Summary Basis of Decision for Minjuvi

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 Minjuvi is located below.

Recent Activity for Minjuvi

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.

The following table describes post-authorization activity for Minjuvi, a product which contains the medicinal ingredient tafasitamab. 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 that are found in PAATs.

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

Updated: 2023-07-07

Drug Identification Number (DIN):

DIN 02518627 – 200 mg tafasitamab, powder for solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Drug product (DIN 02518627) market notification Not applicable Date of first sale: 2021-12-06 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 247025 2020-12-04 Issued NOC under NOC/c Guidance 2021-08-19 NOC issued under the NOC/c Guidance for New Drug Submission.
Summary Basis of Decision (SBD) for Minjuvi

Date SBD issued: 2021-11-25

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

Tafasitamab

Drug Identification Number (DIN):

  • DIN 02518627 - 200 mg tafasitamab, powder for solution, intravenous administration

Inc.yte Corporation

New Drug Submission Control Number: 247025

On August 19, 2021, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Incyte Corporation for the drug product Minjuvi. The product was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit. Patients should be advised of the fact that the market authorization was issued with conditions.

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 Minjuvi is favourable for use in combination with lenalidomide for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low grade lymphoma, who are not eligible for autologous stem cell transplant (ASCT).

Authorization was based on overall response rate, complete response rate, and durability of response from a single-arm clinical study. An improvement in progression-free survival or overall survival has not been established.

1 What was approved?

Minjuvi, an antineoplastic monoclonal antibody, was authorized for use in combination with lenalidomide for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low grade lymphoma, who are not eligible for autologous stem cell transplant (ASCT).

Authorization was based on overall response rate, complete response rate, and durability of response from a single-arm clinical study. An improvement in progression-free survival or overall survival has not been established. Minjuvi was authorized under the Notice of Compliance with Conditions (NOC/c) Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit.

Minjuvi is not authorized for use in pediatric patients (<18 years of age), as no clinical safety or efficacy data are available for this population.

Among 81 patients treated in one clinical study (the L-MIND study), 72% were 65 years of age and older. These patients had more serious treatment emergent adverse events (57%) than younger patients (39%). Evidence from clinical studies does not suggest that use in the geriatric population is associated with differences in effectiveness.

Minjuvi is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

Minjuvi 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.

Minjuvi (200 mg tafasitamab) is presented as a powder for solution. In addition to the medicinal ingredient, the powder contains citric acid monohydrate, polysorbate 20, sodium citrate dihydrate, and trehalose dihydrate.

For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Minjuvi Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Minjuvi approved?

Health Canada considers that the benefit-risk profile of Minjuvi is favourable for use in combination with lenalidomide for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low grade lymphoma, who are not eligible for autologous stem cell transplant (ASCT).

Authorization was based on overall response rate, complete response rate and durability of response from a single-arm clinical study. An improvement in progression-free survival or overall survival has not been established.

Minjuvi was authorized under the Notice of Compliance with Conditions (NOC/c) Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit.

Each year, approximately 10,000 Canadians are diagnosed with non-Hodgkin lymphoma. Diffuse-large B-cell lymphoma, a cancer that starts in a type of white blood cells called B lymphocytes, is the most common subtype of non-Hodgkin lymphoma accounting for approximately 30% to 40% of all cases. Patients with DLBCL often respond well to treatment with chemotherapy with many patients experiencing long-lasting remissions after undergoing treatment with well-established protocols such as rituximab together with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, in a significant proportion of patients the disease does not respond (is refractory) or it returns after an initial response (relapses).

Until recently, the only potentially effective treatment for patients with relapsed/refractory disease was high dose chemotherapy followed by hematopoietic stem cell transplant, which may not be available to all patients for a variety of reasons including patient fitness and age. Recent authorizations have made chimeric antigen receptor T-cells (CAR-T) and antibody drug conjugates available. While CAR-T products appear to be highly effective in their ability to induce complete remissions, they are limited to use after two or more lines of therapy, and their availability may be further limited due to the need for access to specialized treatment centres.

An additional treatment option for adults with relapsed or refractory DLBCL, the drug Polivy (polatuzumab vedotin), was recently granted a Notice of Compliance with conditions. Polivy is an antibody-drug conjugate for use in combination with bendamustine and rituximab, however, its efficacy has yet to be demonstrated in randomized controlled studies. As such, relapsed or refractory DLBCL continues to represent an unmet medical need for which the availability of a variety of treatment options may help to improve outcomes.

