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REBLOZYL was studied in the multicenter, randomized, double-blind, placebo-controlled, phase 3 BELIEVE trial1,2

Pivotal Phase 3 BELIEVE Trial Design
Pivotal Phase 3 BELIEVE Trial Design

Primary endpoint1

  • ≥33% reduction in RBC transfusion burden of at least 2 units from weeks 13 to 24

KEY SECONDARY ENDPOINTS1,2

  • ≥50% reduction in RBC transfusion burden from baseline of at least 2 units during weeks 13 to 24
  • ≥33% and ≥50% reduction in RBC transfusion burden to assess the durability of response from baseline of at least 2 units during weeks 37 to 48

ADDITIONAL ENDPOINTS2

  • ≥33% or ≥50% reduction from baseline in RBC transfusion burden during any consecutive 24 weeks
  • Duration of reduction in transfusion burden
  • Time to erythroid response

All patients in the pivotal phase 3 BELIEVE trial received regular RBC transfusions1

BASELINE CHARACTERISTICS OF PATIENTS WITH β‑THALASSEMIA IN THE PIVOTAL PHASE 3 BELIEVE TRIAL (ITT POPULATION)1,2

Demographic and
disease characteristics
REBLOZYL + BSC
(n = 224)
Placebo + BSC
(n = 112)
Age, years
Median (min, max) 30.0 (18, 66) 30.0 (18, 59)
Baseline transfusion burden 12 weeks prior to randomization, units/12 weeks
Median (min, max) 6.12 (3, 14) 6.27 (3, 12)

i

The median transfusion burden was 6 units every 12 weeks1

β-thalassemia gene mutation grouping, n (%)
β0/β0 68 (30.4) 35 (31.3)

i

β0/β0 genotype was present in 30% of patients1

Non-β0/β0 155 (69.2) 77 (68.8)
Missinga 1 (0.4) 0
Baseline serum ferritin level, μg/L
N 220 111
Median (min, max) 1441.25 (88, 6400) 1301.50 (136, 6400)

i

Patients had median serum ferritin levels of 1441 μg/L at baseline1

Splenectomy, n (%)
Yes 129 (57.6) 65 (58)

i

58% of patients had a previous splenectomy1

No 95 (42.4) 47 (42)
Sex, n (%)
Male 92 (41.1) 49 (43.8)
Female 132 (58.9) 63 (56.3)
β‑thalassemia diagnosis, n (%)
β-thalassemia 174 (77.7) 83 (74.1)
HbE/β‑thalassemia 31 (13.8) 21 (18.8)
β-thalassemia combined with α‑thalassemia 18 (8) 8 (7.1)
Missinga 1 (0.4) 0
  • Baseline characteristics were balanced between treatment arms2

aMissing category includes patients in the population who had no result for the parameter listed.

The intent-to-treat (ITT) population consisted of all patients, regardless of whether the patient received the study drug.

HbE, hemoglobin E.

REBLOZYL provided substantial clinical benefit by reducing RBC transfusion burden1


Primary endpoint subgroup analysis:
Reduction in RBC transfusion burden with REBLOZYL2

Key secondary endpoints:
Clinically meaningful reductions in transfusion burden were seen with REBLOZYL1


Additional analysis: Reductions in transfusion burden during any consecutive 24-week period with REBLOZYL*

Reduction in transfusion burden from baseline during any consecutive 24-week period2*

Endpoint REBLOZYL
(n = 224)
Placebo
(n = 112)
Risk difference
(95% CI)

≥33% reduction in transfusion burden, n (%)

92 (41.1) 3 (2.7) 38.4
(31.3–45.5)

≥50% reduction in transfusion burden, n (%)

37 (16.5) 1 (0.9) 15.6
(10.5–20.8)

*Not restricted by a specified time period.

