Reblozyl Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ............................................................................................ 2

TABLE OF CONTENTS .............................................................................................................. 2

PART I: HEALTH PROFESSIONAL INFORMATION ...................................................................... 4

1 INDICATIONS ............................................................................................................... 4

1.1 Pediatrics ................................................................................................................ 4

1.2 Geriatrics ................................................................................................................ 4

2 CONTRAINDICATIONS ................................................................................................. 4

4 DOSAGE AND ADMINISTRATION ................................................................................. 5

4.1 Dosing Considerations ............................................................................................ 5

4.2 Recommended Dose and Dosage Adjustment ....................................................... 5

4.3 Reconstitution ........................................................................................................ 8

4.4 Administration ........................................................................................................ 9

4.5 Missed Dose ........................................................................................................... 9

5 OVERDOSAGE .............................................................................................................. 9

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 9

7 WARNINGS AND PRECAUTIONS ................................................................................ 10

7.1 Special Populations............................................................................................... 11

7.1.1 Pregnant Women ........................................................................................... 11

7.1.2 Breast-feeding ................................................................................................ 12

7.1.3 Pediatrics ........................................................................................................ 12

7.1.4 Geriatrics ........................................................................................................ 12

8 ADVERSE REACTIONS ................................................................................................ 12

8.1 Adverse Reaction Overview .................................................................................. 12

8.2 Clinical Trial Adverse Reactions ............................................................................ 14

8.3 Less Common Clinical Trial Adverse Reactions ..................................................... 19

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ........................................................................................................... 20

9 DRUG INTERACTIONS ................................................................................................ 21

9.2 Drug Interactions Overview .................................................................................. 21

9.4 Drug-Drug Interactions ......................................................................................... 22

9.5 Drug-Food Interactions ......................................................................................... 22

9.6 Drug-Herb Interactions ......................................................................................... 22

9.7 Drug-Laboratory Test Interactions ........................................................................ 22

10 CLINICAL PHARMACOLOGY ....................................................................................... 22

10.1 Mechanism of Action ...................................................................................... 22

10.2 Pharmacodynamics ........................................................................................ 22

10.3 Pharmacokinetics ........................................................................................... 23

11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 25

12 SPECIAL HANDLING INSTRUCTIONS ........................................................................... 25

PART II: SCIENTIFIC INFORMATION ....................................................................................... 26

13 PHARMACEUTICAL INFORMATION ............................................................................ 26

14 CLINICAL TRIALS ........................................................................................................ 26

14.1 Clinical Trials by Indication ............................................................................. 26

14.3 Immunogenicity .............................................................................................. 35

15 MICROBIOLOGY ........................................................................................................ 36

16 NON-CLINICAL TOXICOLOGY ..................................................................................... 36

PATIENT MEDICATION INFORMATION – USE IN ΒETA-THALASSEMIA ................................... 39

PATIENT MEDICATION INFORMATION – USE IN MYELODYSPLASTIC SYNDROMES ................ 44

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

Reblozyl® (luspatercept for injection) is indicated for:

Beta(β)-Thalassemia

• the treatment of adult patients with red blood cell (RBC) transfusion-dependent anemia associated with beta(β)-thalassemia.

Myelodysplastic Syndromes (MDS)

• the treatment of adult patients with transfusion-dependent anemia due to very low- to intermediate-risk myelodysplastic syndromes (MDS) who have not been previously treated with an erythropoiesis stimulating agent (ESA-naïve).
• the treatment of adult patients with transfusion-dependent anemia requiring at least two RBC units over 8 weeks resulting from very low- to intermediate-risk myelodysplastic syndromes (MDS) who have ring sideroblasts (RS+) and who have failed or are not suitable for erythropoietin-based therapy.

Limitation of Use:

Reblozyl® is an erythroid maturation agent. It is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.

No clinically meaningful change in liver iron concentration was observed in β-thalassemia patients treated with Reblozyl® plus best supportive care (BSC) compared to patients treated with placebo plus BSC at 48 weeks.

1.1 Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics (> 65 years of age):

Clinical studies of Reblozyl® in β-thalassemia did not include a sufficient number of patients aged 65 years and older to determine whether they respond differently from younger patients.

2 CONTRAINDICATIONS

Reblozyl® is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• There are limited clinical data in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30mL/min/1.73m²) and therefore no dosing recommendations are available.
• Consider the risk of use of Reblozyl® in β-thalassemia patients who were excluded from clinical trials i.e., patients with uncontrolled hypertension, a deep vein thrombosis or stroke in the previous 24 weeks, or use of an erythropoiesis-stimulating agent (ESA) within the previous 24 weeks (see 14 CLINICAL TRIALS).
• No dose adjustments are required for geriatric patients (≥ 65 years of age), patients with mild to moderate renal impairment, or patients with mild to severe hepatic impairment, see 10.3 Pharmacokinetics.
• Discontinue Reblozyl® in case of extramedullary hematopoietic (EMH) masses causing serious complications (see 7 WARNINGS AND PRECAUTIONS).

4.2 Recommended Dose and Dosage Adjustment

The recommended starting dose of Reblozyl® is 1.0 mg/kg once every 3 weeks by subcutaneous (SC) injection.

Assess and review hemoglobin (Hgb) results prior to each administration. If an RBC transfusion occurred prior to dosing, the pre-transfusion Hgb must be considered for dosing purposes.

If the pre-dose Hgb is greater than or equal to 115 g/L and the Hgb level is not influenced by recent transfusion, delay dosing until Hgb is less than or equal to 110 g/L.

Recommended Dosage Adjustment in Β-thalassemia:

If a patient does not achieve a response, defined as a reduction in RBC transfusion burden of at least a third from baseline (≥ 33%), after at least 2 consecutive doses (6 weeks) at the 1.0 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.

If there is an increase in Hgb > 20 g/L within 3 weeks of the previous dose, and in the absence of transfusion, then dose reduce as per Table 1.

Discontinue Reblozyl® if, in the absence of other causes, a patient does not achieve a response (defined as a decrease in transfusion burden for transfusion-dependent Β-thalassemia patients) after 9 weeks of treatment (administration of 3 doses) at the maximum dose level or if unacceptable toxicity occurs at any time.

Dosing recommendations and modifications in patients with β-thalassemia are provided in Table 1.

Table 1: β-thalassemia - Reblozyl^® Dose Titration, Dose Modifications, and Treatment Discontinuation Recommendations

*Grades as per NCI-CTCAE or when not defined Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, and Grade 4 is life-threatening.

Recommended Dosage Adjustment in Very Low- to Intermediate-Risk MDS:

If a patient is not RBC transfusion-free or does not reach Hgb concentration of ≥ 100 g/L and the Hgb increase is < 10 g/L after at least 2 consecutive doses (6 weeks) at the 1.0 mg/kg starting dose, increase the Reblozyl® dose to 1.33 mg/kg.

If the patient is not RBC transfusion-free or does not reach Hgb concentration of ≥ 100 g/L and the Hgb increase is < 10 g/L after at least 2 consecutive doses (6 weeks) at the 1.33 mg/kg dose, increase the Reblozyl® dose to 1.75 mg/kg.

Do not increase the dose more frequently than every 6 weeks (2 doses) or beyond the maximum dose of 1.75 mg/kg.

