1.1 Beta Thalassemia

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

1.2 Myelodysplastic Syndromes Associated Anemia

REBLOZYL 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.

1.3 Myelodysplastic Syndromes with Ring Sideroblasts or Myelodysplastic/ Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis Associated Anemia

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).

1.4 Limitations of Use

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

2.1 Recommended Dosage for Beta Thalassemia

The recommended starting dose of REBLOZYL is 1 mg/kg once every 3 weeks by subcutaneous injection for patients with beta thalassemia. Prior to each REBLOZYL dose, review the patient’s hemoglobin and transfusion record. Titrate the dose based on responses according to Table 1. Interrupt treatment for adverse reactions as described in Table 2. Discontinue REBLOZYL if a patient does not experience a decrease in transfusion burden after 9 weeks of treatment (administration of 3 doses) at the maximum dose level or if unacceptable toxicity occurs at any time.

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.

2.2 Recommended Dosage for Myelodysplastic Syndromes Associated Anemia

The recommended starting dosage of REBLOZYL is 1 mg/kg once every 3 weeks by subcutaneous injection for the treatment of anemia of MDS. Prior to each REBLOZYL dose, review the patient’s hemoglobin and transfusion record. Titrate the dose based on responses according to Table 3. Interrupt treatment for adverse reactions as described in Table 4. Discontinue REBLOZYL if a patient does not experience a decrease in transfusion burden including no increase from baseline hemoglobin after 9 weeks of treatment (administration of 3 doses) at the maximum dose level (1.75 mg/kg), or if unacceptable toxicity occurs at any time.

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.

2.3 Preparation and Administration

REBLOZYL should be reconstituted and administered by a healthcare professional.

Reconstitute REBLOZYL with Sterile Water for Injection, USP only.

Reconstitute the number of REBLOZYL vials to achieve the appropriate dose based on the patient’s weight. Use a syringe with suitable graduations for reconstitution to ensure accurate dosage.

5.1 Thrombosis/Thromboembolism

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

Monitor patients receiving REBLOZYL for signs and symptoms of thromboembolic events and institute treatment promptly.

5.2 Hypertension

Hypertension was reported in 63/554 (11.4%) of REBLOZYL-treated patients. Across clinical studies, the incidence of Grade 3-4 hypertension ranged from 2% to 9.6%.

In adult 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-onset hypertension or exacerbations of preexisting hypertension using anti-hypertensive agents.

5.3 Extramedullary Hematopoietic 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.

5.4 Embryo-Fetal Toxicity

Based on findings from animal reproductive studies, REBLOZYL may cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of luspatercept-aamt to pregnant rats and rabbits during organogenesis resulted in adverse developmental outcomes including increased embryo-fetal mortality, alterations to growth, and structural abnormalities at exposures (based on area under the curve [AUC]) above those occurring at the maximum recommended human dose (MRHD) of 1.75 mg/kg.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with REBLOZYL and for at least 3 months after the final dose [see Use in Specific Populations (8.1, 8.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in the WARNINGS AND PRECAUTIONS reflect exposure to REBLOZYL as a single agent administered across a range of doses (0.125 mg/kg to 1.75 mg/kg) in 571 patients in 4 trials.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Based on findings in juvenile animals, REBLOZYL is not recommended for use in pediatric patients [see Non-Clinical Toxicology (13.1)].

8.5 Geriatric Use

Clinical studies of REBLOZYL in beta thalassemia did not include sufficient numbers of patients age 65 years and older to determine whether they respond differently from younger patients.

Clinical studies of REBLOZYL for treatment of anemia in ESA-naïve and ESA-refractory or -intolerant MDS included 347 (82%) patients ≥ 65 years of age and 167 (39%) patients ≥ 75 years of age. No differences in safety or effectiveness were observed between older (≥ 65 years) and younger patients.

9.1 Controlled Substance

REBLOZYL contains luspatercept-aamt, which is not a controlled substance.

9.2 Abuse

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Abuse of REBLOZYL may be seen in athletes for the effects on erythropoiesis to enhance athletic performance. Abuse of drugs that increase erythropoiesis, such as REBLOZYL, by healthy persons may lead to polycythemia, which may be associated with life-threatening cardiovascular complications (e.g., stroke, myocardial infarction, and thromboembolism).

Luspatercept-aamt and its metabolites neither selectively penetrate the central nervous system, nor produce behavioral effects in animals that are consistent with central nervous system activity.

