Summary Basis of Decision for Empliciti

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:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Empliciti is located below.

Recent Activity for Empliciti

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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 decision was negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

Post-Authorization Activity Table (PAAT) for Empliciti

Updated: 2024-11-22

The following table describes post-authorization activity for Empliciti a product which contains the medicinal ingredient elotuzumab. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.

  • DIN 02455927 - 340 mg/vial (300 mg after reconstitution), elotuzumab, powder for solution, intravenous administration
  • DIN 02455919 - 440 mg/vial (400 mg after reconstitution), elotuzumab, powder for solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
DINs 02455927, 02455919 cancelled (pre market) Not applicable Discontinuation date 2023-12-12 The manufacturer notified Health Canada that sale of the drug has been discontinued pre market. Health Canada cancelled the DINs pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations.
NC # 249751 2021-02-19 Issued NOL 2021-03-10 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to a drug substance manufacturing facility. The submission was considered acceptable, and an NOL was issued.
NC # 233018 2019-10-30 Issued NOL 2020-01-15 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for an alternate site for quality control testing of the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 232012 2019-09-27 Issued NOL 2019-10-18 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the working cell bank manufacturing site and the cell bank qualification protocol. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 206273 2017-06-06 Issued NOC
2018-01-19		 Submission filed as a Level I - Supplement for an additional drug substance manufacturing site and quality control site. The information was reviewed and considered acceptable. An NOC was issued.
NC # 204968 2017-04-24 Issued NOL
2017-07-11		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for an additional drug substance manufacturing suite at an approved site. There were no changes in manufacturing process or specifications. The data were reviewed and considered acceptable, and an NOL was issued.
NDS # 188144 2015-10-01 Issued NOC
2016-06-21		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Empliciti

Date SBD issued: 2016-08-30

The following information relates to the New Drug Submission for Empliciti.

Elotuzumab, 340 mg/vial and 440 mg/vial, powder for solution, intravenous

Drug Identification Number (DIN):

  • 02455927 - 340 mg/vial (300 mg after reconstitution), powder for solution, intravenous
  • 02455919 - 440 mg/vial (400 mg after reconstitution), powder for solution, intravenous

Bristol-Myers Squibb Canada

New Drug Submission Control Number: 188144

 

On June 21, 2016, Health Canada issued a Notice of Compliance to Bristol‑Myers Squibb Canada for the drug product Empliciti.

The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (clinical pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit/risk profile of Empliciti, in combination with lenalidomide and dexamethasone, is favourable for the treatment of patients with multiple myeloma who have received one to three prior therapies.

1 What was approved?

Empliciti is an antineoplastic drug, a first-in-class, immunostimulatory, humanized immunoglobulin G1 (IgG1) monoclonal antibody that specifically targets the Signaling Lymphocytic Activation Molecule Family member 7 (SLAMF7). Empliciti was authorized, in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received one to three prior therapies.

Of the 646 patients enrolled in the pivotal clinical study for Empliciti in combination with lenalidomide and dexamethasone, 57% were ≥65 years of age; the number of patients aged ≥65 years was similar between treatment groups. Compared to younger patients, second primary malignancies were more common among patients aged ≥65 years that received Empliciti in combination with lenalidomide and dexamethasone. No other overall differences in safety or efficacy were observed between patients aged ≥65 years and younger patients (<65 years).

The safety and effectiveness of Empliciti in pediatric patients have not been established.

Empliciti is contraindicated in patients who are hypersensitive to elotuzumab or to any ingredient in the formulation or component of the container. It is used in combination with other medications; therefore, the contraindications applicable to those medications also apply to Empliciti combination therapy. The prescribing information for all medications used in combination with Empliciti must be consulted before starting therapy.