If there is an increase in Hgb > 20 g/L within 3 weeks of the previous dose, and in the absence of transfusion, then dose reduce as per Table 2.

Discontinue Reblozyl® if, in the absence of other causes, a patient does not achieve a response (defined as a decrease in transfusion burden including no increase in hemoglobin from baseline levels) after 9 weeks of treatment (administration of 3 doses) at the maximum dose level or if unacceptable toxicity occurs at any time.

Dosing recommendations and modifications in patients with MDS are provided in Table 2.

Table 2: MDS - Reblozyl^® Dose Titration, Dose Modifications, and Treatment Discontinuation Recommendations

*Grades as per NCI-CTCAE or when not defined Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, and Grade 4 is life-threatening.

Health Canada has not authorized an indication for pediatric use.

4.3 Reconstitution

Reblozyl® should be reconstituted by a healthcare professional.

Reconstitute Reblozyl® with Sterile Water for Injection, USP only.

Table 3 - Reconstitution Volumes

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.

Once reconstituted the solution has a pH of 6.5.

Reconstitution Instructions:

1. 1. Reconstitute with Sterile Water for Injection, USP using volumes described in Table 3 with the stream directed into the lyophilized powder. Allow to stand for one minute.
2. 2. Discard the needle and syringe used for reconstitution. The needle and syringe used for reconstitution should not be used for subcutaneous injection.
3. 3. Gently swirl the vial in a circular motion for 30 seconds. Stop swirling and let the vial sit in upright position for 30 seconds.
4. 4. Inspect the vial for undissolved particles in the solution. If undissolved powder is observed, repeat step 3 until the powder is completely dissolved.
5. 5. Invert the vial and gently swirl in an inverted position for 30 seconds. Bring the vial back to the upright position, and let it sit for 30 seconds.
6. 6. Repeat step 5 seven more time to ensure complete reconstitution of material on the sides of the vial.
7. 7. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit. Reblozyl® is a colourless to slightly yellow, clear to slightly opalescent solution which is free of foreign particulate matter. Do not use if undissolved product or foreign particulate matter are observed.
8. 8. If the reconstituted solution is not used immediately:
9. • Store at room temperature at 20^○C to 25^○C in the original vial for up to 8 hours. Discard if not used within 8 hours of reconstitution.
10. • Alternatively, store refrigerated at 2^○C to 8^○C for up to 24 hours in the original vial. Remove from refrigerated conditions 15-30 minutes prior to injection to allow solution to reach room temperature for a more comfortable injection. Discard if not used within 24 hours of reconstitution.
11. • Do not freeze the reconstituted solution.

Discard any unused portion. Do not pool unused portions from the vials. Do not administer more than 1 dose from a vial. Do not mix with other medications.

4.4 Administration

Reblozyl® should be administered by a healthcare professional.

Calculate the exact total dosing volume of 50 mg/mL solution required for the patient as per Table 3.

Slowly withdraw the dosing volume of the reconstituted Reblozyl® solution from the single-dose vial(s) into a syringe. Divide doses requiring larger reconstituted volumes (i.e., greater than 1.2 mL) into separate similar volume injections and inject into separate sites. If multiple injections are required, use a new syringe and needle for each subcutaneous injection.

Administer the injection subcutaneously into the upper arm, thigh, and/or abdomen.

4.5 Missed Dose

If a planned administration of Reblozyl® is missed, administer Reblozyl® as soon as possible and continue dosing as prescribed, with at least 3 weeks between doses.

5 OVERDOSAGE

Overdosage may cause hemoglobin levels to increase above the desired level. In the event of an overdose, assess Hgb level 7 days after the overdose and once a week thereafter. Treatment should be delayed until Hgb ≤ 110 g/L.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

To help ensure the traceability of biologic products, health professionals should recognize the importance of recording both the brand name and the non-proprietary (active ingredient) name as well as other product-specific identifiers such as the Drug Identification Number (DIN) and the batch/lot number of the product supplied.

Reblozyl® is available in 2 vial strengths, 1 vial / carton (see Table 4).

Table 4 – Dosage Forms, Strengths, Composition and Packaging

7 WARNINGS AND PRECAUTIONS

General

Extramedullary hematopoietic (EMH) masses

In adult patients with transfusion-dependent β-thalassemia from the BELIEVE and longer-term follow-up study, extramedullary hematopoietic (EMH) masses were observed in 10/315 (3.2%) Reblozyl®-treated patients and in no placebo-treated patient. Spinal compression symptoms due to EMH masses occurred in 6/315 (1.9%) Reblozyl®-treated patients. β-thalassemia patients with EMH masses had known risk factors such as medical history of EMH masses at baseline or comorbidity of splenectomy, splenomegaly, hepatomegaly or low baseline hemoglobin (<85 g/L). Signs and symptoms may vary depending on the anatomical location. Monitor β-thalassemia patients 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 (see 4.1 Dosing Considerations). Reblozyl® is not recommended for patients requiring treatment to control the growth of EMH masses.

Cardiovascular

Hypertension

In controlled clinical trials, adult patients treated with Reblozyl® had an average increase in systolic and diastolic blood pressure of 5 mm Hg from baseline, which was not observed in patients who received placebo. In the Phase III trials in patients with β-thalassemia and MDS, hypertension was reported as an adverse event in more patients treated with Reblozyl® compared to placebo/epoetin alfa (see 8 ADVERSE REACTIONS). Monitor blood pressure prior to each administration. Treat new-onset hypertension or exacerbations of pre-existing hypertension as per current guidelines.

Thrombosis / Thromboembolism

In the BELIEVE β-thalassemia trial, thromboembolic events (TEE) were reported as an adverse event in more patients treated with Reblozyl® compared to placebo (see 8 ADVERSE REACTIONS). Reported TEEs included deep vein thrombosis, pulmonary emboli, and ischemic stroke. The potential benefit of treatment with Reblozyl® should be weighed against the potential risk of thromboembolic events in β-thalassemia patients with a splenectomy and other risk factors for developing TEE. Consider

thromboprophylaxis in patients with β-thalassemia at higher risk at increased risk of TEE. Monitor patients receiving Reblozyl® for signs and symptoms of TEE and institute treatment promptly as per standard clinical practice.

Monitoring and Laboratory Tests

Assess and review Hgb results prior to each administration of Reblozyl®. If an RBC transfusion occurred prior to dosing, the pretransfusion Hgb must be considered for dosing purposes, see 4.2 Recommended Dose and Dosage Adjustment.

Monitor blood pressure prior to each administration, see 7 WARNINGS AND PRECAUTIONS, Cardiovascular.

Reproductive Health: Female and Male Potential

• Fertility

  There are no data on the effects of Reblozyl® on human fertility.

  In a fertility and early embryonic development study in rats, there were significant reductions in the average numbers of corpora lutea, implantations, and viable embryos in female rats receiving luspatercept. There was no effect on mating, fertility, or litter parameters when male rats treated with luspatercept were mated with untreated female rats. Effects on fertility in female rats were reversible after a 14-week recovery period. Based on findings in animals, female fertility may be compromised with Reblozyl® (see 16 NON-CLINICAL TOXICOLOGY).

