Summary Basis of Decision for Reblozyl
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Reblozyl is located below.
Recent Activity for Reblozyl
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Summary Basis of Decision (SBD) for Reblozyl
Date SBD issued: 2020-11-30
The following information relates to the new drug submission for Reblozyl.
Luspatercept
Drug Identification Number (DIN):
- DIN 02505541 - 25 mg luspatercept/vial, powder for solution, subcutaneous injection
- DIN 02505568 - 75 mg luspatercept/vial, powder for solution, subcutaneous injection
Celgene Inc.
New Drug Submission Control Number: 236441
On September 25, 2020, Health Canada issued a Notice of Compliance to Celgene Inc. for the drug product Reblozyl.
The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-risk profile of Reblozyl is favourable for the treatment of adult patients with red blood cell transfusion-dependent anemia associated with beta(β)‑thalassemia.
1 What was approved?
Reblozyl was authorized for the treatment of adult patients with red blood cell (RBC) transfusion-dependent anemia associated with beta(β)‑thalassemia.
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.
No data are available to Health Canada regarding the use of Reblozyl in patients younger than 18 years of age. Therefore, Health Canada has not authorized an indication for pediatric use. 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.
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.
Reblozyl was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Reblozyl (25 mg and 75 mg luspatercept) is presented as lyophilized powder for solution. In addition to the medicinal ingredient, the lyophilized powder contains citric acid monohydrate, polysorbate 80, sucrose, tri-sodium citrate dihydrate, and hydrochloric acid and/or sodium hydroxide for pH.
For more information, refer to the Clinical, Non‑clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Reblozyl Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Reblozyl approved?
Health Canada considers that the benefit-risk profile of Reblozyl is favourable for the treatment of adult patients with red blood cell (RBC) transfusion-dependent (TD) anemia associated with beta(β)‑thalassemia.
Beta(β)‑thalassemia is characterized by absent or reduced production and function of the β‑globin chains of hemoglobin, the oxygen carrying molecule in human RBCs. Mutations in the β‑globin gene (approximately 300 identified to date) can be passed on from each of the two carrier parents to affected offspring in a recessive Mendelian manner. The incidence of β‑thalassemia is highest in individuals of Mediterranean, Middle Eastern, and Southeast Asian descent.
Beta(β)‑thalassemia results in ineffective erythropoiesis due to premature RBC death, leading to a state of chronic anemia. There are differences in severity of the disease, dictated by the inherited β‑globin mutations, ranging from individuals who rarely require RBC transfusions to others who need them regularly for survival into adulthood. This latter group usually presents in early childhood with severe anemia (hemoglobin <70 g/L) and falls under the general category of TD β‑thalassemia. Hematopoietic stem cell transplantation (HSCT) is the only available curative therapy for patients with β‑thalassemia, but is limited by the availability of matched donors (approximately 20% of patients). Outside of HSCT, regular blood transfusions combined with iron chelation therapy is the mainstay treatment for individuals with TD β‑thalassemia but complications arise due to iron overload and development of alloantibodies. These alloantibodies decrease the lifespan of transfused blood cells and is an obstacle in obtaining compatible blood for subsequent transfusions.
Currently, there is no available therapy that is approved or widely used to address the underlying ineffective erythropoiesis and anemia associated with β‑thalassemia; the hallmarks of disease pathogenesis and source of clinical morbidity and diminished quality of life. Given the association between ineffective erythropoiesis, anemia, and iron overload, it is possible that interventions that target ineffective erythropoiesis and anemia will have the potential to prevent the progression of iron overload, or help in its amelioration, with or without iron chelation therapy.
Luspatercept, the medicinal ingredient in Reblozyl, is a modified extracellular domain of human activin receptor type IIB (ActRIIB) and the Fc portion of human immunoglobulin G1 (IgG1). The drug binds to and interferes with the functions of transforming growth factor beta (TGF‑β) ligands and thereby inhibits downstream Smad2/3 signaling. Although the role of Smad2/3 in erythropoiesis is not fully understood, inhibition of the Smad2/3 signaling pathway by luspatercept has been shown to promote erythropoiesis and RBC maturation in pre-clinical studies.
The clinical development of Reblozyl in β‑thalassemia culminated in a double-blind controlled Phase III study known as ACE-536-B-THAL-001. In this study, a total of 336 adult patients with RBC TD β‑thalassemia were randomized in a 2:1 ratio to receive either Reblozyl plus best supportive care (BSC) (number of patients [n] = 224) or placebo plus BSC (n = 112), every 3 weeks for 48 weeks.