Empliciti was approved for use under the conditions stated in the Empliciti Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Empliciti (340 mg/vial and 440 mg/vial elotuzumab) is presented as lyophilized powder for intravenous infusion. In addition to the medicinal ingredient, each vial of drug product contains the following inactive ingredients: citric acid monohydrate, polysorbate 80, sodium citrate and sucrose. After reconstitution with sterile water for injection each vial of 340 mg elotuzumab delivers 300 mg of elotuzumab and each vial of 440 mg elotuzumab delivers 400 mg of elotuzumab. Following reconstitution, each mL of concentrate contains 25 mg elotuzumab.

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 Empliciti Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Empliciti approved?

Health Canada considers that the benefit/risk profile of Empliciti, in combination with lenalidomide and dexamethasone, is favourable for the treatment of patients with multiple myeloma who have received one to three prior therapies.  

Multiple myeloma is characterized by uncontrolled proliferation of monoclonal plasma cells, which results in the production of monoclonal immunoglobulin (known as M‑protein), substantial immunosuppression and end-organ damage. Common clinical sequelae include bone pain/fractures, infections, and renal failure. In Canada, stem cell transplant may be considered as a first-line treatment in patients with good performance status and/or in patients with relapsed or refractory multiple myeloma. Other treatments include combination chemotherapy, as well as the use of targeted chemotherapy drugs such as bortezomib, lenalidomide, thalidomide, pomalidomide or carfilzomib. While there are several targeted therapies available, multiple myeloma remains an incurable disease. In particular, there is a high unmet medical need in the setting of relapsed/refractory multiple myeloma.

Empliciti has been shown to be efficacious in patients with relapsed or refractory multiple myeloma who have received one to three prior therapies. The market authorization was based on one pivotal Phase III, open-label, randomized clinical study (Study CA204‑004 [Eloquent‑2]) in 646 patients with multiple myeloma who had received one to three prior therapies and had documented disease progression following the most recent therapy. The patients were randomized to receive either Empliciti in combination with lenalidomide and dexamethasone (E+Ld arm, number [n] = 321) or lenalidomide and dexamethasone (Ld arm, n = 325). The co-primary objectives of the study were to demonstrate statistically significant improvements in progression free survival (PFS) and overall response rate (ORR). Overall survival (OS) was investigated as secondary study objective.

The data from the pivotal study have demonstrated that Empliciti, in combination with lenalidomide and dexamethasone, provides superior efficacy as compared to lenalidomide and dexamethasone alone. The point estimates for median PFS were 19.4 months (95% confidence interval [CI]:16.6, 22.2) and 14.9 months (95% CI: 12.1, 17.2) for the E+Ld and Ld arms, respectively. The hazard ratio for PFS was 0.70 (97.61% CI: 0.55, 0.88) representing a 30% improvement in the risk of progression with the addition of Empliciti to lenalidomide and dexamethasone. The ORRs were 78.5% for E+Ld treated patients and 65.5% for Ld treated patients. The common odds ratio for ORR was 1.94 (99.5% CI: 1.17, 3.23), in favour of E+Ld (p value of 0.0002). The higher rates of response observed in the E+Ld treatment arm were also associated with an improvement in duration of response.

The data for overall survival (OS) are not yet mature; however, the hazard ratio for OS based on these data was 0.77 (98.6% CI: 0.58, 1.03), in favour of the E+Ld treatment arm. The median OS for the E+Ld treatment arm was 43.66 months (95% CI: 40.34, not estimable [NE]) compared to 39.56 months (95% CI: 33.25, NE) for Ld alone.

Notably, there is uncertainty associated with the benefit of Empliciti in combination with lenalidomide and dexamethasone in patients who have received prior treatment with lenalidomide. These patients comprised only 5%‑6% of the study population, and patients refractory to prior lenalidomide treatment were not enrolled in the study. In order to ensure that prescribers are aware of the limitations of the dataset, the pivotal trial inclusion/exclusion criteria, regarding prior lenalidomide treatment, have been clearly described in the Empliciti Product Monograph.