7.1 Special Populations

7.1.1 Pregnant Women

Embryo-fetal toxicity

There are no available human data to inform the drug-associated risk; however, based on findings in animals, Reblozyl® may cause fetal harm when administered to a pregnant woman. Luspatercept was a selective development toxicant in the rat, and a maternal and fetal development toxicant in the rabbit. In both species, effects included increased resorptions and post-implementation loss, decreased litter size, and an increased incidence of skeletal alterations. See 16 NON-CLINICAL TOXICOLOGY.

Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Reblozyl®.

Pregnancy testing is recommended for females of childbearing potential prior to initiating treatment with Reblozyl®.

Advise females of childbearing potential to use effective contraception during treatment with Reblozyl® and for at least 3 months after the last dose. If Reblozyl® is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be informed of the potential for hazard to the fetus.

7.1.2 Breast-feeding

Luspatercept was detected in the milk of lactating rats following a single subcutaneous dose of luspatercept (30 mg/kg); mean lacteal transfer was 12% (see 16 NON-CLINCIAL TOXICOLOGY). The safe use of Reblozyl® during breast-feeding has not been established.

It is unknown if the drug is excreted in human milk or absorbed systemically after ingestion by a nursing infant. As many drugs are excreted in human milk, and because of the unknown effects of luspatercept in infants, taking into account the importance of the drug to the mother, a decision should be made whether to discontinue breast-feeding during treatment with Reblozyl® and for 3 months after the final dose or to discontinue Reblozyl®.

7.1.3 Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

Geriatrics (> 65 years of age):

Clinical studies of Reblozyl® in β-thalassemia did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.

Clinical studies of Reblozyl® in MDS included patients with ages ranging from 18 to 95 years old, with a median age of 72 years. No differences in safety or effectiveness were observed between older (≥65 years) and younger patients when compared to placebo.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

β-thalassemia (BELIEVE Trial):

In the double-blind, randomized, placebo-controlled, multicentre, Phase III, BELIEVE trial, 332 adult patients with transfusion-dependent (TD) β-thalassemia were included in the Safety Population: 223 in the Reblozyl® arm and 109 in the placebo arm following a 2:1 randomization scheme.

The most common treatment emergent adverse events (TEAEs) in patients treated with Reblozyl® (≥ 10% and with ≥ 1% frequency versus placebo) were: headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, and dizziness.

Serious TEAEs occurred in 15.2% of patients treated with Reblozyl® compared to 5.2% of patients treated with placebo. More patients treated with Reblozyl® experienced serious TEAEs of infections compared to patients treated with placebo (5.8% vs. 2.8%), including septic shock (1% vs. none), cellulitis (1% vs. none) and cholangitis (1% vs. none). Other serious TEAEs reported in ≥ 1% of patients treated with Reblozyl® were anemia (1.3%), cerebrovascular accident, deep vein thrombosis, and pyrexia (1% each).

Dose delay/interruption due to an adverse event occurred in 15.2% of Reblozyl® and 10.1% of placebo treated patients. In the Reblozyl® arm, the most common adverse events leading to dose delay/interruption were upper respiratory tract infection (1.8%), alanine aminotransferase increased (1.3%), and cough (1.3%). Dose reduction due to an adverse event occurred in 2.7% of Reblozyl® and 2.8% of placebo-treated patients. In the Reblozyl® arm the most common adverse event leading to dose reduction of Reblozyl® was hypertension (0.9%).

Treatment discontinuation due to an adverse event occurred in 5.4% of Reblozyl® and 0.9% of placebo treated patients. The most common adverse events leading to discontinuation of Reblozyl® were arthralgia (0.9%), back pain (0.9%), and deep vein thrombosis (0.9%).

Hypersensitivity reactions (systemic including eyelid edema, drug hypersensitivity, swelling face, periorbital edema, hypersensitivity, face edema, lip swelling, drug eruption) were reported in 4.5% of patients receiving Reblozyl®. All events were Grade 1-2 and non-serious.

Injection site reactions (including injection site erythema, injection site pruritus, injection site swelling, and injection site rash) were reported in 2.2% of Reblozyl® and 1.8% of placebo treated patients. All events were Grade 1.

Very Low- to Intermediate-Risk MDS with Ring Sideroblasts Who Have Failed or Are Not Suitable for Erythropoietin-based Therapy (MEDALIST Trial):

In the double-blind, randomized, placebo-controlled, multicentre, Phase III, MEDALIST trial, 229 adult patients with RBC transfusion-dependent (TD) very low-, low-, or intermediate-risk MDS with ring sideroblasts were included in the Safety Population: 153 in the Reblozyl® arm and 76 in the placebo arm.

The most common TEAEs in patients treated with Reblozyl® (≥ 10% and with ≥ 1% frequency versus placebo) were: fatigue, diarrhea, asthenia, nausea, dizziness, back pain, cough, headache, dyspnea, urinary tract infection, bronchitis, and constipation. Asthenia, fatigue, dizziness and headache occurred more frequently during the first 3 months of treatment.

Serious TEAEs occurred in 31.4% of patients on Reblozyl® and 30.3% of patients on placebo. Serious TEAEs reported in ≥ 1% of patients treated with Reblozyl® were pneumonia, urinary tract infection, transformation to AML, back pain, syncope (2% each), and sepsis, basal cell carcinoma, cardiac failure, angina pectoris, atrioventricular block, femur fracture, anemia, and acute kidney injury (1.3% each).

Dose delay/interruption due to an adverse event occurred in 15.0% of Reblozyl® and 5.3% of placebo-treated patients. In the Reblozyl® arm, the most common adverse events leading to dose delay/interruption were urinary tract infection, aspartate aminotransferase increased, neutropenia, and muscle weakness (1.3% each).

Dose reduction due to an adverse event occurred in 4.6% of Reblozyl®-treated patients compared to none for placebo-treated patients. Adverse events leading to dose reduction were based on single patient experiences of: asthenia, fatigue, back pain, myalgia, neutropenia, vomiting, and aminotransferase increased.

Treatment discontinuation due to an adverse event occurred in 8.5% of Reblozyl® and 7.9% of placebo-treated patients. The most common adverse events leading to discontinuation of Reblozyl® were transformation to AML, fatigue, and sepsis (1.3% each).

Hypersensitivity reactions (systemic including eyelid edema, drug hypersensitivity, swelling face, periorbital edema, hypersensitivity, face edema) were reported in 4.6% of patients receiving Reblozyl®. All events were Grade 1-2 and non-serious.

Injection site reactions (including injection site erythema, injection site pruritus, injection site rash, injection site swelling) were reported in 4.6% of Reblozyl® and 2.6% of placebo-treated patients. All events were Grade 1 and non-serious.

Transformation to AML was reported in 2.0% of Reblozyl® treated patients and 1.3% of placebo patients.

Very Low- to Intermediate-Risk MDS Patients Who Are ESA-Naïve (COMMANDS Trial):

In the double-blind, randomized, active-controlled, multicentre, Phase III, COMMANDS trial, the safety of Reblozyl® was evaluated in 356 randomized ESA-naïve patients: 178 in the Reblozyl® arm and 178 in the Epoetin Alfa arm.