Tafasitamab, the medicinal ingredient of Minjuvi, is a CD19-targeting humanized monoclonal antibody derived from a murine monoclonal antibody that is expressed in Chinese hamster ovary (CHO) cells. This antibody was engineered to increase binding affinity to Fc-gamma receptors irrespective of patient genotype. CD19 is a transmembrane protein that is expressed by all cells of the B-cell lineage, including the malignant cells that comprise large B-cell lymphomas. Tafasitamab selectively binds to CD19 and facilitates the killing of normal and malignant B-cells through several Fc-related functions including antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis and direct cytotoxicity mediated by caspase-induced apoptosis. Tafasitamab does not mediate complement dependent cytotoxicity.

Minjuvi has shown promising evidence of efficacy when used in combination with lenalidomide in adult patients with relapsed or refractory DLBCL. The market authorization with conditions was based on evidence from the pivotal, Phase II, single-arm L-MIND study, where a clinically meaningful overall response rate of 53.5% was observed. The overall response rate is comprised of complete and partial responses observed in the study. The complete response rate was 35.2%, which is considered substantial in this relapsed or refractory population. Overall, responses were durable with an estimated median duration of response of 34.6 months. In order to confirm the effectiveness of the product, the final clinical study report for the Phase III study MOR208C310 will be submitted to Health Canada for evaluation as part of the post-approval commitments.

In the L-MIND study, the most common adverse reactions associated with Minjuvi in combination with lenalidomide reported in at least 30% of patients, were neutropenia, anemia, thrombocytopenia, asthenia, diarrhea, and respiratory tract infection.

Treatment-emergent adverse events (TEAEs) were experienced by 98.8% of the 80 patients who received both Minjuvi and lenalidomide. Grade 3 to 5 TEAEs were experienced by 76.3% of patients and four patients had serious TEAEs that were fatal. The rate of serious TEAEs overall was 43.8%. In 12.5% of patients, TEAEs led to the discontinuation of both study drugs. Serious TEAEs led to the discontinuation of Minjuvi in 13.8% of patients and the discontinuation of lenalidomide in 22.5% of patients.

The following warnings have been included in a Serious Warnings and Precautions box in the Product Monograph for Minjuvi: infection, myelosuppression, progressive multifocal leukoencephalopathy, and hepatitis B virus reactivation. Infusion-related reactions and tumour lysis syndrome are additional risks associated with this combination regimen. The combination of tafasitamab and lenalidomide is not recommended for use in pregnant women due to the risk of fetal B-cell depletion posed by Minjuvi as well as the known teratogenicity associated with lenalidomide.

A Risk Management Plan (RMP) for Minjuvi was submitted by Incyte Corporation to Health Canada. 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. Upon review of the RMP, several issues were identified by Health Canada. These issues were communicated to the sponsor and were subsequently satisfactorily addressed by the sponsor. As a result, the revised RMP is considered acceptable.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Minjuvi Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name Minjuvi was accepted.

Overall, the therapeutic benefits of Minjuvi in combination with lenalidomide seen in the pivotal, Phase II, L-MIND study are promising and are considered to outweigh the potential risks.

Minjuvi has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Minjuvi Product Monograph to address the identified safety concerns. As described within the framework of the NOC/c Guidance, safety monitoring on the use of Minjuvi will be ongoing. Further evaluation will take place upon the submission of additional clinical study data to further confirm the efficacy and safety of Minjuvi in treating patients with DLBCL.

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 Minjuvi?

The sponsor filed a request for Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance for the review of the New Drug Submission (NDS) for Minjuvi. An assessment was conducted and it was determined there was promising evidence of clinical effectiveness that the drug has the potential to provide a significant increase in efficacy such that the overall benefit/risk profile is improved over existing therapies for a disease that is not adequately managed by a drug marketed in Canada.

Subsequent review led to the decision to issue the sponsor market authorization under the Notice of Compliance with Conditions (NOC/c) Guidance, in recognition of the promising but unconfirmed evidence of clinical effectiveness in the submission. In keeping with the provisions of the NOC/c Guidance, the sponsor agreed to provide additional information to confirm the clinical benefit.