More patients treated with Reblozyl (21.4%) compared to placebo (4.5%) achieved the primary efficacy endpoint of a ≥33% reduction in baseline RBC transfusion burden from Weeks 13 to 24. A similar number of patients treated with Reblozyl (19.6%) compared to patients treated with placebo (3.6%) also achieved a ≥33% reduction in baseline RBC transfusion burden from Weeks 37 to 48 (a key secondary efficacy endpoint). The efficacy of Reblozyl was supported by two open-label Phase II supportive studies where 80.6% and 70.8% of patients with TD β‑thalassemia, respectively, exhibited either a 20% (ACE-536-04) or 50% (ACE-536-06) reduction in transfusion requirements over a 12‑week rolling window compared to baseline.
Important treatment emergent adverse events (TEAEs) reported for patients treated with Reblozyl include hypertension, thrombosis, hepatobiliary events, and infections. Serious TEAEs were three times more frequent in patients treated with Reblozyl (15.2%) compared to patients treated with placebo (5.2%). More patients treated with Reblozyl experienced serious TEAEs of infections compared to patients treated with placebo (5.8% vs. 2.8%), including septic shock, cellulitis, and cholangitis. Other serious TEAEs reported were anemia, cerebrovascular accident, deep vein thrombosis, and pyrexia. Treatment discontinuation due to an adverse event occurred in more patients treated with Reblozyl (5.4%) compared to patients treated with placebo (0.9%). The most common adverse events leading to discontinuation of Reblozyl were arthralgia, back pain, and deep vein thrombosis.
Market authorization was based on a positive benefit-risk profile of Reblozyl in the treatment of adult patients with RBC TD anemia associated with β‑thalassemia. The recommended starting dose of Reblozyl is 1 mg/kg administered subcutaneously once every 3 weeks with dose titration up to 1.25 mg/kg for patients who do not achieve a reduction in RBC transfusion burden of at least one-third after two consecutive doses. Patients who do not achieve a reduction in RBC transfusion burden of at least one-third after nine weeks of treatment at the 1.25 mg/kg dose or who experience unacceptable toxicity should permanently discontinue therapy.
A Risk Management Plan (RMP) for Reblozyl was submitted by Celgene Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme, and when needed, to describe measures that will be put in place to minimize risks associated with the product.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Reblozyl Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements.
A Look‑alike Sound‑alike brand name assessment was performed and the proposed name Reblozyl was accepted.
Overall, Reblozyl has been shown to have a favourable benefit-risk profile based on non-clinical and clinical studies.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non‑clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Reblozyl?
The New Drug Submission for Reblozyl was reviewed under the Priority Review Policy. Sufficient evidence was provided demonstrating Reblozyl provided an effective treatment, prevention or diagnosis of a disease or condition for which no drug is presently marketed in Canada.
Submission Milestones: Reblozyl
| Submission Milestone | Date |
|---|---|
| Pre-submission meetings | 2019-07-12 - 2019-11-13 |
| Request for priority status | |
| Filed | 2019-12-27 |
| Approval issued by Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics | 2020-01-23 |
| Submission filed | 2020-02-24 |
| Screening | |
| Screening Acceptance Letter issued | 2020-03-30 |
| Response filed | 2020-04-29 |
| Review | |
| Review of Risk Management Plan complete | 2020-08-12 |
| Quality Evaluation complete | 2020-09-18 |
| Clinical/Medical Evaluation complete | 2020-09-24 |
| Labelling Review complete | 2020-09-24 |
| Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate | 2020-09-25 |
The Canadian regulatory decision on the review of Reblozyl was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency and the United States Food and Drug Administration were used as added reference.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
Requirements for post‑market commitments are outlined in the Food and Drugs Act and Regulations.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
Luspatercept, the medicinal ingredient in Reblozyl, is a recombinant fusion protein of a modified extracellular domain (ECD) of human activin receptor type IIB (ActRIIB) and the Fc portion of human immunoglobulin G1 (IgG1). The drug binds certain transforming growth factor beta (TGF‑β) ligands and works by inhibiting Smad2/3 signaling. Inhibition of the Smad2/3 signaling pathway has been shown to promote erythropoiesis and red blood cell (RBC) maturation in pre-clinical studies.
The multiple-dosing pharmacokinetics, pharmacodynamics, and exposure-response relationships of luspatercept over a dose range of 0.2 to 1.25 mg/kg have been characterized in a total of 309 healthy volunteers and patients with β‑thalassemia.
When injected subcutaneously into healthy subjects, the pharmacokinetics of luspatercept resembles that of a one compartment model, with elimination from the central compartment.
