Summary Basis of Decision for Poteligeo
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 Poteligeo is located below.
Recent Activity for Poteligeo
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 Poteligeo
Date SBD issued: 2022-10-25
The following information relates to the new drug submission for Poteligeo.
Mogamulizumab
Drug Identification Number (DIN):
- DIN 02527715 - 4 mg/mL mogamulizumab, solution, intravenous administration
Kyowa Kirin, Inc.
New Drug Submission Control Number: 251277
On June 2, 2022, Health Canada issued a Notice of Compliance to Kyowa Kirin, Inc. for the drug product Poteligeo.
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 Poteligeo is acceptable for the treatment of adult patients with relapsed or refractory mycosis fungoides or Sézary syndrome after at least one prior systemic therapy.
1 What was approved?
Poteligeo, an antineoplastic agent, was authorized for the treatment of adult patients with relapsed or refractory mycosis fungoides or Sézary syndrome after at least one prior systemic therapy.
Poteligeo is not authorized for use in pediatric patients (younger than 18 years of age), as no clinical safety or efficacy data are available for this population.
No overall differences in safety were observed in geriatric patients (65 years of age and older) compared to patients aged less than 65 years in clinical trials.
Poteligeo (4 mg/mL mogamulizumab) is presented as a solution. In addition to the medicinal ingredient, the solution contains citric acid monohydrate, glycine, polysorbate 80, and water for injection. It may also contain hydrochloric acid or sodium hydroxide for pH adjustment.
The use of Poteligeo 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.
The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Poteligeo Product Monograph is available through the Drug Product Database.
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.
2 Why was Poteligeo approved?
Health Canada considers that the benefit-risk profile of Poteligeo is acceptable for the treatment of adult patients with relapsed or refractory mycosis fungoides or Sézary syndrome after at least one prior systemic therapy.
Mycosis fungoides and Sézary syndrome are the two most common types of cutaneous T‑cell lymphoma (CTCL), a rare but serious and potentially life-threatening form of non-Hodgkin’s lymphoma. In mycosis fungoides, malignant T‑cell lymphocytes affect the skin with potential involvement of other sites as disease progresses. Sézary syndrome occurs when malignant lymphocytes (known as Sézary cells) appear in the blood and skin. It is unknown if Sézary syndrome is an advanced form of mycosis fungoides or a separate disease.
The incidence of mycosis fungoides in Europe and the United States is approximately 6 cases per million people per year, has an onset of 55 to 60 years of age, and is most common in males and Blacks. The incidence of Sézary syndrome is poorly defined, with approximately 0.8 cases per million people per year. Sézary syndrome is most common in males, Whites, and older adults.
Cutaneous T‑cell lymphoma is staged (Stage I to IV) using the four anatomical compartments affected by disease (i.e., skin, lymph nodes, viscera, and blood); each of the compartments has prognostic significance. The course of mycosis fungoides and Sézary syndrome is variable. Mycosis fungoides, including advanced‑stage mycosis fungoides, is often a chronic disease with a persistent or relapsing course and a median survival of 20 years. In contrast, Sézary syndrome has a median survival of 3.1 years. Relapsed or refractory mycosis fungoides and Sézary syndrome tend to be resistant to chemotherapy.
Although there is no national guideline for the treatment of CTCL in Canada, local (Alberta Clinical Practice Guidelines) and international (National Comprehensive Cancer Network Clinical Practice Guidelines) treatment guidelines are generally consistent in recommending various localized treatments (such as ultraviolet‑B phototherapy) for early stages of the disease and various combinations of systemic therapies for refractory, relapsed, or advanced stages of the disease.
Poteligeo (mogamulizumab), a new molecular entity, is a humanized monoclonal antibody directed against CC chemokine receptor 4 (CCR4), a G protein-coupled receptor that is involved in the trafficking of lymphocytes to various organs. In healthy individuals, CCR4 is selectively expressed on a subset of T cells, including Type 2 helper T cells and regulatory T cells. However, in T‑cell malignancies, such as mycosis fungoides and Sézary syndrome, CCR4 is overexpressed or expressed at high frequency on the surface of cancer cells. Poteligeo targets and binds to CCR4, enhancing antibody-dependent cell-mediated cytotoxicity of malignant lymphocytes and resulting in the depletion of these cells.
