study, with spinal cord compression due to EMH masses occurring in 1 patient with a prior history of EMH. REBLOZYL is not indicated for use in patients with non-transfusion-dependent beta thalassemia.

Possible risk factors for the development of EMH masses in patients with beta thalassemia include history of EMH masses, splenectomy, splenomegaly, hepatomegaly, or low baseline hemoglobin (<8.5 g/dL). Signs and symptoms may vary depending on the anatomical location. Monitor patients with beta thalassemia at initiation and during treatment for symptoms and signs or complications resulting from the EMH masses and treat according to clinical guidelines. Discontinue treatment with REBLOZYL in case of serious complications due to EMH masses. Avoid use of REBLOZYL in patients requiring treatment to control the growth of EMH masses.

Embryo-Fetal Toxicity

REBLOZYL may cause fetal harm when administered to a pregnant woman. REBLOZYL caused increased post-implantation loss, decreased litter size, and an increased incidence of skeletal variations in pregnant rat and rabbit studies. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 3 months after the final dose.

ADVERSE REACTIONS

Beta-Thalassemia

Serious adverse reactions occurred in 3.6% of patients on REBLOZYL. Serious adverse reactions occurring in 1% of patients included cerebrovascular accident and deep vein thrombosis. A fatal adverse reaction occurred in 1 patient treated with REBLOZYL who died due to an unconfirmed case of acute myeloid leukemia (AML).

Most common adverse reactions (at least 10% for REBLOZYL and 1% more than placebo) were headache (26% vs 24%), 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%).

ESA-naïve adult patients with Myelodysplastic Syndromes

Grade ≥3 (≥2%) adverse reactions included hypertension and dyspnea.

The most common (≥10%) all-grade adverse reactions included diarrhea, fatigue, hypertension, peripheral edema, nausea, and dyspnea.

ESA-refractory or -intolerant adult patients with Myelodysplastic Syndromes

Grade ≥3 (≥2%) adverse reactions included fatigue, hypertension, syncope and musculoskeletal pain. A fatal adverse reaction occurred in 5 (2.1%) patients.

The most common (≥10%) adverse reactions included fatigue, musculoskeletal pain, dizziness, diarrhea, nausea, hypersensitivity reactions, hypertension, headache, upper respiratory tract infection, bronchitis, and urinary tract infection.

LACTATION

It is not known whether REBLOZYL is excreted into human milk or absorbed systemically after ingestion by a nursing infant. REBLOZYL was detected in milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because many drugs are excreted in human milk, and because of the unknown effects of REBLOZYL in infants, a decision should be made whether to discontinue nursing or to discontinue treatment. Because of the potential for serious adverse reactions in the breastfed child, breastfeeding is not recommended during treatment and for 3 months after the last dose.

DRUG ABUSE POTENTIAL

Abuse: Abuse of REBLOZYL may be seen in athletes for the effects on erythropoiesis. Misuse of drugs that increase erythropoiesis, such as REBLOZYL, by healthy persons may lead to polycythemia, which may be associated with life-threatening cardiovascular complications.

For more information, please see US Full Prescribing Information for REBLOZYL.

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2007-US-2400451   12/2024