The most frequently reported (greater than 10%) adverse drug reactions of luspatercept were diarrhea (14.6%), fatigue (14.6%), hypertension (12.9%), peripheral oedema (12.9%), asthenia (12.4%), nausea (11.8%), and dyspnea (11.8%). The most common (>2%) Grade > 3 adverse reactions included hypertension and dyspnea.

Discontinuation due to an adverse reaction occurred in 17 (9.6%) patients treated with Reblozyl® vs. 11 (6.3%) patients treated with epoetin alfa. Dose interruption due to an adverse reaction occurred in 48 (27.0%) patients treated with Reblozyl® vs. 40 (22.7%) patients treated with epoetin alfa. Dose reduction due to an adverse reaction occurred in 5 (2.8%) patients treated with Reblozyl® vs. 6 (3.4%) patients treated with epoetin alfa.

Asthenia, fatigue, nausea, diarrhoea, dizziness, hypertension, and dyspnea occurred more frequently during the first 3 months of treatment.

Hypersensitivity reactions (including eyelid edema, drug hypersensitivity, swelling face, periorbital edema, hypersensitivity, face edema, angioedema, lip swelling, drug eruption) were reported in 1.7% of patients receiving Reblozyl® and 1.1% of epoetin alfa-treated patients.

Injection site reactions (including injection site erythema, injection site pruritus, injection site swelling, and injection site rash) were reported in 2.8% of Reblozyl® and 0.6% of epoetin alfa-treated patients.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

β-thalassemia (BELIEVE Trial):

The TEAEs reported in adult patients enrolled in the BELIEVE trial are listed in Table 5 and reflect a median treatment duration of 64.1 weeks (range 3-97) in the Reblozyl® arm, compared with 64.0 weeks (range 9-92) in the placebo arm. All TEAEs observed in ≥ 5% of the Reblozyl®-treated patients and Grade 3 or 4 TEAEs observed in ≥ 1% of the Reblozyl®-treated patients are included in the table (≥

1% greater frequency versus placebo is applied). TEAEs are included without regard to causality.

Table 5 - Treatment Emergent Adverse Events (≥ 5%) Reported in Patients with β-thalassemia Treated with Reblozyl^® from the BELIEVE Trial (Safety Population)

^aLimited to Grade 3 reactions with the exception of 4 events of Grade 4 hyperuricemia

^bGrouped term includes: abdominal pain and abdominal pain upper

^cGrouped term includes: hyperuricemia and blood uric acid increased

^dGrouped term includes: essential hypertension, hypertension, and hypertensive crisis

Very Low- to Intermediate Risk MDS with Ring Sideroblasts Who Have Failed or Are Not Suitable for Erythropoietin-based Therapy (MEDALIST Trial):

The TEAEs reported in adult patients enrolled in the MEDALIST trial are listed in Table 6 and reflect a median treatment duration of 49.0 weeks (range 6-114) in the Reblozyl® arm compared with 24.0 weeks (range 7-89) in the placebo arm. All TEAEs observed in ≥ 5% of the Reblozyl®-treated patients and Grade 3 or 4 TEAEs observed in ≥ 1% of the Reblozyl®-treated patients are included in the table (≥ 1% greater frequency versus placebo is applied). TEAEs are included without regard to causality.

^aAt least 1 event was reported as serious

^bGrouped terms include: fatigue and asthenia

^cGrouped terms include: renal failure, acute kidney injury, chronic kidney disease, renal impairment ^dGrouped terms include: essential hypertension, hypertension, hypertensive crisis

Very Low- to Intermediate-Risk MDS Patients Who Are ESA-Naïve (COMMANDS Trial):

The TEAEs reported in adult patients enrolled in the COMMANDS trial are listed in Table 7. At the time of the planned interim analysis of the COMMANDS trial, the median duration of treatment in the luspatercept treatment group was longer than the epoetin alfa arm (41.6 vs. 27.0 weeks, respectively) and a higher proportion of patients in the luspatercept arm vs. the epoetin alfa arm completed 48 weeks of treatment: 45.5% vs 32.4%, respectively.

All TEAEs observed in ≥ 5% of the Reblozyl®-treated patients and Grade 3 or 4 TEAEs observed in ≥3 % of the Reblozyl®-treated patients are included in the table. TEAEs are included without regard to causality.

MDS patients without ring sideroblast (RS-)

RS- patients are more likely to experience serious adverse events, Grade 5 treatment-emergent adverse events, adverse events leading to drug discontinuation or dose reduction compared to patients with ring sideroblasts (RS+). In the COMMANDS trial, RS- patients showed higher incidence of some adverse reactions compared to RS+ patients in both treatment arms. When comparing RS subgroups in the luspatercept arm, asthenia, nausea, vomiting, dyspnoea, cough, thromboembolic events, alanine aminotransferase increased, aspartate aminotransferase increased, and thrombocytopenia occurred more frequently in the RS- subgroup.

8.3 Less Common Clinical Trial Adverse Reactions

β-thalassemia (BELIEVE Trial):

Less common clinically significant adverse events (<5%, all grades with incidence greater than placebo) in the BELIEVE trial include:

Blood and Lymphatic disorders: anemia (4.5%), EMH masses (3.2%)

Ear and labyrinth disorders: vertigo (3%)

Eye disorders: eyelid edema (1%), periorbital edema (1%)

Gastrointestinal disorders: lip swelling (0.4%)

General disorders and administration site conditions: face edema (0.4%), injection site reaction (2%), injection site swelling (0.4%)

Hepatobiliary Disorders: cholangitis (1%), drug-induced liver injury (0.4%), portal vein thrombosis (0.4%)

Immune System Disorders: drug hypersensitivity (0.4%), hypersensitivity (0.4%)

Infections and infestations: cellulitis (2%), septic shock (1%), urinary tract infection (2%)

Investigations: urine albumin/creatinine ratio increased (2%)

Nervous System Disorder: cerebrovascular accident (1%), Spinal cord compression (1.9%)

Respiratory, Thoracic, and Mediastinal Disorders: pulmonary embolism (0.4%)

Skin and subcutaneous tissue disorders: drug eruption (0.4%), swelling face (0.4%)

Vascular disorders: deep vein thrombosis (1%), thrombophlebitis superficial (1%)

Very Low- to Intermediate-Risk MDS with Ring Sideroblasts Who Have Failed or Are Not Suitable for

Erythropoietin-based Therapy (MEDALIST Trial):

Less common clinically significant adverse events (<5%, all grades with incidence greater than placebo) in the MEDALIST trial include:

Cardiac disorders: angina pectoris (4.6%), atrioventricular block (2.0%), cardiac failure (1.3%)

Infections and infestations: pneumonia (3.3%), sepsis (1.3%)

Injury, poisoning and procedural complications: femur fracture (1.3%)

Neoplasms benign, malignant and unspecified: basal cell carcinoma (1.3%)

Respiratory, Thoracic, and Mediastinal Disorders: pulmonary fibrosis (0.7%)

Very Low- to Intermediate Risk MDS Patients Who Are ESA-Naïve (COMMANDS Trial):

Less common clinically significant adverse events (<5%), all grades with incidence greater than Epoetin Alfa) in the COMMANDS trial include:

General disorders and administration site conditions: injection site erythema (1.1%), injection site rash (0.6%), injection site pruritus (0.6%).