The efficacy and safety of Poteligeo were evaluated in an open-label, multicentre, randomized, one-way crossover Phase III study (Study 0761-010) in 372 adult patients with relapsed or refractory mycosis fungoides or Sézary syndrome who had failed at least one prior course of systemic therapy. Patients were stratified by disease type (mycosis fungoides or Sézary syndrome) and disease stage (Stage IB/II or III/IV) then randomized in a 1:1 ratio to receive the recommended doses of Poteligeo (1.0 mg/kg intravenously on days 1, 8, 15, and 22 of the first 28-day cycle and on days 1 and 15 of each subsequent 28-day cycle) or vorinostat (400 mg orally daily). Patients randomized to the vorinostat arm and who received at least two full treatment cycles were permitted to cross over to receive Poteligeo if they demonstrated progression of disease or were unable to tolerate vorinostat treatment. Of the 136 patients (73%) in the vorinostat arm who crossed over to Poteligeo, 109 (80%) crossed over due to disease progression and 27 (20%) crossed over due to intolerance. The median duration of exposure to Poteligeo was 170 days (6 cycles) while the median duration of exposure to vorinostat was 84 days (3 cycles).
At baseline, 58% of patients were male, 70% of patients were White, and the median age was 64 years (range: 25 to 101 years). The median number of prior systemic therapies was three. In the Poteligeo arm, CCR4 expression status was available for 140 patients (75%); all had greater than 1% of lymphocytes stain positive for CCR4 and 134 patients (96%) had greater than 10% of lymphocytes stain positive for CCR4. Patients in the vorinostat arm had a similar CCR4 expression status.
The primary efficacy endpoint was investigator-assessed (IA) progression-free survival (PFS), defined as the time from the date of randomization until documented progression of disease or death. The primary efficacy analysis demonstrated that treatment with Poteligeo resulted in a statistically significant improvement in IA PFS compared to vorinostat, a hazard ratio (HR) of 0.53 (95% confidence interval [CI]: 0.41, 0.69). The estimated median PFS was 7.7 months (95% CI: 5.67, 10.33) for the Poteligeo arm and 3.1 months (95% CI: 2.87, 4.07) for the vorinostat arm. Overall response rate (ORR), a key secondary efficacy endpoint, was based on global composite response criteria that combine measures from all four disease compartments (skin, blood, lymph nodes, and viscera). The IA ORR was supportive of the primary efficacy result with 28% ORR in the Poteligeo arm compared to 5% in the vorinostat arm (a difference of 23%, 95% CI: 12.8, 33.1).
The proportion of patients with treatment-emergent adverse events (TEAEs) and serious adverse reactions were comparable between the two treatment arms. In the Poteligeo arm, the most frequently reported adverse reactions were infusion-related reaction (33.2%), drug eruption (22.8%), fatigue (18.5%), and diarrhea (10.3%). The incidences of moderate to severe adverse reactions included infusion-related reaction (1.6%) and drug eruption (4.3%). Two possible adverse reactions leading to death were sepsis and polymyositis.
The incidences (Poteligeo arm versus [vs.] vorinostat arm) of adverse drug reactions (84.8% vs. 95.7%), moderate to severe adverse reactions (25.5% vs. 34.9%), adverse reaction leading to death (1.1% vs. 1.6%), and adverse reaction leading to drug discontinuation (13.6% vs. 21.5%) were lower in the Poteligeo arm compared to the vorinostat arm.
Adverse events of special interest identified for Poteligeo include infusion-related reactions, infections, dermatologic toxicity, autoimmune complications, stress cardiomyopathy, and graft-versus-host disease in patients who receive allogeneic hematopoietic stem cell transplantation. In literature, hepatitis B reactivation and cytomegalovirus-related infection were identified as potential risks associated with Poteligeo.
Appropriate warnings and precautions are in place in the approved Poteligeo Product Monograph to address the identified safety concerns.
A Risk Management Plan (RMP) for Poteligeo was submitted by Kyowa Kirin, Inc. 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, the RMP was considered to be acceptable.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Poteligeo Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements. The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Poteligeo was accepted.
Overall, Poteligeo has been shown to have an acceptable 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 issued 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 Poteligeo?