The safety of Empliciti in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies was evaluated in the pivotal Study CA204-004. A total of 318 patients were treated with Empliciti 10 mg/kg in combination with lenalidomide and dexamethasone (E+Ld treatment arm) for a median number of 19 cycles (versus [vs.] 14 cycles in the Ld treatment arm, n = 317).

Overall, there were fewer deaths among E+Ld treated patients and there were also fewer deaths within 60 days of the last treatment administered. Nearly all patients enrolled in either treatment arm experienced at least one adverse event of any grade (>99% in each arm). Grade 3-4 adverse events occurred more often among E+Ld treated patients (77.7% vs. 65.6%). Serious adverse events also occurred more often in E+Ld treated patients (any grade: 65.4% vs. 56.5%; Grade 3-4: 48.1% vs. 36.6%). The most frequent serious adverse reactions in the Empliciti arm as compared to the control arm were: pneumonia (15.4% vs. 11%), respiratory tract infection (3.1% vs. 1.3%), pulmonary embolism (3.1% vs. 2.5%) and herpes zoster (0.9% vs. 0.6%).

In terms of specific risks, infusion reactions represented the greatest safety concern. Symptoms consistent with an infusion reaction were reported in 10.4% of patients who received Empliciti. Most of these were Grade 1 and 2, whereas 1.3% of patients had a Grade 3-4 infusion reaction. All patients received premedication to reduce the risk of infusion reactions and most infusion reactions occurred during or shortly after the first infusion of Empliciti. This identified safety concern and the need for administering premedication prior to Empliciti infusion are specifically referred to in the Warnings and Precautions section of the Empliciti Product Monograph.

In addition to infusion reactions, other safety concerns included infection, deep vein thrombosis and pulmonary embolism, second primary malignancies, and hepatotoxicity. Notably, treatment with lenalidomide/dexamethasone was prolonged in the E+Ld arm (median number of 19 cycles vs. 14 cycles in the Ld arm), which may have contributed to the increased rates of adverse events in general and of infections, deep vein thrombosis and pulmonary embolism. Each of the identified risks has been appropriately addressed in the Warnings and Precautions and Adverse Reactions sections of the Empliciti Product Monograph.

A Risk Management Plan (RMP) for Empliciti was submitted by Bristol-Myers Squibb Canada 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. In addition, as part of the marketing authorization for Empliciti, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. Commitments include (but are not limited to) providing an updated Canadian RMP in accordance with Health Canada’s recommendations for additional risk minimization measures (see section What follow-up measures will the company take?).

A Look‑alike Sound‑alike assessment was performed and the proposed name Empliciti was accepted.

Overall, the benefits of Empliciti therapy (in combination with lenalidomide and dexamethasone) seen in the pivotal study are considered to outweigh the potential risks. Empliciti has an acceptable safety profile based on the clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Empliciti Product Monograph to address the identified safety concerns.

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 Empliciti?

The drug submission for Empliciti was reviewed under the Priority Review Policy. Empliciti demonstrated a significant increase in effectiveness with an improved benefit/risk profile compared to a commonly used existing treatment regimen for relapsed or refractory multiple myeloma, a condition where there exists an unmet medical need.

 

Submission Milestones: Empliciti

Submission Milestone Date
Pre-submission meeting: 2015-06-17
Request for priority status  
Filed: 2015-07-28
Approval issued by Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics: 2015-08-17
Submission filed: 2015-10-01
Screening  
Screening Deficiency Notice issued: 2015-10-30
Response filed: 2015-12-11
Screening Acceptance Letter issued: 2015-12-24
Review  
On-Site Evaluation: 2016-06-16 - 2016-06-17
Quality Evaluation complete: 2016-06-21
Clinical Evaluation complete: 2016-06-21
Labelling Review complete: 2016-03-02
Notice of Compliance (NOC) issued by Director General, Biologics and Genetic Therapies Directorate 2016-06-21

The Canadian regulatory decision on the non-clinical and clinical review of Empliciti was based on a critical assessment of the Canadian data package. Foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.

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?