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial Findings

β-thalassemia (BELIEVE Trial):

Changes in selected post-baseline laboratory parameters that were observed in the BELIEVE study are listed in Table 8.

Table 8 – Selected Laboratory Abnormalities Reported in the BELIEVE Trial (Safety Population)

ALP = alkaline phosphate; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal

Very Low- to Intermediate Risk MDS with Ring Sideroblasts Who Have Failed or Are Not Suitable for Erythropoietin-based Therapy (MEDALIST Trial):

Changes in selected post-baseline laboratory parameters that were observed in the MEDALIST trial are listed in Table 9.

Table 9 – Selected Laboratory Abnormalities Reported in Trial ACE-536-MDS-001 (Safety Population)

ALP = alkaline phosphate; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal

Very Low- to Intermediate-Risk MDS Patients Who Are ESA-Naïve (COMMANDS Trial):

Shifts from Grades 0-2 at baseline to Grades 2-3 abnormalities for selected laboratory tests in ACE-536-MDS-002 are listed in Table 10.

Table 10 – Selected Treatment-Emergent Laboratory Abnormalities in COMMANDS (ACE-536-MDS-002) Trial that Shift to Grades 2-3

^a Number of patients at Grades 0-1 at baseline.

^b GFR= glomerular filtration rate (GFR (mL/min)

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

No formal drug interaction studies have been conducted with Reblozyl®.

9.4 Drug-Drug Interactions

Iron-chelating agents: No clinically significant differences in luspatercept PK parameters were observed when used concomitantly with iron-chelating agents.

Interactions with other drugs have not been established.

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

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

10.2 Pharmacodynamics

Increases in Hemoglobin

In patients having received < 4 units of RBC transfusion within 8 weeks prior to study, hemoglobin (Hgb) increased within 7 days of initiating Reblozyl® and correlated with the time to luspatercept maximum serum concentration (Cmax). The greatest Hgb increase occurred after the first dose with additional smaller increases observed after subsequent doses. Hemoglobin levels returned to baseline approximately 8 weeks from the last dose (0.6 to 1.25 mg/kg) in patients with β-thalassemia, and approximately 6 weeks from the last dose (0.75 to 1.75 mg/kg) in patients with MDS. Increasing luspatercept serum exposure (AUC) was associated with greater Hgb increase in patients with β-thalassemia and in patients with MDS.

Cardiac Electrophysiology

The potential for QTc prolongation with Reblozyl® was evaluated in 638 patients with either MDS (an unapproved indication) or β-thalassemia who were treated with multiple doses (0.125 to 1.75 mg/kg) of Reblozyl® (n=474) or placebo (n=164). At steady-state mean Cmax for the maximum therapeutic dose (1.75 mg/kg), the upper bound of the 2-sided 90% CI for the mean difference in QTc change from baseline between Reblozyl® and placebo was < 10ms. Therefore, Reblozyl ® does not cause any clinically meaningful prolongation of the QTc interval at therapeutic doses.

10.3 Pharmacokinetics

Luspatercept exhibited linear pharmacokinetics (PK) over the dose range of 0.2 to 1.25 mg/kg in patients with β-thalassemia, and over the dose range of 0.125 to 1.75 mg/kg in patients with MDS. Luspatercept serum concentration reached steady state after 3 doses when administered every 3 weeks. The accumulation ratio of luspatercept was approximately 1.5. Luspatercept PK parameters, in patients with β-thalassemia are summarized in Table 11, and in patients with MDS in Table 12.

Table 11 - Summary of Luspatercept Pharmacokinetic Parameters in Patients With β-Thalassemia

^a Includes all dose groups (0.2 to1.25 mg/kg) in Phase II study

Data are based on non-compartmental analysis and all PK parameters are summarized by the arithmetic mean (% CV).

AUC_21d = area under the concentration-time curve during the first dosing interval (1-21 days); C_max = maximum concentration during the first dosing interval; CV = coefficient of variation; N = sample size; t_1/2 = elimination half-life.

Table 12 - Summary of Luspatercept Pharmacokinetic Parameters in Patients With MDS after Multiple Doses

^a All PK parameters are summarized by geometric mean (geometric CV%).

AUC_ss = area under the concentration-time curve at steady state for the starting dose (1 mg/kg); C_max.ss = maximum concentration for at steady state (1 mg/kg); CV = coefficient of variation; t_1/2 = elimination half-life.

Absorption

The median (range) time to maximum concentration (Tmax) of luspatercept was observed at approximately 7 (6-10) days post-dose in patients with β-thalassemia and at approximately 7 (4-21) days post-dose in patients with MDS. The absorption of luspatercept was not significantly affected by the subcutaneous injection sites (upper arm, thigh, or abdomen).

Distribution:

In a population PK analysis, the mean (%CV) apparent volume of distribution (Vd/F) of luspatercept was estimated to be 7.1 (26.7%) L for patients with β-thalassemia and 9.7 (26.5%) L for patients with MDS.

Metabolism:

Luspatercept is expected to be catabolized into amino acids by general protein degradation processes in multiple tissues.

Elimination

The mean (%CV) half-life (t1/2) of luspatercept was approximately 11 (24.2%) days in patients with β-thalassemia. In a population PK analysis, the mean (%CV) apparent total clearance (CL/F) was estimated to be 0.44 (38.5%) L/day in patients with β-thalassemia. The mean (%CV) half-life (t1/2) of luspatercept was approximately 13 (31.6%) days and the mean (%CV) apparent total clearance (CL/F) was 0.52 (41.2%) L/day in patients with MDS.

Special Populations and Conditions

No clinically significant differences in the luspatercept PK was observed based on age (18 to 66 years), sex, baseline albumin (30 – 56 g/L), baseline serum erythropoietin (2.4 to 972 U/L), RBC transfusion burden (0 to 34 units/24 weeks), β-thalassemia genotype (β0/β0 vs. non-β0/β0), and splenectomy in patients with β-thalassemia. No clinically significant differences in luspatercept PK was observed in MDS patients based on age (27-95 years), sex, baseline albumin (31-53 g/L), baseline serum erythropoietin (10 to 2450 U/L), RBC transfusion burden (0-43 units/24 weeks), and ring sideroblasts status (negative vs. positive).

• Pediatrics

  Luspatercept pharmacokinetics in patients < 18 years of age has not been evaluated.

• Geriatrics

  Clinical studies of Reblozyl® in β-thalassemia did not include sufficient numbers of patients aged 65 years and older to determine if luspatercept pharmacokinetics are different from younger patients. No clinically significant differences in luspatercept PK were observed in MDS patients < 65, 65 – 74, and ≥ 75 years of age.

• Sex

  Gender had no clinically significant effect on luspatercept exposure (AUC or clearance).

• Ethnic Origin

  Race (Asian vs. Caucasian) had no clinically significant effect on luspatercept exposure (AUC or clearance).

• Hepatic Insufficiency

  No formal studies of Reblozyl® in patients with hepatic impairment have been conducted. No clinically important differences in luspatercept exposure were observed in patients with mild to severe hepatic impairment i.e. elevated liver enzymes (ALT or AST, up to 3 x ULN [upper limit of normal]) and elevated bilirubin (4-246 μmol/L). Pharmacokinetic data are not available for patients with AST or ALT ≥ 3x ULN.