12.1 Mechanism of Action

Luspatercept-aamt is a recombinant fusion protein that binds several endogenous TGF-β superfamily ligands, thereby diminishing Smad2/3 signaling. 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. Luspatercept-aamt promoted erythroid maturation through differentiation and increasing the percentage of late-stage erythroid precursors (normoblasts) in the bone marrow of mice and increased erythroid precursors in humans, thereby increasing erythropoiesis.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Luspatercept-aamt exhibited linear pharmacokinetics (PK) over the dose range of 0.2 to 1.25 mg/kg (0.2 to 1.25 times the recommended starting dosage) in patients with beta thalassemia, and from 0.125 mg/kg to 1.75 mg/kg (0.125 to 1.75 times the recommended starting dosage) in patients with MDS. The geometric mean (% coefficient of variation [%CV]) steady-state AUC at the starting dose of 1 mg/kg was 126 (35.9%) day•µg/mL for patients with beta thalassemia and 154 (37.4%) day•µg/mL for patients with MDS. Luspatercept-aamt serum concentration reached steady state after 3 doses when administered every 3 weeks. The accumulation ratio of luspatercept-aamt was approximately 1.5.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of REBLOZYL or of other luspatercept products.

In the BELIEVE trial, the median duration of exposure was 64 weeks, with a median ADA sampling period of 50 weeks. Of the 220 patients in the BELIEVE trial with beta thalassemia who require regular RBC transfusions treated with REBLOZYL and evaluable for the presence of anti-luspatercept-aamt antibodies, 4 patients (1.81%) tested positive for treatment-emergent anti-luspatercept-aamt antibodies, including 2 patients (0.9%) who had neutralizing antibodies detected. The majority of anti-luspatercept-aamt antibodies were of low titers.

In the COMMANDS trial, the median duration of exposure was 42 weeks, with the median ADA sampling period of 27 weeks. In the MEDALIST trial, the median duration of exposure was 49 weeks, with the median ADA sampling period of 46 weeks. Of the 331 ESA-naïve (COMMANDS trial) and ESA-refractory or -intolerant (MEDALIST trial) patients with MDS who were treated with REBLOZYL, 21 patients (6.3%) tested positive for treatment-emergent anti-luspatercept-aamt antibodies, including 14 patients (4.2%) who had neutralizing antibodies. The majority of anti-luspatercept-aamt antibodies were of low titers.

There were no severe acute systemic hypersensitivity reactions reported for patients with anti-luspatercept-aamt antibodies in REBLOZYL clinical trials, and there was no association between hypersensitivity type reaction or injection site reaction and presence of anti-luspatercept-aamt antibodies. There was no apparent effect of anti-luspatercept-aamt antibodies on clinical response.

Anti-Drug Antibody Effects on Pharmacokinetics

Among patients in the BELIEVE trial with luspatercept-aamt exposure data available, luspatercept‑aamt mean trough concentration (Ctrough) was approximately 35% lower in 4 patients with beta thalassemia who tested positive for treatment‑emergent anti‑luspatercept‑aamt antibodies (2.19 μg/mL) compared to patients with beta thalassemia who did not develop treatment‑emergent anti‑luspatercept‑aamt antibodies (3.38 μg/mL). There is insufficient data to assess whether the observed anti-luspatercept-aamt antibody associated pharmacokinetic changes reduce effectiveness in patients with beta thalassemia.

Among 21 ESA-naïve and ESA-refractory or -intolerant patients with MDS in the COMMANDS and MEDALIST trials who tested positive for treatment-emergent anti‑luspatercept‑aamt antibodies, there were no identified clinically significant effects of anti‑luspatercept‑aamt antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of luspatercept‑aamt over the treatment duration.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or mutagenicity studies have been conducted with luspatercept-aamt.

In a repeat-dose toxicity study, juvenile rats were administered luspatercept-aamt subcutaneously at 1, 3, or 10 mg/kg once every 2 weeks from postnatal day 7 to 91. Hematologic malignancies (granulocytic leukemia, lymphocytic leukemia, malignant lymphoma) were observed at 10 mg/kg resulting in exposures (based on area under the curve [AUC]) approximately 4.4 times the maximum recommended human dose (MRHD) of 1.75 mg/kg.