The NDS for Minjuvi was reviewed under Project Orbis, an international partnership designed to give cancer patients faster access to promising treatments. The submission for Minjuvi was classified as a Project Orbis Type C submission, where the United States Food and Drug Administration (FDA) had already issued a positive decision and subsequently shared their completed review documents with Health Canada.

The Canadian regulatory decision on the Minjuvi NDS was made independently. The review of the submission for Minjuvi was based on a critical assessment of the data package submitted to Health Canada and reviews completed by the United States FDA as described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

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

Submission Milestones: Minjuvi

Submission Milestone Date
Pre-submission meeting 2020-09-15
Acceptance of Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance 2020-11-02
New Drug Submission filed 2020-12-04
Screening  
Screening Acceptance Letter issued 2020-12-24
Review  
Review of Risk Management Plan complete 2021-06-22
Quality Evaluation complete 2021-07-06
Non-Clinical Evaluation complete 2021-07-07
Labelling Review complete 2021-07-09
Clinical/Medical Evaluation complete 2021-07-12
Biostatistics Evaluation complete 2021-07-12
Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN) issued 2021-07-12
Review of Response to NOC/c-QN:  
Response filed (Letter of Undertaking) 2021-07-20
Clinical/Medical Evaluation complete 2021-07-27
Labelling Review complete 2021-08-17
Notice of Compliance (NOC) issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate under the Notice of Compliance with Conditions (NOC/c) Guidance 2021-08-19
4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations and in the Notice of Compliance with Conditions (NOC/c) Guidance. In addition, the sponsor has agreed to submit, as a Supplemental New Drug Submission-Confirmatory (S/NDS-c), the final clinical study report for Study MOR208C310. This Phase III, multicentre, randomized, double-blind, placebo-controlled study compares the efficacy and safety of Minjuvi plus lenalidomide in addition to rituximab together with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) versus R-CHOP in previously untreated, high intermediate, and high-risk patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). The primary outcome measure is progression-free survival as per investigator assessment based on the Lugano Response Criteria for Malignant Lymphoma with overall survival considered a key secondary outcome measure. The approximate date of completion of the study is June 2025. The approximate date for the filing to Health Canada of the S/NDS-c is December 2025.

The sponsor acknowledges that failure to show an improvement in progression-free survival for Minjuvi plus lenalidomide plus R-CHOP versus R-CHOP alone, may result in regulatory action related to the indication granted under this NOC/c, which could include revocation.

5 What post-authorization activity has taken place for Minjuvi?

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 decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

The PAAT for Minjuvi 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

As described above the review of Minjuvi was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration (FDA) as a Project Orbis Type C submission. The review completed by the United States FDA was used as an added reference, as per Method 3 of the foreign review approach described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Clinical Pharmacology

Tafasitamab, the medicinal ingredient in Minjuvi, is an Fc-enhanced monoclonal antibody that targets the CD19 antigen expressed on the surface of pre-B and mature B lymphocytes and on several B-cell malignancies, including diffuse large B cell lymphoma (DLBCL).

Upon binding to CD19, tafasitamab mediates B-cell lysis through apoptosis and immune effector mechanisms including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). In vitro laboratory studies conducted in DLBCL tumour cell lines have demonstrated that treatment with tafasitamab, in combination with lenalidomide, was associated with greater cytotoxicity than observed when cells were treated with either agent alone.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacology data support the use of Minjuvi for the recommended indication.

Population Pharmacodynamics

Data from five clinical studies were used to evaluate the changes of peripheral B cells before, during, and after tafasitamab treatment. The reductions of B cells ranged from -42.07% to -96.91% for lymphoma studies and +6.57% to -91.74% for leukemia studies. The median nadir of reduction ranged from -80% to -100%. The time interval to reach the median nadir was between 8 to 16 weeks. A trend of B cell recovery was observed after tafasitamab cessation in a study with 12-week follow up. 