• Renal Insufficiency

  No formal studies of Reblozyl® in patients with renal impairment have been conducted. Based on estimated eGFR, no clinically important differences in exposure to luspatercept were observed in patients with mild to moderate renal impairment (mild [eGFR 60-89 mL/min/1.73 m²]; moderate [eGFR 30-59 mL/min/1.73 m²]). Pharmacokinetic data are not available for patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²).

• Obesity

  The apparent clearance (CL/F) and volume of distribution (Vd/F) of luspatercept increased with increasing body weight (34 to 97 Kg) in patients with β-thalassemia. The apparent CL/F and Vd/F of luspatercept increased with increasing body weight (46 to 124 Kg) in patients with MDS.

11 STORAGE, STABILITY AND DISPOSAL

Store vials refrigerated at 2-8˚C in original carton to protect from light. Do not freeze.

Reconstituted vials in the original container can be stored for up to 8 hours when stored at room temperature or for 24 hours when stored at 2-8˚C.

12 SPECIAL HANDLING INSTRUCTIONS

Do not freeze. Avoid aggressive shaking.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: luspatercept

Molecular mass: Approximately 76 kD

Structural: Luspatercept is a recombinant fusion protein consisting of two identical chains, each consisting of a modified form of the extracellular domain (ECD) of human activin receptor type IIB (ActRIIB) linked to the human IgG1 Fc domain.

Physicochemical properties: Luspatercept is produced in Chinese hamster ovary cells by recombinant DNA technology. Reblozyl® (luspatercept for injection) is supplied as a sterile, preservative-free, white to off-white, lyophilized powder in single-dose vials for subcutaneous use after reconstitution.

14 CLINICAL TRIALS

The clinical efficacy and safety of Reblozyl® were evaluated in adult patients with transfusion dependent (TD) β-thalassemia-associated anemia in the BELIEVE trial, in adult patients with transfusion-dependent anemia resulting from very low- to intermediate-risk MDS with ring sideroblasts in the MEDALIST trial, and in adult patients with transfusion-dependent anemia without previous erythropoiesis-stimulating agent use resulting from very low- to intermediate-risk MDS in the COMMANDS trial.

14.1 Clinical Trials by Indication

β-thalassemia (BELIEVE Trial):

Trial Design and Study Demographics

Table 13 - Summary of Patient Demographics for Clinical Trial in β-thalassemia (BELIEVE Trial)

In the BELIEVE trial, adult patients with β-thalassemia requiring regular RBC transfusions (6-20 RBC units per 24 weeks) with no transfusion-free period greater than 35 days during that 24-week period were randomized 2:1 to Reblozyl ^® or placebo. 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 or patients who had major organ damage (liver disease, heart disease, lung disease, renal insufficiency). Patients with recent (within past 24 weeks) deep vein thrombosis or stroke or recent use (within past 24 weeks) of erythropoiesis-stimulating agents, 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% Caucasian, 34.8% Asian, and 0.3% Black or African American.

Table 14 summarizes the baseline disease-related characteristics.

Table 14 – Baseline Disease Characteristics of β-thalassemia in the BELIEVE Trial

HbE=hemoglobin E ^a“Missing” category includes patients in the population who had no result for the parameter listed ^bN=220; ^cN=111; ^dN=169; ^eN=85.

Study Results

The efficacy of Reblozyl ® in adult patients with RBC transfusion dependent β-thalassemia was based on the reduction in RBC transfusion burden defined by the number of patients who achieved a specified rate of transfusion burden reduction (see Table 15).

The trial was unblinded when all patients had received at least 48 weeks of treatment or discontinued treatment.

Table 15 - Results of Study in β-thalassemia the BELIEVE Trial (ITT Population)

^a The p-value was from the Cochran-Mantel-Haenszel (CMH) test to compare Reblozyl^® treatment group to placebo group. ITT = intent to treat; RBC = red blood cells

Subgroup analysis based on the primary endpoint hazard ratio were generally consistent across the pre-defined subgroups including patients with the β0/β0 gene mutation, or patients with a high transfusion burden (>6 units/12 weeks) at baseline.

Very Low- to Intermediate Risk MDS with Ring Sideroblasts Who Have Failed or Are Not Suitable for Erythropoietin-based Therapy (MEDALIST Trial):

Trial Design and Study Demographics

Table 16 - Summary of Patient Demographics for Clinical Trial in Very Low- to Intermediate-Risk MDS with Ring Sideroblasts (MEDALIST Trial)

IPSS-R: Revised International Prognostic Scoring System (IPSS-R)

In the MEDALIST trial, adult patients with very low- to intermediate-risk MDS requiring regular RBC transfusions (≥2 RBC units per 8 weeks) with ring sideroblasts with no transfusion-free period greater than 56 days during the 16-week period prior to randomization were randomized 2:1 to Reblozyl® or placebo. Reblozyl® was administered subcutaneously once every 3 weeks. 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.

Patients were required to have received prior treatment with an erythropoiesis-stimulating agent (ESA) or determined to be unlikely to respond to ESA treatment with serum erythropoietin (EPO) (>200 U/L). The MEDALIST trial excluded patients with deletion 5q (del 5q), WBC count ≥ 13 x 109/L, neutrophils < 0.5 x 109/L, platelets < 50 x109/L, or with prior use of a disease modifying agent for treatment of MDS.

The median age was 71 years (range: 26-95); 62.9% were male, and 69% were Caucasian. Race was not reported for 29.7% of patients.

Table 17 summarizes the baseline demographics and disease-related characteristics.

Table 17 – Baseline Demographics and Disease Characteristics of MDS in MEDALIST Trial

EPO = erythropoietin; ESA = erythropoiesis-stimulating agent; IPSS-R = International Prognostic Scoring System-Revised; MDS = myelodysplastic syndromes; RARS = refractory anemia with ring sideroblasts; RBC = red blood cells; RCMD = refractory cytopenia with multilineage dysplasia; SD = standard deviation; WHO = World Health Organization

^a Time since original MDS diagnosis was defined as the number of years from the date of original diagnosis to the date of informed consent. ^b Baseline EPO was defined as the highest EPO value within 35 days of the first dose of study drug. ^c Per the WHO 2008 criteria. ^d Locally diagnosed MDS-RS and multilineage dysplasia.

Study Results

In the MEDALIST trial, the efficacy of Reblozyl® was established based on the proportion of patients who were RBC transfusion independent (RBC-TI), defined as the absence of any RBC transfusion during any consecutive 8-week period within the first 24 weeks of treatment, see Table 18.

Table 18 - Efficacy Results from the MEDALIST Trial (ITT Population)

^a 2-sided p-value from Cochran-Mantel-Haenszel (CMH) test stratified for average baseline RBC transfusion requirement (≥6 units versus < 6 units for RBC per 8 weeks), and baseline IPSS-R score (very low or low versus intermediate). ^b Defined as the absence of any RBC transfusion during any consecutive 56-day (8-week) period during the primary phase of the treatment period (first 24 weeks of double-blind treatment).