  • The estimated transfusion burden reduction from baseline per patient based on the consecutive 24‑week analysis was2:
    • 6.55 RBC units per 24 weeks in patients with ≥33% reduction in RBC transfusion burden
    • 8.27 RBC units per 24 weeks in patients with ≥50% reduction in RBC transfusion burden

Analysis limitations

  • Patients may have experienced multiple periods of response intermittently between periods without response over the 48-week assessment period2
  • These exploratory analyses should not be interpreted to determine treatment difference between arms in these select endpoints because of potential selection bias, insufficient sample size, and a higher probability of making a false positive finding

Additional analysis information

  • The total (cumulative) duration of RBC transfusion burden reduction was defined as the sum of individual response periods (≥33% reduction from baseline in RBC transfusion burden of at least 2 units), with overlapping response periods excluded, over the entire 48-week study2
  • All patients in both arms were eligible to receive BSC as needed: RBC transfusions; iron-chelating agents; use of antibiotic, antiviral, and antifungal therapy; and nutritional support1

This analysis looks at the reduction in transfusion burden over a longer period of time, which may be important in adult patients with β-thalassemia who require regular transfusions2

Additional analysis: Time to response and total cumulative duration of response at 48 weeks

Time from the first dose to response and total (cumulative) duration of response during any consecutive 12-week period2

REBLOZYL
(n = 224)
Placebo
(n = 112)

Patients with ≥33% transfusion burden reduction from baseline of at least 2 units, n (%)

158 (70.5) 33 (29.5)

Time to response, median (min, max)

12 days
(2 days, 360 days)
107 days
(2 days, 386 days)

Among responders, total cumulative duration of transfusion burden reduction, median (min, max)

298 days
(84 days, 631 days)
171 days
(84 days, 533 days)

Analysis limitations

  • Patients may have experienced multiple periods of response intermittently between periods without response over the 48-week assessment period2
  • These exploratory analyses should not be interpreted to determine treatment difference between arms in these select endpoints because of potential selection bias, insufficient sample size, and a higher probability of making a false positive finding

Additional analysis information

  • The total (cumulative) duration of RBC transfusion burden reduction was defined as the sum of individual response periods (≥33% reduction from baseline in RBC transfusion burden of at least 2 units), with overlapping response periods excluded, over the entire 48-week study2
  • The time to response was defined as the first day of the start of the ≥33% reduction from baseline in RBC transfusion burden of at least 2 units during any rolling 12-week period2
  • Each response period was a continuous period in which a subject had response during any 12-week interval2
  • The median treatment exposure was approximately 64 weeks in both groups2
  • All patients in both arms were eligible to receive BSC as needed: RBC transfusions; iron-chelating agents; use of antibiotic, antiviral, and antifungal therapy; and nutritional support1
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Indication

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

REBLOZYL is indicated 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 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%) 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 10.7% (61/571) of REBLOZYL-treated patients. Across clinical studies, the incidence of Grade 3 to 4 hypertension ranged from 1.8% to 8.6%. 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 adult patients with MDS with normal baseline blood pressure, 26 (29.9%) patients developed SBP ≥130 mm Hg and 23 (16.4%) patients developed DBP ≥80 mm Hg. Monitor blood pressure prior to each administration. Manage new or exacerbations of preexisting hypertension using anti-hypertensive agents.

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%)

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.

Please click here for full Prescribing Information for REBLOZYL.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Thrombosis/Thromboembolism

In adult patients with beta thalassemia, thromboembolic events (TEE) were reported in 8/223 (3.6%) 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 10.7% (61/571) of REBLOZYL-treated patients. Across clinical studies, the incidence of Grade 3 to 4 hypertension ranged from 1.8% to 8.6%. In adult patients with MDS with normal baseline blood pressure, 26 (29.9%) patients developed SBP ≥130 mm Hg and 23 (16.4%) patients developed DBP ≥80 mm Hg. Monitor blood pressure prior to each administration. Manage new or exacerbations of preexisting hypertension using anti-hypertensive agents.

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

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.

Please click here for full Prescribing Information for REBLOZYL.

Indication

REBLOZYL is indicated 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 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%) 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 10.7% (61/571) of REBLOZYL-treated patients. Across clinical studies, the incidence of Grade 3 to 4 hypertension ranged from 1.8% to 8.6%. In adult patients with MDS with normal baseline blood pressure, 26 (29.9%) patients developed SBP ≥130 mm Hg and 23 (16.4%) patients developed DBP ≥80 mm Hg. Monitor blood pressure prior to each administration. Manage new or exacerbations of preexisting hypertension using anti-hypertensive agents.

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

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.

Please click here for full Prescribing Information for REBLOZYL.

References: 1. REBLOZYL [Prescribing Information]. Summit, NJ: Celgene Corporation; 2020. 2. Data on file. Celgene Corporation. Summit, New Jersey.