Reblozyl does not cause any clinically meaningful prolongation of the corrected QT (QTc) interval at therapeutic doses.
Interactions with other drugs and food have not been established.
For further details, please refer to the Reblozyl Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Reblozyl in patients with β‑thalassemia was established in one pivotal double-blind controlled Phase III study (ACE-536-B-THAL-001) and two open-label Phase II supportive studies (ACE-536-04 and ACE-536-06).
The supportive studies ACE-536-04 (n = 64) and ACE-536-06 (n = 51) enrolled adult patients with both transfusion-dependent (TD) and non‑TD beta(β)‑thalassemia. Promising evidence of efficacy for Reblozyl was demonstrated, where 80.6% and 70.8% of patients with TD β‑thalassemia, respectively, exhibited either a 20% (ACE-536-04) or 50% (ACE-536-06) reduction in transfusion requirements over a 12‑week rolling window compared to baseline.
In the ACE-536-B-THAL-001 study, 336 adult patients with TD β‑thalassemia were randomized in a 2:1 ratio to receive either Reblozyl plus best supportive care (BSC) (number of patients [n] = 224) or placebo plus BSC (n = 112), every 3 weeks for 48 weeks. The primary efficacy endpoint was the number of patients in each arm who achieved a ≥33% reduction in RBC transfusion burden from baseline, with a reduction of at least two RBC units in the fixed 12‑week period from Weeks 13 to 24. Key secondary efficacy endpoints were a reduction in RBC transfusion burden by ≥33% from Weeks 37 to 48, ≥50% from Weeks 13 to 24, and ≥50% from Weeks 37 to 48. Eligible patients including those randomized to placebo treatment were given the option of open-label Reblozyl treatment for up to 5 years after the study was unblinded.
In this study, more patients treated with Reblozyl (21.4%) compared to placebo (4.5%) achieved the primary efficacy endpoint of a ≥33% reduction in baseline RBC transfusion burden from Weeks 13 to 24 (risk difference of 17%, 95% confidence interval [CI]: 10.4; 23.6, p<0.0001). A similar percentage of Reblozyl patients (19.6%) compared to placebo (3.6%) also achieved a ≥33% reduction in baseline RBC transfusion burden from Weeks 37 to 48 (risk difference of 16%, 95% CI: 9.8; 22.4, p<0.0001). Although fewer Reblozyl patients overall achieved a ≥50% reduction in baseline transfusion burden, a clinical benefit was still reported relative to placebo treated patients from Weeks 13 to 24 (7.6% vs. 1.8%) or from Weeks 37 to 48 (10.3% vs. 0.9%). No clinically meaningful reduction in liver iron concentrations was reported for Reblozyl‑treated patients compared to patients treated with placebo.
Indication
The New Drug Submission for Reblozyl was filed by the sponsor with the following indication:
- Reblozyl (luspatercept for injection) is an erythroid maturation agent indicated for the treatment of adult patients with beta(β)‑thalassemia-associated anemia who require red blood cell (RBC) transfusions.
To ensure safe and effective use of the product, Health Canada approved the following indication:
- Reblozyl (luspatercept for injection) is indicated for the treatment of adult patients with red blood cell (RBC) transfusion-dependent anemia associated with beta(β)‑thalassemia.
Health Canada has included important limitations of use to accompany the approved indication. 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. Additionally, no clinically meaningful change in liver iron concentration was observed in β‑thalassemia patients treated with Reblozyl plus BSC compared to patients treated with placebo plus BSC at 48 weeks.
For more information, refer to the Reblozyl Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety of Reblozyl in patients with β‑thalassemia was established in the pivotal Phase III study (ACE-536-B-THAL-001) and the two supportive studies (ACE-536-04 and ACE-536-06) described in the Clinical Efficacy section.
In ACE-536-B-THAL-001, more patients treated with Reblozyl compared to placebo experienced treatment-emergent adverse events (TEAEs) during the study. Important TEAEs include hypertension, thrombosis, hepatobiliary events, and infections. The most common TEAEs (≥10% and with ≥1% frequency vs. placebo) in patients treated with Reblozyl were headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, and dizziness. Serious TEAEs were three times more frequent in patients treated with Reblozyl compared to patients treated with placebo (15.2% vs. 5.2%). 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 (1%), deep vein thrombosis (1%), and pyrexia (1%).
Dose delay or 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%), increased alanine aminotransferase (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. 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, back pain, and deep vein thrombosis (1% each).
There was no significant difference in immunogenicity in patients treated with Reblozyl compared to patients treated with placebo. Only two patients in the Reblozyl arm tested positive for neutralizing antibodies.