As part of the marketing authorization for Empliciti, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to):

  • Submitting an updated Canadian Risk Management Plan according to Health Canada’s recommendations for additional risk minimization measures.
  • Submitting a final report of the exposure-response analysis based on Studies CA204-004 and CA204-006. In this analysis, the clinical, pharmacological and biological factors, including but not limited to the disease state, serum M-protein, serum β2‑microglobulin, race, gender and body weight, will be investigated to assess their impact on the exposure-response relationship. The analysis is expected to provide information to aid in determining whether there is a need for dose optimisation in patients with multiple myeloma who have low exposure to elotuzumab at the approved dose (10 mg/kg).The results of the analysis should be submitted as a Supplement to New Drug Submission (SNDS) in support of changes to the dosage and administration recommendations for Empliciti, if necessary.
5 What post-authorization activity has taken place for Empliciti?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada’s decision was negative or positive. The PAAT will continue to be updated during the product’s lifecycle.

The PAAT for Empliciti is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision

Clinical Pharmacology

The medicinal ingredient of Empliciti, elotuzumab, is a humanized immunoglobulin G subclass 1 (IgG1) monoclonal antibody that specifically targets the cell surface glycoprotein Signaling Lymphocytic Activation Molecule Family member 7 (SLAMF7).

The protein SLAMF7 is expressed on myeloma cells, Natural Killer (NK) cells, plasma cells and at lower levels on specific immune cell subsets of differentiated cells within the hematopoietic lineage. This protein is not detected on normal solid tissues or hematopoietic stem cells. Elotuzumab directly activates NK cells through both the SLAMF7 pathway and Fc receptors. Elotuzumab also targets SLAMF7 on myeloma cells and facilitates the interaction with NK cells to mediate the killing of myeloma cells through antibody-dependent cellular cytotoxicity (ADCC). 

The clinical pharmacological data support the use of Empliciti for the specified indication.

The pharmacokinetics of elotuzumab alone and in combination with lenalidomide and dexamethasone were studied in patients with multiple myeloma who received doses ranging from 0.5 to 20 mg/kg elotuzumab. In a population pharmacokinetics analysis that incorporated these data, elotuzumab exhibited nonlinear pharmacokinetics. An inverse relationship between clearance and dose was suggestive of target-mediated clearance, which resulted in greater than proportional increases in systemic exposure (area under the concentration time curve [AUC]). The volume of distribution parameter for elotuzumab appeared to be independent of dose.

Based on the submitted population pharmacokinetics analysis using data from 375 patients, the clearance parameter of elotuzumab increased with increasing body weight. The population pharmacokinetics analysis suggested that the following factors had no clinically important effect on the clearance parameter of elotuzumab: age (37 to 88 years), gender, race, baseline lactate dehydrogenase (LDH), albumin, renal impairment, mild hepatic impairment or the Eastern Cooperative Oncology Group (ECOG) performance status.

For further details, please refer to the Empliciti Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Empliciti, in combination with lenalidomide and dexamethasone, was evaluated in the pivotal Phase III, open-label, randomized clinical study (Study CA204-004 [Eloquent 2]) in patients with multiple myeloma who had received one to three prior therapies and had documented disease progression following the most recent therapy. A total of 646 patients were randomized to receive either Empliciti in combination with lenalidomide and dexamethasone (E+Ld arm, number [n] = 321) or lenalidomide and dexamethasone (Ld arm, n = 325). Treatment was administered in 4‑week cycles until disease progression or unacceptable toxicity. Empliciti 10 mg/kg was administered intravenously each week for the first 2 cycles and every 2 weeks thereafter. Prior to Empliciti infusion, dexamethasone was administered as a divided dose: an oral dose of 28 mg and an intravenous dose of 8 mg. In the control group and on weeks without Empliciti, dexamethasone 40 mg was administered as a single oral dose once weekly. Lenalidomide 25 mg was taken orally once daily for the first 3 weeks of each cycle. Assessment of tumor response was conducted every 4 weeks according to European Society for Blood and Marrow Transplantation (EBMT) response criteria. The co‑primary objectives of the study were to demonstrate statistically significant improvements in progression-free survival (PFS), and overall response rate (ORR, i.e., the proportion of randomized patients who had either partial response or complete response), as determined by a blinded Independent Review Committee using the EBMT response criteria. The overall survival (OS) was investigated as a secondary study objective.