In a combined male and female fertility and early embryonic development study in rats, luspatercept-aamt was administered subcutaneously to animals at doses of 1 to 15 mg/kg. There were significant reductions in the average numbers of corpora lutea, implantations, and viable embryos in luspatercept-aamt-treated females. Effects on female fertility were observed at the highest dose with exposures (based on AUC) approximately 7-times the MRHD of 1.75 mg/kg. Adverse effects on fertility in female rats were reversible after a 14-week recovery period. No adverse effects were noted in male rats.

14.1 Beta Thalassemia

The efficacy of REBLOZYL was evaluated in adult patients with beta thalassemia in the BELIEVE trial (NCT02604433). BELIEVE was a multicenter, randomized, double-blind, placebo-controlled trial in which (n=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 were randomized 2:1 to REBLOZYL (n=224) or placebo (n=112). In BELIEVE, 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 excluded patients with a diagnosis of Hemoglobin S/β-thalassemia or isolated alpha (α)-thalassemia (e.g., Hemoglobin H) or who had major organ damage (liver disease, heart disease, lung disease, renal insufficiency). Patients with recent deep vein thrombosis or stroke or recent use of ESA, immunosuppressant, or hydroxyurea therapy were also excluded. The median age was 30 years (range: 18-66). 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.

Table 12 summarizes the baseline disease-related characteristics in the BELIEVE study.

The efficacy of REBLOZYL in adult patients with beta thalassemia was established based upon the proportion of patients achieving RBC transfusion burden reduction (≥33% reduction from baseline) with a reduction of at least 2 units from Week 13 to Week 24.

Efficacy results are shown in Table 13.

14.2 Treatment of Myelodysplastic Syndromes with Associated Anemia in ESA-naïve Patients

The efficacy of REBLOZYL was evaluated in the COMMANDS trial (NCT03682536), a multi‑center, open‑label, randomized active‑controlled trial comparing REBLOZYL versus epoetin alfa in patients with anemia due to IPSS‑R very low, low, or intermediate‑risk myelodysplastic syndromes or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN RS‑T) in ESA‑naïve patients (with endogenous sEPO levels of < 500 U/L) who require regular red blood cell transfusions. For eligibility, patients were required to have had 2 to 6 RBC units/8 weeks confirmed for a minimum of 8 weeks immediately preceding randomization.

The COMMANDS trial included 356 patients randomized 1:1 to REBLOZYL (N=178) or epoetin alfa (N=178). Randomization was stratified by RBC transfusion burden, RS status, and endogenous serum erythropoietin (sEPO) level at baseline. Treatment was started at 1 mg/kg subcutaneously every 3 weeks. Two dose level increases were allowed (to 1.33 mg/kg and to 1.75 mg/kg). Doses were held and subsequently reduced for adverse reactions, reduced if the hemoglobin increased by ≥ 2 g/dL from the prior cycle, and held if the predose hemoglobin was ≥ 12 g/dL.

All patients received best supportive care, which included RBC transfusions as needed. Patients were treated for 24 weeks and were assessed for efficacy at that time point. Treatment beyond 24 weeks was optional based upon response to treatment and absence of disease progression.

The median age of the 356 study participants was 74 years (range: 33, 93 years). The trial population was 56% male and 44% female; 79.5% were White, 0.6% Black or African American, 12.1% Asian, and race was not reported in 7.9% of patients. Ethnicities were reported as 85.4% for Not Hispanic or Latino patients, 6.5% for Hispanic or Latino patients, 7.6% for patients with no ethnicity reported, and 0.6% were unknown. IPSS‑R risk classification at baseline was 9.3% very low, 72.2% low, 17.4% intermediate, 0.3% high, and 0.8% missing. Table 14 summarizes the baseline disease‑related characteristics in the COMMANDS study.

The efficacy of REBLOZYL in the treatment of anemia in ESA‑naïve adult patients with MDS was established at the time of the interim efficacy analysis based upon the proportion of patients who experienced both red blood cell transfusion independence (RBC‑TI) [defined as the absence of any RBC transfusion during any consecutive 12‑week period] and an associated concurrent mean improvement in hemoglobin by at least 1.5 g/dL for any consecutive 12 week period during Weeks 1-24.

At the time of the interim efficacy analysis, 301 subjects were included in the efficacy analysis, of which 147 were in the luspatercept arm and 154 were in the epoetin alfa arm, which is about 85% of the total information. The key efficacy results are shown in Table 15.