Population Pharmacokinetics

Two population pharmacokinetic studies were conducted using data from clinical studies to characterize the pharmacokinetics of tafasitamab, to evaluate exposure variability, and to assess the potential impact of covariates on pharmacokinetics. The pharmacokinetics of tafasitamab was well characterized by a two-compartment model with first-order elimination. Body weight had a significant impact on clearance and volume of distribution. This finding supports body weight-based dosing. Mild to moderate renal impairment and mild hepatic impairment did not significantly affect the pharmacokinetics of tafasitamab. The data was insufficient to evaluate the impact of severe renal impairment and moderate to severe hepatic impairment on the pharmacokinetics of tafasitamab. The prevalence of anti-drug antibodies was relatively low and did not show an apparent impact on the pharmacokinetics of tafasitamab.

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

Clinical Efficacy

Pivotal Study

L-MIND Study

The efficacy of Minjuvi was evaluated in the ongoing pivotal Phase II, single-arm, open-label, multicentre study (L-MIND study [Study MOR208C203]) that enrolled adult patients with relapsed or refractory diffuse large B-cell lymphoma (r/rDLBCL). To participate, patients must have received at least one, but not more than three, prior systemic regimens, one of which must have included a CD20-targeting agent such as rituximab. Patients could not be candidates for stem cell transplant. Key exclusion criteria limited enrollment to patients who did not have other types of lymphoma (e.g., primary mediastinal B-cell lymphoma, Burkitt lymphoma, did not have double/triple hit genetics, and who were not primary refractory). However, although primary refractory patients were to be excluded, they comprised 15% of study patients. Therefore, the scope of the indication does not exclude these patients.

In total, the study enrolled 81 patients to receive Minjuvi in combination with lenalidomide for up to 12 cycles, followed by Minjuvi monotherapy until disease progression or unacceptable toxicity occurred. The demographics and baseline characteristics of the population were considered representative of an advanced DLBCL with a median age of 72 years and a slight preponderance among males compared to females. Each patient’s level of functioning in terms of their ability to care for themselves, daily activity, and physical ability was measured using the Eastern Cooperative Oncology Status (ECOG) scale which ranges from 0 to 5. A status of 0 represents a fully active patient. A status of 4 which represents a completely disabled patient. A status of 5 indicates the patient is deceased. This study enrolled patients with ECOG performance statuses ranging from 0 to 2, with the majority of patients having a status of 0 or 1, and only seven having a status of 2. Seventy-five percent of patients had DLBCL diagnosed greater than one year prior to treatment.

Patients received Minjuvi by intravenous infusion at a dose of 12 mg/kg. Minjuvi was administered according the following schedule, with each cycle lasting 28 days:

  • Cycle 1: Administer the infusion on Day 1, 4, 8, 15, and 22 of the cycle.
  • Cycles 2 and 3: Administer the infusion on Day 1, 8, 15 and 22 of each cycle.
  • Cycle 4 until disease progression: Administer the infusion on Day 1 and 15 of each cycle.

During the first 12 cycles of treatment, patients also orally self-administered lenalidomide at a dose of 25 mg once per day for the first 21 days of each cycle. Of the 81 enrolled patients, 80 received both drugs and 30 patients completed 12 cycles of combination therapy. Prior to Cycle 12, one patient discontinued Minjuvi alone, 4 patients discontinued lenalidomide alone, and 45 patients discontinued both drugs. The majority of discontinuations were due to progressive disease. Thirty-four patients continued receiving Minjuvi monotherapy from Cycle 13 onward and 22 were still on treatment at the time of the most recent data cut-off (November 30, 2019).

The primary efficacy outcome was the overall response rate (ORR) defined as the proportion of patients who achieved a best overall response of complete response or partial response. Responses were evaluated by an independent review committee who assessed response status based on the 2007 international working group revised response criteria for malignant lymphoma (i.e., Cheson 2007 criteria). While there have been more recent updates to the response criteria, these are generally considered acceptable and include the use of positron emission tomography (PET), which aids in differentiating complete from partial responses.

The sponsor’s most up-to-date evaluation of response, which considered the full-analysis set, excluded one of the 81 enrolled patients as this patient received only Minjuvi. Among the group of 80 patients, the reported ORR was 57.5% (95% Confidence Interval [CI]: 45.9, 68.5). The complete response rate was 40%, while partial responses were observed in 17.5% of patients. A best response of progressive disease was observed in 16.3% of patients.