The data from the pivotal study demonstrated that E+Ld provides superior efficacy compared to Ld alone. The point estimates for median PFS were 19.4 months (95% confidence interval [CI]: 16.6, 22.2) and 14.9 months (95% CI: 12.1, 17.2) for the E+Ld and Ld arms, respectively. The hazard ratio for PFS was 0.70 (97.61% CI: 0.55, 0.88) representing a 30% improvement in the risk of progression with the addition of Empliciti to lenalidomide and dexamethasone. The ORRs were 78.5% for E+Ld treated patients and 65.5% for Ld treated patients. The common odds ratio for ORR was 1.94 (99.5% CI: 1.17, 3.23), in favour of E+Ld, (p value of 0.0002).The higher rates of response observed in the E+Ld treatment arm were also associated with an improvement in duration of response.

The data for the secondary endpoint, OS, are not yet mature. The hazard ratio for OS, updated 1-year after the final PFS analysis, was 0.77 (98.6% CI: 0.58, 1.03), in favour of the E+Ld treatment arm. The median OS for the E+Ld treatment arm was 43.66 months (95% CI: 40.34, NE) compared to 39.56 months (95% CI: 33.25, NE) for Ld alone.

Notably, in accordance with the inclusion/exclusion criteria for patient enrollment in the pivotal trial, patients who were refractory to prior treatment with lenalidomide or who experienced ≥Grade 3 adverse events while receiving prior lenalidomide were not enrolled in the trial. Additionally, no more than 10% of subjects per arm were permitted to have received prior treatment with lenalidomide. Actual enrollment of patients that had received prior lenalidomide was 16/321 (5.0%) and 21/325 (6.5%) in the E+Ld and Ld arms, respectively. Consequently, there is uncertainty associated with the benefit of Empliciti in combination with lenalidomide and dexamethasone in patients who have received prior treatment with lenalidomide. In order to ensure that prescribers are aware of the limitations of the dataset, the pivotal trial inclusion/exclusion criteria with respect to prior lenalidomide treatment have been clearly described in the Empliciti Product Monograph.

Overall, the efficacy data provided in this submission support the authorization of Empliciti, in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received one to three prior therapies.

For more information, refer to the Empliciti Product Monograph, approved by Health Canada and available through the Drug Product Database.

Indication

The original New Drug Submission (NDS) for Empliciti was filed with the following proposed indication:

  • Empliciti is indicated for the treatment of patients with multiple myeloma, who have received one or more prior therapies, in combination with lenalidomide and dexamethasone or in combination with bortezomib and dexamethasone.

Data provided to support the authorization of Empliciti when used in combination with bortezomib and dexamethasone for the treatment of patients with multiple myeloma who have received one or more prior therapies was found to be inadequate. Accordingly, Health Canada requested a withdrawal of the proposed indication regarding the use of Empliciti in combination with bortezomib and dexamethasone, and approved the following indication:

  • Empliciti, in combination with lenalidomide and dexamethasone, is indicated for the treatment of patients with multiple myeloma who have received one to three prior therapies.

Clinical Safety

The clinical safety of Empliciti in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies was evaluated in the pivotal Phase III randomized, controlled, open-label Study CA204-004 (Eloquent 2), described in the Clinical Efficacy section . A total of 318 patients were treated with Empliciti 10 mg/kg in combination with lenalidomide and dexamethasone (E+Ld treatment arm) for a median number of 19 cycles vs. 14 cycles in the Ld treatment arm, n = 317).