Injection site reactions were reported in 2.2% of Reblozyl‑ and 1.8% of placebo‑treated patients.
The adverse events reported in the two supportive studies (ACE-536-04 and ACE-536-06) were generally consistent with those reported in ACE-536-B-THAL-001, with the exception of more cases of peripheral edema having been reported in the supportive studies.
Overall, the safety data are acceptable for the treatment of adult patients with RBC TD β‑thalassemia anemia given the reported benefit in reduction in transfusion burden, although long-term surveillance is ongoing to further document the chronic safety profile of this treatment in adult patients with β‑thalassemia associated anemia.
Appropriate warnings and precautions are in place in the Reblozyl Product Monograph to address the identified safety concerns.
For more information, refer to the Reblozyl Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Repeat‑dose toxicity studies, 13 weeks and 6 months in duration, were conducted in cynomolgus monkeys. With respect to the pharmacology of the drug, animals treated with luspatercept once every 2 weeks had minimal to mild increases in at least one of: RBC counts, hemoglobin, hematocrit, monocytes, and/or reticulocytes at a dose of ≥1 mg/kg in males and ≥0.3 mg/kg in females (occurring in at least one time-point). Histopathological analyses revealed evidence of toxicity in the kidneys, brain, and lymph nodes. In the kidneys, membranoproliferative glomerulonephritis was observed at ≥1 mg/kg and interstitial fibrosis/fibroplasia was reported at 6 mg/kg. In the brain, changes to the choroid plexus occurred at ≥1 mg/kg. In the lymph nodes (mandibular and axillary), extramedullary hematopoiesis was observed at ≥0.3 mg/kg.
Carcinogenicity studies were not conducted for luspatercept, which is standard for biologic drugs and is in accordance with International Council for Harmonisation (ICH) guidelines (ICH S6). Further, immunogenicity of luspatercept observed with chronic administration to rodents precluded the option of conducting a two‑year study. Nonetheless, three malignancies (lymphoma, myeloid leukemia, and lymphoid leukemia) were observed in a juvenile toxicity study in rats. A relationship between these cancers to luspatercept treatment cannot be ruled out and the mechanistic relationship between inhibition of Smad2/3 signaling and tumorigenesis and/or tumour suppression is not fully understood. These malignancies were observed at 10 mg/kg luspatercept, resulting in exposures (based on area under the curve [AUC]) approximately 8 times the maximum recommended human (β‑thalassemia) dose 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, including a 6‑month study in monkeys.
Luspatercept binds certain TGF‑β ligands and works by inhibiting Smad2/3 signalling. Surface plasmon resonance showed that luspatercept binds to various TGF‑β superfamily ligands, including growth differentiation factor (GDF) 11 (GDF 11), GDF8, bone morphogenetic protein (BMP) 6 (BMP6), BMP9, BMP10, and activin B.
Mechanistically, TGF‑β superfamily ligands are broadly acting during development. They control tissue patterning along the axes of the vertebrate body; e.g., signaling through ActRIIB occurs during mesendodermal specification. Therefore, it is expected that interference with ActRIIB signalling during development would produce detrimental embryo‑fetal effects.
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 maximum recommended human (β‑thalassemia) dose 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 developmental toxicity studies (range-finding and definitive studies) were conducted in pregnant rats and rabbits at doses of 0, 5, 15, or 30 mg/kg and 0, 5, 20, or 40 mg/kg, respectively. Embryo-fetal effects seen in both species included decreased numbers of pregnant females, reductions in numbers of live fetuses, reduction in fetal body weights, increases in resorptions, increased post-implantation loss, and skeletal variations. In both species, the no-observed-adverse-effect level for embryo-fetal effects of luspatercept was observed 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.
In one study, luspatercept was detected in the milk of lactating rats following a single subcutaneous 30 mg/kg dose of luspatercept, with a mean lacteal transfer of 12%. In addition, luspatercept was detected in fetal serum.
A number of pharmacodynamic studies were conducted to understand the relationship between luspatercept and erythropoietin. Erythropoietin is produced in the kidneys and plays a key role in RBC production. It acts to stimulate erythropoiesis in response to hypoxia, which can be caused by anemia. Treatment with luspatercept does lead to short-term decreases in erythropoietin at the mRNA and protein levels, but there is a lack of durability of this effect over the longer term. Overall, the studies concluded that luspatercept and erythropoietin operate through two independent modes of action.