During review, it was noted that the sponsor re-evaluated each patient’s diagnosis via a central pathology laboratory. This re-evaluation confirmed DLBCL among 71 patients; however, the remainder were classified as having a non-DLBCL histology (e.g., low grade follicular lymphoma, mantle cell lymphoma, or marginal zone lymphoma). Two patients could not be evaluated. Given the misclassification of 10 patients in the initially enrolled population, the sponsor was asked to provide the ORR results among patients with confirmed DLBCL histology. Among this set of patients, the ORR was 53.5% (38/71), the complete response rate was 35.2% (25/71) and a best response of partial response was achieved by 18.3% (13/71) of patients.

The duration of response was a key secondary endpoint considering that the primary outcome was the ORR. Among all responders (in the confirmed DLBCL set of patients) the median duration of response was 34.6 months (95% CI: 21.7, not estimable [NE]); however, a difference in the median durations of response between complete responders compared to partial responders was noted. Among complete responders, the median duration of response was not reached (95% CI: 26.1 months, NE). Partial responses were associated with a median duration of response of 5.7 months (1.8, NE).

Of note, the combination treatment of Minjuvi and lenalidomide has not been directly compared to either drug alone or to other treatment options in a randomized controlled study. In addition to the study described above, the sponsor provided the results of a single-arm study MOR208C201, in which Minjuvi was administered as monotherapy. The results of this study and a retrospective cohort study of lenalidomide monotherapy in r/rDLBCL are described below.

Non-Pivotal Studies

Study MOR208C201

Minjuvi was evaluated as a monotherapy in 35 patients with r/r DLBCL in the single-arm, open-label, multicentre Phase II study MOR208C201. The primary efficacy outcome of this study was to evaluate the ORR based on the 2007 revised response criteria for malignant lymphoma (i.e., Cheson 2007). Notably, the dosing regimen for Minjuvi differed in this study compared to the pivotal, Phase II, L-MIND study (described above). Whereas L-MIND applied weekly dosing (12 mg/kg) for the first 3 cycles, followed by bi-weekly dosing, Study MOR208C201 required weekly dosing until Week 8 after which point responders could continue treatment on a weekly dosing regimen. Therefore, patients enrolled in this non-pivotal study had the potential to be exposed to Minjuvi to a greater extent then those in the pivotal L-MIND study.

The reported ORR among the 35 enrolled r/rDLBCL patients, as per central radiology assessment, was 17.1% (95% CI: 6.6, 33.6). Complete responses occurred in three patients (8.6%) and partial responses were reported for three patients (8.6%). The median duration of response was not reached among the six responders.

RE-MIND Study

To evaluate the efficacy of lenalidomide alone, the sponsor provided the observational retrospective cohort RE-MIND study (MOR208C206). This study sought to match patients using propensity score methods to the cohort enrolled in the pivotal, Phase II, L-MIND study. The purpose of the study was to compare the ORRs observed among patients who received only lenalidomide versus those who received the combination of Minjuvi and lenalidomide followed by Minjuvi monotherapy (in L-MIND). The RE-MIND study reported a lenalidomide monotherapy ORR of 34.2% (95% CI: 23.7, 46.0) and a CR rate of 13.2% among patients who received lenalidomide monotherapy. However, after consultation with Health Canada biostatisticians, it was concluded that any recommendation for authorization should be based on the magnitude of the ORR reported in the L-MIND study rather than based on comparative results reported in the RE-MIND study.

For these reasons, the efficacy of Minjuvi in combination with lenalidomide followed by Minjuvi monotherapy was evaluated based on the results of the single-arm L-MIND study, which was considered acceptable in the context of an advanced consideration for a Notice of Compliance with conditions submission.

Indication

The New Drug Submission for Minjuvi was filed by the sponsor with the following indication:

Minjuvi (tafasitamab powder for solution for infusion) is indicated in combination with lenalidomide followed by Minjuvi monotherapy for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), including DLBCL arising from low grade lymphoma, who are not eligible for, or refuse, autologous stem cell transplant (ASCT).

To ensure safe and effective use of the product, Health Canada approved the following indication:

Minjuvi (tafasitamab) is indicated in combination with lenalidomide for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low-grade lymphoma who are not eligible for autologous stem cell transplant.