The sponsor filed a request for Priority Review Status under the Priority Review Policy for the review of the New Drug Submission (NDS) for Poteligeo. However, the request was rejected as the sponsor did not fulfil the criterion of a “significant increase in efficacy and/or significant decrease in risk such that the overall benefit/risk profile is improved over existing therapies for a disease or condition that is not adequately managed by a drug marketed in Canada”. The submission was subsequently filed and reviewed as a non-priority NDS.
The review of the NDS for Poteligeo was based on a critical assessment of the data package submitted to Health Canada with the use of the review completed by the United States Food and Drug Administration as an added reference for the clinical pharmacology and quality component of this submission (Method 3 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: Poteligeo
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2018-07-25 |
| Request for priority status filed | 2021-01-29 |
| Request for priority status rejected by Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics | 2021-02-19 |
| New Drug Submission filed | 2021-03-31 |
| Screening | |
| Screening Acceptance Letter issued | 2021-05-17 |
| Review | |
| Request granted to pause review clock for 85 days (extension to respond to clarification request) | 2022-01-24 |
| Non-clinical evaluation completed | 2022-02-28 |
| Clinical/medical evaluation completed | 2022-03-02 |
| Quality evaluation completed | 2022-05-18 |
| Review of Risk Management Plan completed | 2022-05-20 |
| Labelling review completed | 2022-05-31 |
| Biostatistics evaluation completed | 2022-06-02 |
| Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate | 2022-06-02 |
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
Mogamulizumab, the medicinal ingredient in Poteligeo, is a defucosylated, humanized immunoglobulin G1 (IgG1) kappa monoclonal antibody that binds to CC chemokine receptor 4 (CCR4), a G protein-coupled receptor for CC chemokines that is involved in the trafficking of lymphocytes to various organs. The CCR4 is expressed on the surface of some T‑cell malignancies and is expressed on regulatory T cells and a subset of Type 2 helper T cells. Non-clinical in vitro studies demonstrate that mogamulizumab binding targets a cell for antibody-dependent cellular cytotoxicity, resulting in the depletion of target cells.
Mogamulizumab exposure-response relationships and the time course of pharmacodynamics response are unknown. The pharmacokinetics of mogamulizumab was evaluated in adult patients with T‑cell malignancies over a dose range of 0.01 to 1 mg/kg (0.01 to 1 times the recommended dosage). Based on the population pharmacokinetics analysis, the exposure of mogamulizumab increased proportionally with dose. Following repeated dosing of the recommended dosage, steady state concentrations were reached after 8 doses (12 weeks), and the systemic accumulation was 1.6‑fold. At steady state, the peak concentration is 32 mcg/mL (68%), the trough concentration is 11 mcg/mL (239%), and the area under the concentration-time curve is 5,577 mcg•h/mL (125%).
The geometric mean (% geometric coefficient of variation [GCV%]) central volume of distribution is 3.57 L (20.1%). The geometric mean (GCV%) clearance is 12 mL/h (83.7%) and elimination half-life (t1/2) is 17 days (65.5%).
No clinically significant changes in the pharmacokinetics of mogamulizumab were observed based on age (range: 22 to 101 years), sex, ethnicity, renal impairment (creatinine clearance < 90 mL/min, estimated by Cockcroft-Gault), mild (total bilirubin ≤ the upper limit of normal [ULN] and any aspartate transaminase [AST] < ULN, or total bilirubin < 1 to 1.5 times ULN and any AST) or moderate (total bilirubin > 1.5 to 3 times ULN and any AST) hepatic impairment, disease subtype (mycosis fungoides [MF] or Sézary syndrome [SS]), degree of CCR4 expression, or Eastern Cooperative Oncology Group status. The effect of severe hepatic impairment (total bilirubin > 3 times ULN and any AST) on mogamulizumab pharmacokinetics is unknown.