^c Defined as the absence of any RBC transfusion during any consecutive 84-day (12 week) period during the primary phase of the treatment period (first 24 weeks of double-blind treatment).

^d Defined as the absence of any RBC transfusion during any consecutive 84-day (12 week) period during Week 1 to Week 48.

ITT = intent to treat; RBC = red blood cell; RBC-TI = RBC transfusion independence.

Of the patients who achieved the primary endpoint (RBC-TI ≥8 weeks during Weeks 1-24), 62% (36/58) had more than 1 episode of RBC-TI during the treatment period.

Very Low- to Intermediate-Risk MDS Patients Who Are ESA-Naïve (COMMANDS Trial):

Trial Design and Study Demographics

Table 19 - Summary of Patient Demographics for Clinical Trial in Very Low- to Intermediate-Risk MDS in COMMANDS Trial (ACE-536-MDS-002) (ITT Population)

IPSS-R = International Prognostic Scoring System-Revised; MDS = myelodysplastic syndromes; RBC = red blood cells.

The efficacy of Reblozyl® was evaluated in a Phase 3, multicenter, randomized, open-label, active controlled trial, the COMMANDS trial, comparing luspatercept versus epoetin alfa in patients with anemia due to IPSS-R very low- to intermediate-risk myelodysplastic syndromes.

A total of 356 adult patients were randomized to receive luspatercept (N=178) every 3 weeks or epoetin alfa (N=178) every week. All patients were eligible to receive best supportive care, which included RBC transfusions as needed. Patients enrolled on study had endogenous serum erythropoietin (sEPO) levels of < 500 U/L, had 2 to 6 RBC units every 8 weeks confirmed for a minimum of 8 weeks immediately preceding randomization, and did not have prior treatments with erythropoiesis-stimulating agents. Patients with deletion 5q (del5q) MDS, secondary MDS, unclassifiable MDS or uncontrolled hypertension were excluded from the study.

Randomization was stratified by RBC transfusion burden (≤4 vs. ≥ 4 pRBC units/ 8 weeks), RS status (RS+ vs RS-; RS+ defined as RS ≥ 15% of erythroid precursors in bone marrow or ≥ 5% but < 15% if SF3B1 mutation was present) and endogenous EPO level (≤ 200 vs > 200 to < 500 U/L at baseline. Luspatercept 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 ≥ 20 g/L from the prior cycle, and held if the predose hemoglobin was ≥ 120 g/L.

Table 20 summarizes the baseline demographics and disease-related characteristics.

Table 20 – Baseline Demographics and Disease Characteristics of MDS in COMMANDS (ACE-536-MDS-002) (ITT Population)

MDS = myelodysplastic syndromes; SLD = single lineage dysplasia; MLD = multilineage dysplasia; RS = ring sideroblasts; MDS/MPN-RS-T = myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis; EPO = erythropoietin; IPSS-R = International Prognostic Scoring System-Revised; pRBC = packed red blood cells; WHO = World Health Organization

^a After applying 14/3-day rule, (only Hb values that are measured at least 14 days after a transfusion may be used unless there is another transfusion within 3 days after the Hb assessment. If a transfusion within 3 days after the Hb assessment occurs, that Hb value will be used despite being < 14 days after the previous transfusion), the baseline Hgb value (efficacy) is defined as the lowest Hgb value from the central, local laboratory, or pre-transfusion Hgb from transfusion records that is within 35 days on or prior to the first dose of study drug if it was available.

^b The number of months from the date of original diagnosis to the date of informed consent.

^c The MDS diagnosis was made using the screening bone marrow evaluation for 2 subjects. 1 patient had an original diagnosis date 28-Apr-2021 and an ICF date 23-Apr-2021. 1 subject had an original diagnosis date 15-Jul-2021 and an ICF date 07-Jul-2021.

^d Baseline transfusion burden: the number of RBC units received 8 weeks prior to or on the first dose date.

Study Results

The efficacy was established by the planned interim efficacy analysis based upon the proportion of patients who experienced red blood cell transfusion independence (RBC-TI) with an associated mean improvement in hemoglobin by at least 1.5 g/dL for any consecutive 12-week period during Weeks 1-24. A total of 301 subjects who were completed 169 days (24 weeks) of treatment or discontinued early were included in the efficacy analysis for the primary and key secondary endpoints, of which 147 were in the luspatercept arm and 154 in the epoetin alfa arm.

The key efficacy results are shown in Table 21.

Table 21 - Efficacy Results from the Interim Analysis of COMMANDS Trial (ACE-536-MDS-002) (Efficacy Analysis Population^a)

RBC-TI = red blood cell transfusion independence; HI-E per IWG: hematologic improvement – erythroid response per International Working Group (2006).

^a The efficacy analysis population is comprised of subjects who completed 169 days (24 weeks) of treatment or discontinued early.

^b 2-sided p-value is presented and the statistical significance level is two-sided p-value 0.03.

^c Based on Cochran-Mantel-Haenszel (CMH) test stratified by baseline RBC transfusion burden (< 4, ≥ 4 pRBC units), RS status (RS+, RS-) and sEPO level (≤ 200, > 200 U/L).

^d The median duration (95% CI) of RBC-TI ≥12 weeks was 126.6 weeks (108.3, Not Estimable) and 77.0 weeks (39.0, Not Estimable) in the Reblozyl^® arm and Epoetin Alfa arm, respectively.

14.3 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to luspatercept in the studies described below with the incidence of antibodies in other studies or other products may be misleading.

Of 284 patients with β-thalassemia who were treated with Reblozyl® and evaluable for the presence of anti-luspatercept antibodies, 4 patients (1.4%) tested positive for treatment-emergent anti-luspatercept antibodies, including 2 patients (0.7%) who had neutralizing antibodies. Of 316 patients with MDS (COMMANDS or MEDALIST) who were treated with Reblozyl® and evaluable for the presence of anti-luspatercept antibodies, 21 patients (6.6%) tested positive for treatment-emergent anti-luspatercept antibodies, including 14 patients (4.4%) who had neutralizing antibodies.

Luspatercept serum concentrations tended to decrease in the presence of neutralizing antibodies. There were no severe acute systemic hypersensitivity reactions reported for patients with anti-luspatercept antibodies in Reblozyl® clinical trials, and there was no association between hypersensitivity type reaction or injection site reaction and presence of anti-luspatercept antibodies.

Patients with treatment emergent anti-luspatercept antibodies were more likely to report a serious treatment emergent adverse event (69.4% [25/36] for anti-luspatercept antibodies positive patients vs. 45.7% [164/359] for anti-luspatercept antibodies negative patients) or a Grade 3 or 4 treatment emergent adverse event (77.8% [28/36] for anti-luspatercept antibodies positive patients vs. 56.8% [204/359] for anti-luspatercept antibodies negative patients) compared to patients without anti-luspatercept antibodies in the TD MDS pool.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

No carcinogenicity or mutagenicity studies have been conducted with luspatercept.

Repeat-Dose Toxicity Studies:

In repeat-dose toxicity studies toxicities in rats included: membranoproliferative glomerulonephritis; congestion, necrosis and/or mineralization of the adrenal glands; hepatocellular vacuolation and necrosis; and mineralization of the glandular stomach. In monkeys, toxicities included: membranoproliferative glomerulonephritis; vascular degeneration and inflammatory infiltrates in the choroid plexus.