Authorization was based on overall response rate, complete response rate and durability of response from a single-arm clinical study. An improvement in progression-free survival or overall survival has not been established.

The indication was modified to stipulate DLBCL not otherwise specified, which is in line with the study population enrolled and the World Health Organization’s 2016 lymphoma classification guidance. The pivotal study supporting Minjuvi in combination with lenalidomide excluded patients with double- or triple-hit lymphomas. These patients are often considered a subset of DLBCL. By adding “not otherwise specified”, it is clear that these patients are not included in the indication.

Overall Analysis of Efficacy

Relapsed and refractory DLBCL is a life-threatening condition for which there are few available treatment options. Other recently approval treatments are for use as later lines of treatment or are authorized with conditions. It is therefore advantageous for r/rDLBCL patients to have access to new treatment strategies that could improve outcomes.

In the pivotal study, treatment with Minjuvi resulted in a high ORR (53.5%) that was predominantly comprised of complete responses. Taking this into consideration along with the durability of the responses and a safety profile that is significant but manageable and similar to that of other B-cell targeting antibodies used in the treatment of DLBCL, the benefit-risk assessment for Minjuvi, when used in combination with lenalidomide followed by Minjuvi monotherapy is considered favourable for the treatment of r/rDLBCL. As such, a Notice of Compliance with conditions was recommended for Minjuvi based on the promising evidence of clinical efficacy observed in the pivotal, Phase II, single-arm study. Continued authorization requires the submission of additional clinical study data to further confirm the efficacy of Minjuvi in treating patients with DLBCL.

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

Clinical Safety

Throughout the clinical development program, 427 patients received Minjuvi, either as a monotherapy or in combination with other treatments. The safety of Minjuvi when used in combination with lenalidomide for the treatment of patients with r/rDLBCL was evaluated in the pivotal, Phase II, L-MIND study, as this was the only study in which the two drugs were administered together. A description of the L-MIND study is found in the Clinical Efficacy section.

In the L-MIND study, 98.8% of the 80 patients treated with both Minjuvi and lenalidomide experienced treatment-emergent adverse events (TEAEs). Grade 3 to 5 TEAEs were experienced by 76.3% of patients and four patients had serious TEAEs that were fatal. The causes of death included a cerebrovascular accident, respiratory failure, progressive multifocal leukoencephalopathy, and a sudden death. The overall rate of serious TEAEs was 43.8%. In 12.5% of patients, TEAEs led to the discontinuation of both study drugs. Serious TEAEs led to the discontinuation of Minjuvi in 13.8% of patients and the discontinuation of lenalidomide in 22.5% of patients.

The most commonly reported TEAEs (occurring in more than 20% of patients) were neutropenia, anemia, thrombocytopenia, diarrhea, asthenia, cough, edema peripheral, pyrexia, respiratory tract infection, and decreased appetite. Notably, TEAEs that fell within the Infectious and Infestations Systems Organ Class were very common with 67.5% of patients experiencing a TEAE in this class. The most commonly observed infections were those of the upper respiratory tract and severe infections, including opportunistic infections and reactivations were observed. One patient experienced reactivation of hepatitis B (Grade 2). Progressive multifocal leukoencephalopathy, a neurological condition associated with John Cunningham (JC) virus infection, resulted the in death of one patient. Each of these events have established relationships with other B-cell depleting treatments, therefore, Health Canada recommended that these events be added to a Serious Warnings and Precautions box in the Minjuvi Product Monograph, along with the risk of serious infections.

Other important adverse events included myelosuppression, which may be partially related to the use of lenalidomide. Events of neutropenia, anemia, and thrombocytopenia were very common. Myelosuppression was added to a Serious Warnings and Precautions box in the Product Monograph for Minjuvi. In addition, the Dosage and Administration section of the Minjuvi Product Monograph includes a dose modification table that gives specific dosing instructions in the event of thrombocytopenia and/or neutropenia. Recommendations to consult the lenalidomide Product Monograph are also recommended throughout the Minjuvi Product Monograph.

Infusion-related reactions were experienced by 6.2% of patients in the L-MIND study. All were Grade 1 reactions and resolved. It was noted that all patients received premedication with H1 antagonists, antipyretics and/or glucocorticoids. The Minjuvi Product Monograph instructs healthcare providers to administer premedication before initiating Minjuvi infusion for at least the first three infusions. After this point, premedication is optional if patients have not experienced a reaction. In all cases, healthcare practitioners are instructed to monitor for infusion-related reactions throughout the infusion of Minjuvi.