Overall, the pharmacodynamic analyses do not delve into how luspatercept addresses the lack of β‑globin (or the surplus of α‑globin) in actual patients with β‑thalassemia. However, the results of these studies demonstrate proof of concept for the indicated clinical use.
In view of the intended use of Reblozyl, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product. Appropriate warnings and precautions are in place in the Reblozyl Product Monograph to address the identified safety concerns.
For more information, refer to the Reblozyl Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
Characterization of the Drug Substance
Luspatercept, the medicinal ingredient in Reblozyl, is a recombinant protein that consists of two identical chains. Each chain contains a modified form of the ECD of human ActRIIB, linked to human IgG1 Fc domain. Luspatercept specifically binds GDF‑11 and inhibits the interaction between soluble GDF‑11 and ActRIIB on cell surfaces. This inhibits late-stage erythropoiesis. There is no effector function associated with luspatercept.
Detailed characterization studies were performed to provide assurance that luspatercept consistently exhibits the desired characteristic structure and biological activity.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
The luspatercept drug substance is expressed in suspension culture using Chinese hamster ovary cells. The resulting culture is harvested and purified using protein A affinity, anion exchange, and hydrophobic interaction chromatography. Viral inactivation and filtration steps ensure removal of viral particles to acceptable levels. The drug substance is 0.22 µm‑filtered into polyethylene terephthalate glycol bottles and stored at ≤‑65°C.
Reblozyl drug product manufacturing consists of drug substance thaw, formulation, sterile filtration, filling, lyophilisation, labelling, and packaging. The drug product is filled in a 2R Type I glass vial with a bromobutyl rubber stopper and an aluminum flip-off seal, and stored at 2 to 8°C.
The Reblozyl drug product is available in two strengths: 25 mg/vial and 75 mg/vial as a powder for reconstitution. Both strengths are reconstituted with water for injection to a final luspatercept concentration of 50 mg/mL.
Both the drug substance and drug product manufacturing processes were validated. During validation, all process parameters, in-process controls, release testing results, and stability results met acceptance criteria for all drug substance batches and drug product lots. The results of the validation studies demonstrated that manufacturing facilities are capable of consistently manufacturing the drug substance and drug product of acceptable quality.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of the medicinal ingredient with the excipients is supported by the stability data provided.
Control of the Drug Substance and Drug Product
The criticality of process parameters, in-process controls, and quality attributes were appropriately assigned, and were based on experience during development studies. Three drug substance manufacturing processes and four drug product manufacturing processes have been used throughout the development of the product. Comparability studies, based on characterization data and results of lot release and stability testing, demonstrated that all of the processes produced material of comparable product quality.
All in-house methods were validated, and compendial methods were appropriately verified at each testing site. Specifications were based on historical data, and are considered suitable for control of the drug substance and drug product. All batch release data met acceptance criteria.
Stability of the Drug Substance and Drug Product
Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance (48 months at ≤‑65°C) and drug product (36 months at 2 to 8°C) were adequately supported and are considered to be satisfactory.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
The proposed packaging and components are considered acceptable.
Facilities and Equipment
The design, operations, and controls of the facility and equipment that are involved in production are considered suitable for the activities and products manufactured. The sponsor demonstrated that the manufacturing facilities are capable of consistently manufacturing the drug substance and drug product of acceptable quality.
An on-site evaluation (OSE) of the facility involved in the manufacture and testing of drug substance was not recommended due to mitigating risk factors, including a successful OSE that had been recently performed for another product involving a similar manufacturing process.
Based on a risk assessment score determined by Health Canada, an OSE of the drug product manufacturing facility was not deemed necessary.
Both sites involved in production are compliant with Good Manufacturing Practices.
Adventitious Agents Safety Evaluation
Testing for adventitious agents was performed and was found to be compliant with the ICH guidelines, ICH Q5A (R1) and ICH Q5D.
Each cell line was tested for sterility and mycoplasma by compendial methods, and was found to be free of non-viral adventitious agents. In addition, all the cell banks underwent viral testing, and were free of endogenous and adventitious viral contaminants other than A‑ and C‑type retroviral particles.
Viral clearance studies indicate that the maximum number of retroviral-like particles in the maximum proposed dose of 1.75 mg/kg is 1 particle per ≥2.57 × 109 doses. This suggests there is minimal risk of exposure to viral adventitious or endogenous agents for patients.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| REBLOZYL | 02505541 | BRISTOL-MYERS SQUIBB CANADA | LUSPATERCEPT 25 MG / VIAL |
| REBLOZYL | 02505568 | BRISTOL-MYERS SQUIBB CANADA | LUSPATERCEPT 75 MG / VIAL |