Repeat dose studies were conducted in cynomolgus monkeys. In a 6-month study, monkeys received 0, 0.3, 1 or 6 mg/kg luspatercept once every two weeks, followed by a 3-month recovery period. In a 13-week study, monkeys received 0, 1, 6 or 30 mg/kg Reblozyl®, followed by a 10-week recovery period. Increases in blood parameters (increased red blood cell count, hemoglobin, hematocrit and reticulocytes) occurred at ≥ 1 mg/kg in males and ≥ 0.3 mg/kg in females (at least one time point). Creatinine and/or blood urea nitrogen (BUN) were increased at ≥ 1 mg/kg. Ferritin and ALP were increased at ≥ 6 mg/kg. The microalbumin:creatinine ratio was increased in one 1 mg/kg and two 6 mg/kg animals at most time-points. Hematology and clinical chemistry parameters were reversible in the recovery period, urine biomarkers showed a trend to pre-study levels. Histopathological analyses revealed evidence of toxicity in the kidneys, brain and lymph nodes.

Kidney: Membranoproliferative glomerulonephritis was observed at ≥ 1 mg/kg. Immune complex deposition was observed in intramembranous locations and/or mesangia of affected glomeruli. Interstitial or tubular hemorrhage with or without accompanying hemosiderin deposition was identified in the cortex and/or medulla at ≥ 1 mg/kg. Interstitial fibrosis/fibroplasia was identified at 6 mg/kg; however, subtle interstitial changes, including increased extracellular matrix, vacuolization of interstitial cells and/or degeneration/atrophy of tubules, were identified in the medulla, near the corticomedullary junction at ≥ 1 mg/kg. Minimal to mild interstitial mixed inflammatory cell infiltrates were seen in 2 of 6 animals in the 6 mg/kg dose group. Animals that received 1 mg/kg recovered following the 3-month recovery period; whereas, animals that received 6 mg/kg only partially recovered.

Brain: Changes to the choroid plexus occurred in the interstitium and blood vessels at ≥ 1 mg/kg, and included: vascular degeneration (small to medium sized blood vessels), deposition of pigment (hemosiderin), deposition of eosinophilic proteinaceous material, a mixed inflammatory cell infiltrate (small numbers of neutrophils, macrophages, and lymphocytes including plasma cells), and an infiltrate of foamy (vacuolated) macrophages. Immunohistochemistry results revealed increased deposition of immune components. These effects improved during the recovery period.

Lymph nodes: Extramedullary hematopoiesis in the mandibular and axillary lymph nodes occurred at 0.3 and 1 mg/kg, and was reversible during the recovery period.

In a repeat dose study, adult Sprague Dawley rats received 0, 1, 3 or 15 mg/kg luspatercept once every two weeks for 13 weeks, followed by a 10-week recovery period. The effects observed in the rat were similar to those observed in the monkey and occurred at similar doses. Increases in blood parameters occurred at ≥ 3 mg/kg. Membranoproliferative glomerulonephritis was observed at ≥ 1 mg/kg with, with increase in BUN at 15mg/kg. Increased levels of ALP were observed and, in the liver, minimal to mild hepatocellular vacuolation was observed at all doses, and minimal focal or multifocal hepatic necrosis was observed at ≥ 3 mg/kg. In the adrenal glands, minimal to moderate cortical necrosis was observed at ≥ 3 mg/kg. Following the recovery period, treatment-related effects persisted in the kidney, liver and adrenal gland.

In a repeat-dose definitive juvenile toxicity study, hematologic malignancies were observed in 3 out of 44 rats examined in the highest dose group (10mg/kg). The occurrence of these tumors in young animals is unusual and the relationship to luspatercept treatment cannot be ruled out. Juvenile rats were administered luspatercept 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 8 times the maximum recommended human (β-thalassemia) dose (MRHD) of 1.25 mg/kg. No other proliferative or pre-neoplastic lesions, attributable to luspatercept, have been observed in any species in other nonclinical safety studies conducted with luspatercept, including a 6-month study in monkeys.

Fertility and Early Embryonic Development Studies:

In a combined male and female fertility and early embryonic development study in rats, luspatercept was administered subcutaneously to animals at doses of 0, 1, 3 or 15 mg/kg. There were significant reductions in the average numbers of corpora lutea, implantations, and viable embryos in luspatercept-treated females. Effects on female fertility were observed at the highest dose (15 mg/kg) with exposures (based on AUC) approximately 12 times the MRHD of 1.25 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.

Embryo-Fetal Development (EFD) Studies:

Luspatercept is a developmental toxicant. Embryo-fetal developmental toxicity studies (range-finding and definitive studies) were conducted in the pregnant Sprague Dawley rat and New Zealand White rabbit. In definitive studies, rats received 0, 5,15 or 30 mg/kg, and rabbits received 0, 5, 20 or 40 mg/kg administered twice during the period of organogenesis. Embryofetal effects seen in both species included: reductions in numbers of live fetuses, reduction in fetal body weights, increases in resorptions, and increased post-implantation loss.

Maternal toxicity: The number of pregnant rats was significantly reduced at 30 mg/kg, and the number pregnant rabbits was reduced at ≥20 mg/kg. In both species, and the average number of resorptions and percent post-implantation loss were increased (30 mg/kg in rat and ≥ 20 mg/kg in rabbit).

Fetal Toxicity: In rat, skeletal variations occurred at ≥ 5 mg/kg. Gross malformations occurred at 15 mg/kg (n=3 fetuses) that were considered possibly related to luspatercept. Malformations included: agnathia with a small oral opening and absent tongue; depressed eye bulge, cleft palate, cleft snout and no nares; and, thread like tail, no anal opening, as well as skeletal malformations (only one sacral vertebra, no caudal vertebra and an extra ossification point in the sacral vertebra). There was an increase in embryo/fetal death at 30 mg/kg, which may have masked a dose response of these malformations. Other malformations that were observed were considered not treatment related because they had been previously observed in historical controls. In rabbit, skeletal variations occurred at ≥ 5 mg/kg. Skeletal malformations to the ribs and vertebra occurred in fetuses at 20 mg/kg (n=1) and 40 mg/kg (n=5). There was one grossly malformed fetus at 40 mg/kg that had gastroschisis with portions of the liver, intestines, stomach and spleen protruding; this fetus also had a malpositioned cervical vertebral centrum. In both species, the NOAEL for embryo fetal effects of luspatercept was observed in the EFD studies at the lowest dose tested, 5 mg/kg, which corresponds to an estimated exposure in rats and rabbits of 4.9 and 9.9 times greater, respectively, than the estimated clinical exposure.

Pre and Postnatal Development (PPND) Studies:

Parental generation Sprague Dawley rats received 0, 3, 10 or 30 mg/kg luspatercept; F1 generation rats were not dosed directly, but received luspatercept in utero and through breast milk. F1 rats had lower body weights and adverse effects of the kidney, including: minimal to mild membranoproliferative glomerulonephritis, and/or tubular atrophy/hypoplasia, and vessel ectasia occasionally associated with hemorrhage. Kidney effects were considered adverse at ≥ 3 mg/kg.