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity (the development of anti-drug antibodies [ADAs], which have the potential to neutralize the biological activity of the drug). No patients in the pivotal L-MIND study showed evidence of treatment emergent ADAs.

Based on its mechanism of action, Minjuvi may cause fetal B-cell depletion when administered to a pregnant woman. Minjuvi is not recommended during pregnancy or in women of childbearing potential who are not using contraception.

It is not known whether tafasitamab (the medicinal ingredient in Minjuvi) is excreted in human milk; however, maternal immunoglobulin G (IgG) is known to be excreted in human milk. Because of the potential for adverse reactions in nursing infants from tafasitamab, women are advised not to breastfeed during treatment with Minjuvi until at least 3 months after the last dose.

Overall Analysis of Safety

In the L-MIND study, the majority of the 80 patients treated with Minjuvi in combination with lenalidomide experienced TEAEs. Infection-related adverse events including pneumonia, as well as events of myelosuppression (neutropenia, anemia, and thrombocytopenia) were very common. Importantly, opportunistic infections, including progressive multifocal leukoencephalopathy and hepatitis B reactivation occurred. Fatal adverse events occurred in four patients with one patient experiencing fatal progressive multifocal leukoencephalopathy that was considered related to treatment. While the safety profile is remarkable, it is considered acceptable given the severity of the condition and its similarity to other regimens (e.g., anti-CD20-based regimens) used to treat the same disease. The continued authorization of Minjuvi requires the submission of additional clinical study data to further confirm the safety of Minjuvi in treating patients with DLBCL.

Appropriate warnings and precautions are in place in the approved Minjuvi Product Monograph to address the identified safety concerns. The risks of infection, myelosuppression, progressive multifocal leukoencephalopathy, and hepatitis B reactivation are conveyed in a Serious Warnings and Precautions box in the Minjuvi Product Monograph. Additional risk mitigation has been included in the form of dosing adjustment guidance for infusion-related reactions and myelosuppression as well as guidance to monitor and treat for infections including progressive multifocal leukoencephalopathy and hepatitis B reactivation, both of which are commonly warnings in product monographs for other B-cell targeting antibodies. The Minjuvi Product Monograph also refers the reader to the Product Monograph for lenalidomide, which is commonly associated with myelosuppression and is known to be teratogenic, to ensure that prescribers are aware of the risk mitigation strategies associated with its use.

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

7.2 Non-Clinical Basis for Decision

As described above, the review of Minjuvi was completed by Health Canada as part of an international partnership with the United States FDA as a Project Orbis Type C submission. The review completed by the United States FDA was used as an added reference, as per Method 3 of the foreign review approach described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The non-clinical data provided with the submission included in vitro and in vivo pharmacology, pharmacokinetic, toxicokinetic and toxicology studies. The results of the non-clinical studies as well as the potential risks to humans have been included in the Minjuvi Product Monograph. In view of the intended use of Minjuvi, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

Tafasitamab (the medicinal ingredient in Minjuvi) demonstrated increased efficacy in combination with the immune modulating drug lenalidomide in vitro and in vivo.

In cynomolgus monkeys, tafasitamab mediated B cell depletion from peripheral blood at doses ranging from 0.3 mg/kg to 100 mg/kg during the treatment period. The B cell depletion in peripheral blood was reversible within the recovery period. The safety pharmacology parameters assessed within the repeat-dose toxicity studies did not reveal any unwanted effects on vital organs (cardiovascular, respiratory, and central nervous system).

The presence of anti-drug antibodies had no obvious impact on the pharmacokinetics of tafasitamab.

Cynomolgus monkeys administered 100 mg/kg tafasitamab demonstrated a mean maximum serum concentration (Cmax; observed after the 13th dose) of 4,595 μg/mL and an exposure (AUC0-144h from the 1st dose) of 8,375.0 μg·day/mL, which is approximately 8 to 9 times the human exposure based on AUC and Cmax at the clinical dose of 12 mg/kg/week.