Overall, there were fewer deaths among E+Ld treated patients and there were also fewer deaths within 60 days of the last treatment administered. Nearly all patients enrolled in either treatment arm experienced at least one adverse event of any grade (>99% in each arm). Grade 3-4 adverse events occurred more often among E+Ld treated patients (77.7% vs. 65.6%). Serious adverse events also occurred more often in E+Ld treated patients (any grade: 65.4% vs. 56.5%; Grade 3-4: 48.1% vs. 36.6%). The most frequent serious adverse reactions in the E+Ld arm compared to the control arm were pneumonia (15.4% vs. 11%), respiratory tract infection (3.1% vs. 1.3%), pulmonary embolism (3.1% vs. 2.5%) and herpes zoster (0.9% vs. 0.6%).

The proportion of patients who discontinued any component of the treatment regimen due to adverse reactions was similar for both treatment arms; 6.0% among E+Ld treated patients and 6.3% among the control patients.

In terms of specific risks, infusion reactions represented the greatest safety concern. Symptoms consistent with an infusion reaction were reported in 10.4% of patients who received Empliciti. Most of these were Grade 1 and 2, whereas 1.3% of patients had a Grade 3-4 infusion reaction. All patients received premedication to reduce the risk of infusion reactions and most infusion reactions occurred during or shortly after the first infusion of Empliciti. This identified safety concern and the need for administering premedication prior to Empliciti infusion are specifically referred to in the Warnings and Precautions section of the Empliciti Product Monograph.

Additional safety concerns included infection (occurred in 81.4% of patients in the E+Ld treatment arm vs. 74.4% patients in the Ld arm), deep vein thrombosis and pulmonary embolism (in 7.2% and 3.5% of E+Ld treated patients and 3.8% and 2.5% of patients treated with Ld, respectively), second primary malignancies (observed in 6.9% of E+Ld treated patients and in 4.1% of patients treated with Ld), and hepatotoxicity (reported in 2.5% and 0.6% of E+Ld and Ld treated patients, respectively). Each of these risks has been included in the Warnings and Precaution section of the Empliciti Product Monograph.

Empliciti can be detected by laboratory assays used for the clinical monitoring of endogenous M-protein and consequently, it can interfere with correct response classification. Therefore, the Warnings and Precautions section of the Empliciti Product Monograph also contains a specific warning regarding its impact on the determination of complete response and possibly relapse from complete response in patients with IgG kappa myeloma protein.

Additional supportive safety information for Empliciti in combination with lenalidomide and dexamethasone was derived from a non-comparative, Phase Ib/II, dose-escalation study that included 101 subjects with relapsed multiple myeloma (Study HuLuc63-1703). In the Phase I portion of the study, doses of 5, 10 and 20 mg/kg were investigated in 28 subjects; however, a maximum tolerable dose was not identified for Empliciti in combination with 25 mg lenalidomide and 40 mg dexamethasone. In the Phase II portion of the study, 36 and 37 patients were treated with the 10 and 20 mg/kg doses, respectively. The overall incidence of Grade 3 or 4 adverse events was 78.1% and the incidence of serious adverse events was 57.5%. The most common Grade 3 or 4 adverse events were cytopenias and the most common serious adverse events were infections. In the Phase II portion of the study, 8 subjects (11%) had infusion reactions as determined by the investigator.

Overall, the reported safety profile of Empliciti, in combination with lenalidomide and dexamethasone, is considered acceptable for the treatment of multiple myeloma patients who have received one to three prior therapies. Appropriate warnings and precautions are in place in the approved Empliciti Product Monograph to address the identified safety concerns.

For more information, refer to the Empliciti Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

The non-clinical data support the use of Empliciti, in combination with lenalidomide and dexamethasone, for the treatment of multiple myeloma.

Elotuzumab recognizes human SLAMF7 protein and it does not bind to SLAMF7 from any other species tested. Consequently, non-clinical safety and toxicology studies consisted primarily of in vitro assessments conducted on human cells and tissues, and limited in vivo animal studies.

No carcinogenicity, mutagenicity, reproductive or developmental toxicity studies were conducted due to the lack of a relevant species.