No major outliers were observed in clinically relevant baseline demographic and disease characteristic subgroups.

14.3 Myelodysplastic Syndromes with Ring Sideroblasts or Myelodysplastic/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis Associated Anemia in ESA-refractory or -intolerant Patients

The efficacy of REBLOZYL was evaluated in the MEDALIST trial (NCT02631070), a multi-center, randomized, double-blind, placebo-controlled trial in patients with IPSS-R very low, low, or intermediate-risk myelodysplastic syndromes who have ring sideroblasts and require red blood cell transfusions (2 or more RBC units over 8 weeks). For eligibility, patients were required to have had an inadequate response to prior treatment with an erythropoiesis-stimulating agent (ESA), be intolerant of ESAs, or have a serum erythropoietin > 200 U/L. The MEDALIST trial excluded patients with deletion 5q (del 5q), white blood cell count > 13 Gi/L, neutrophils < 0.5 Gi/L, platelets < 50 Gi/L, or with prior use of a disease modifying agent for treatment of MDS.

The MEDALIST trial included 229 patients randomized 2:1 to REBLOZYL (n=153) or placebo (n=76). Randomization was stratified by baseline RBC transfusion burden and baseline IPSS-R. Treatment was started at 1 mg/kg subcutaneously every 3 weeks; the dose could be increased after completion of the first 2 cycles if the patient had at least one RBC transfusion in the prior 6 weeks. Two dose level increases were allowed (to 1.33 mg/kg and to 1.75 mg/kg). Doses were held and subsequently reduced for adverse reactions, reduced if the hemoglobin increased by ≥ 2 g/dL from the prior cycle, and held if the predose hemoglobin was ≥ 11.5 g/dL.

All patients received best supportive care, which included RBC transfusions as needed. The primary efficacy assessment was conducted after completion of 24 weeks on study drug. Patients with a decrease in transfusion requirement or increase in hemoglobin could continue on blinded study drug thereafter until unacceptable toxicity, loss of efficacy, or disease progression.

The median age of the 229 study participants was 71 years (range: 26, 95 years). The trial population was 63% male and 69% White. Table 16 summarizes the baseline disease-related characteristics in the MEDALIST study.

The efficacy of REBLOZYL in adult patients with MDS-RS and MDS-RS-T was established based upon the proportion of patients who were red blood cell transfusion independent (RBC-TI), defined as the absence of any RBC transfusion during any consecutive 8-week period occurring entirely within Weeks 1 through 24.

The efficacy results are shown in Tables 17 and 18.

Table 18 shows the proportion of patients who achieved RBC-TI ≥ 8 weeks during Weeks 1-24 by diagnosis and baseline transfusion requirement.

16.1 How Supplied

REBLOZYL (luspatercept-aamt) for injection is a white to off-white lyophilized powder supplied in a single-dose vial. Each carton contains one vial.

REBLOZYL 25 mg/vial (NDC 59572-711-01)
REBLOZYL 75 mg/vial (NDC 59572-775-01)

16.2 Storage

Store vials refrigerated at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze.

Thromboembolic Events

Advise beta thalassemia patients of the potential risk of thromboembolic events. Review known risk factors for developing thromboembolic events and advise patients to reduce modifiable risk factors (e.g., smoking, use of oral contraceptives) [see Warnings and Precautions (5.1)].

Effects on Blood Pressure

Caution patients that REBLOZYL may cause an increase in blood pressure [see Warnings and Precautions (5.2)].

Extramedullary Hematopoietic Masses

Advise patients with beta thalassemia of the potential risk of extramedullary hematopoietic masses. Review possible risk factors for developing extramedullary hematopoietic masses. Instruct patients to report possible signs and symptoms of EMH masses [see Warnings and Precautions (5.3)].

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception while receiving REBLOZYL and for at least 3 months after the final dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with REBLOZYL [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)].

Lactation

Advise females not to breastfeed during treatment with REBLOZYL and for 3 months after the final dose [see Use in Specific Populations (8.2)].

Manufactured by:
Celgene Corporation, a Bristol-Myers Squibb Company
86 Morris Avenue
Summit, NJ 07901
U.S. License No. 2252

REBLOZYL® is a registered trademark of Celgene Corporation, a Bristol-Myers Squibb Company.

REBPI.007