A toxicological assessment was performed in cynomolgus monkeys and included pivotal 8-week and 13-week repeat-dose intravenous infusion toxicity studies. The toxicology studies performed did not uncover any adverse effects or target organ toxicity.

Genotoxicity and carcinogenicity studies were not performed with tafasitamab as per International Council for Harmonisation (ICH) guidelines. No reproductive and developmental toxicity studies were conducted as tafasitamab administration is in combination with lenalidomide, a drug known to be teratogenic or causing embryo-fetal lethality.

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

7.3 Quality Basis for Decision

As described above, the review of Minjuvi was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration (FDA) as a Project Orbis Type C submission and as per the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. Health Canada’s review of the quality data was based on a critical assessment of the quality data, including FDA evaluation reports and Health Canada laboratory testing. While the review of the submission was a partnership with the FDA, Health Canada made an independent decision regarding the quality data.

Characterization of the Drug Substance

Tafasitamab is a fragment crystallizable (Fc)-engineered humanized recombinant immunoglobulin G1 (IgG1)/IgG2 hybrid monoclonal antibody. It is derived from the murine monoclonal antibody (mAb) 4G7 by humanization of the variable domain. Tafasitamab is expressed in Chinese hamster ovary (CHO) cells.

Tafasitamab is a B-cell depleting antibody that binds to the B-cell surface antigen CD19.  Tafasitamab has amino acid substitutions at heavy chain S243D and I336E designed to increase the binding affinity to Fcγ receptors (e.g. FcγRIIa and FcγRIIIa) in order to enhance the effector functions such as antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. 

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

Comparability of tafasitamab lots produced by different processes during development and by the proposed commercial process was were demonstrated. Lot release, stability, and characterization data were used to support the comparability assessment.

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

The drug substance 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. Results from genetic characterization studies also demonstrated stability of these cell banks.

The tafasitamab drug substance is expressed in Chinese Hamster Ovary (CHO) cells as a secreted protein. The clarified harvest from the fermentation process is purified using a series of chromatography and filtration steps. The purified eluate undergoes ultrafiltration and diafiltration, final formulation and filtration, followed by storage at 5°C or -40°C.  

The formulated drug substance is stored in portable stainless steel pool tanks for short term hold and transferred to drug product manufacturing. Alternately, the drug substance is transferred into portable stainless steel cryovessels for long term storage. Available stability data demonstrate suitability of both container closure systems with respect to maintaining product quality and microbial integrity.

Drug Product

The tafasitamab manufacturing process consists of sterile filtration, filling including partial stoppering, lyophilisation including complete stoppering, crimping, vial coding, and visual inspection. The vials are labelled, placed in folding carton boxes, and stored at 5 ± 3°C until shipment/distribution. All filling operations take place in an aseptic environment using conventional pharmaceutical equipment and facilities.

Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.

The materials used in the manufacture of the drug substance and drug product (including biological-sourced materials) are considered suitable and/or meet standards appropriate for their intended use. The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits.

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 tafasitamab 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 International Council for Harmonisation (ICH) guidelines.

Each lot of Minjuvi drug product is tested for appearance, content, identity, potency, purity, and impurities. Established test specifications and validated analytical test methods are considered acceptable.

Through Health Canada’s lot release testing and evaluation program, consecutively manufactured final product lots were tested using a subset of release methods and an assessment of the sponsor's testing data performed. The testing process and the assessment confirmed that the methods used in-house are acceptable for their intended use and positively supported the quality review recommendation.

The results for all of the batches were within the proposed specification limits.

Minjuvi is a Schedule D (biologic) drug and is, therefore, subject to Health Canada’s Lot Release Program before sale as per Health Canada’s Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

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 shelf life for Minjuvi of 36 months when stored at 5°C ± 3°C, in the original carton protected from light for Minjuvi is considered acceptable.

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.

Facilities and Equipment

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

Based on a risk assessment score determined by Health Canada, an on-site evaluation of the drug substance and drug product manufacturing facilities was deemed not necessary.

The manufacturing site involved in the production is compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

The tafasitamab 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) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.

Raw materials and product contact materials used for the manufacturing of Minjuvi present no bovine spongiform encephalopathy (BSE) or transmissible spongiform encephalopathy (TSE) transmission risk.

The excipients used in the drug product formulation are not of animal or human origin.

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