In vivo studies conducted in mice demonstrated that elotuzumab inhibited the growth of human myeloma xenografts and its anti‑tumor activity was more pronounced when combined with lenalidomide.

The results of the non-clinical studies have been included in the Empliciti Product Monograph. In view of the intended use of Empliciti, there are no pharmacological and toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Empliciti Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

Elotuzumab is a humanized IgG1 monoclonal antibody that targets the cell surface glycoprotein Signaling Lymphocytic Activation Molecule Family member 7 (SLAMF7). Elotuzumab consists of the complementarity determining regions (CDR) of the parent mouse antibody, MuLuc63, grafted onto human IgG1 heavy chain and kappa light chain framework regions.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that elotuzumab consistently exhibits the desired characteristic structure and biological activity.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.

Manufacturing Process and Process Controls of the Drug Substance and Drug Product

Drug Substance

Elotuzumab is produced from cell culture using an NS0 mouse myeloma based cell line. The manufacture is based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation (ICH) guidelines.

The manufacturing process for elotuzumab has been evaluated and validated at critical stages during production that ensures consistent quality. The development, characterization, and validation of the elotuzumab manufacturing process are built upon a comprehensive integrated science- and risk-based approach i.e., Quality by Design (QbD) approach, which incorporates process and product understanding derived from elotuzumab-specific studies. The results from the process validation studies demonstrate that elotuzumab is manufactured by a process that is robust and capable to consistently produce a high quality product which meets specifications.

Drug Product

The manufacturing process for the drug product, Empliciti, consists of pooling of the thawed formulated drug substance, mixing, sterile filtration, filling into vials, partial stoppering, lyophilization, full stoppering, and capping/sealing of the vials. Multiple drug substance lots may be used in a single drug product batch.

Empliciti is supplied as a sterile, white to off-white, preservative-free, lyophilized cake contained in 20-cc Type I glass vials, closed with 20-mm stoppers and sealed with aluminum flip off seals. Each vial of drug product contains 340 mg or 440 mg of elotuzumab and contains the following inactive ingredients: citric acid monohydrate, polysorbate 80, sodium citrate and sucrose. After reconstitution with sterile water for injection each vial of 340 mg delivers 300 mg of elotuzumab and each vial of 440 mg delivers 400 mg of elotuzumab. After reconstitution, each mL of concentrate contains 25 mg elotuzumab. Prior to intravenous administration, the reconstituted concentrate is diluted with either 0.9% sodium chloride injection or 5% dextrose injection to protein concentrations from 1 mg/mL to 6 mg/mL.

Similarly to the drug substance manufacturing process, a QbD approach was employed, and the manufacturing process for Empliciti has been evaluated and validated at critical stages during production to ensure consistent quality. An appropriate testing strategy is in place that demonstrates a suitable level of robustness for control of Empliciti.

Analytical procedures have been carefully selected according to their ability to confirm the safety, efficacy, and activity of elotuzumab drug substance and Empliciti drug product. The methods were validated in full accordance with the ICH guidelines for method validation.

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 elotuzumab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications and analytical procedures are validated and in compliance with ICH guidelines.

Through Health Canada’s lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated, and found to meet the specifications of the drug product and demonstrate consistency in manufacturing.

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 and drug product were adequately supported and are considered to be satisfactory. The proposed 36‑month shelf life at 2°C‑8°C for Empliciti is considered acceptable.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.

An On-Site Evaluation (OSE) of the facility involved in the manufacture and testing of the drug substance, elotuzumab, has not been conducted due to the high volume of other OSEs being performed during the review period, and the similarity of operations performed at this facility and those performed at another site which was the subject of a recent OSE by Health Canada.

An OSE of the facility involved in the drug product manufacturing was recently conducted and the facility was evaluated in good standing.

Both sites involved in production are compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

The elotuzumab manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses). Purification process steps designed to remove and inactivate viruses are adequately validated.

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