For further details, please refer to the Poteligeo Product Monograph, approved by Health Canada and available through the Drug Product Database
Clinical Efficacy
The clinical efficacy of Poteligeo was evaluated in an open-label, multicentre, randomized, one-way crossover Phase III study (Study 0761-010) comparing the efficacy of Poteligeo to vorinostat in adult patients with relapsed or refractory MF or SS who had failed at least one prior course of systemic therapy. Vorinostat was selected as the comparator because it is utilized as a standard of care in clinical practice in the United States for cutaneous T‑cell lymphoma (CTCL), including the relapsed or refractory setting in patients with CTCL who have progressive, persistent, or recurrent disease on or following two systemic therapies. In Canada, vorinostat was authorized for the treatment of cutaneous manifestations in patients with advanced CTCL who have progressive, persistent, or recurrent disease subsequent to prior systemic therapies. Locally (per Alberta Clinical Practice Guidelines for the treatment of MF and SS) vorinostat is recommended for MF advanced stage and strongly recommended for SS and erythrodermic MF.
In this study, 372 patients with relapsed or refractory disease were stratified by disease type (MF [55%] or SS [45%]) and disease stage (Stage IB/II or III/IV), then randomized in a 1:1 ratio to receive the recommended doses of Poteligeo (number of patients [n] = 186) or vorinostat (n = 186). Poteligeo (1.0 mg/kg) was administered intravenously on days 1, 8, 15, and 22 of the first 28-day cycle and on days 1 and 15 of each subsequent 28-day cycle. Vorinostat (400 mg) was given orally once daily. Patients randomized to the vorinostat arm and who received treatment for at least two full cycles were permitted to cross over to receive Poteligeo if they demonstrated progression of disease or were unable to tolerate vorinostat treatment. Of the 136 patients (73%) in the vorinostat arm who crossed over to Poteligeo, the majority of patients (n = 109; 80%) crossed over due to disease progression and 27 patients (20%) crossed over due to intolerance. The median duration of exposure to Poteligeo was 170 days (6 cycles) while the median duration of exposure to vorinostat was 84 days (3 cycles).
At baseline, 58% of patients were male, 70% of patients were White, and the median age was 64 years (range: 25 to 101 years). The median number of prior systemic therapies was three. In the Poteligeo arm, CCR4 expression status, as assessed by immunohistochemical analysis, was available for 140 patients (75%). Skin biopsy results showed that all had greater than 1% of lymphocytes stain positive for CCR4 and 134 patients (96%) had greater than 10% of lymphocytes stain positive for CCR4. Patients in the vorinostat arm had a similar CCR4 expression status.
The primary efficacy endpoint, investigator-assessed (IA) progression-free survival (PFS), was defined as the time from the date of randomization until documented progression of disease or death. The primary efficacy analysis demonstrated that treatment with Poteligeo resulted in a statistically significant improvement in IA PFS compared to vorinostat, with a hazard ratio (HR) of 0.53 (95% confidence interval [CI]: 0.41, 0.69). The estimated median PFS was 7.7 months (95% CI: 5.67, 10.33) in the Poteligeo arm and 3.1 months (95% CI: 2.87, 4.07) in the vorinostat arm. The results were supported by a blinded independent review (IR) committee assessment, with an estimated median PFS of 6.7 months (95% CI: 5.63, 9.37) in the Poteligeo arm and 3.8 months in the vorinostat arm (95% CI: 3.00, 4.70); HR of 0.64 (95% CI: 0.49, 0.84).
The overall response rate (ORR), a key secondary efficacy endpoint, was based on global composite response criteria that combine measures from all four disease compartments (skin, blood, lymph nodes, and viscera). The IA ORR was supportive of the primary efficacy result with a 28% ORR in the Poteligeo arm compared to 5% in the vorinostat arm (a difference of 23% [95% CI: 12.8, 33.1]), and confirmed by IR committee assessment.
One uncertainty with Study 0761-010 is the poor performance of the vorinostat arm compared to its performance as described in the vorinostat product monograph. While it is not appropriate to run comparisons across different studies, one explanation for the poor performance of the vorinostat arm may be the short exposure to vorinostat in this study. Patients randomized to the Poteligeo arm had a median exposure of 6 cycles, while patients in the vorinostat arm had a median exposure of 3 cycles before 136 patients (73.1%) crossed over to receive Poteligeo. According to the vorinostat product monograph, response to treatment may take up to 6 months; therefore, 3 cycles of vorinostat may not provide sufficient time for a response.
Further, the efficacy results appeared to be driven by SS and there are emerging data suggesting that SS and MF may be distinct entities with differing pathogenesis. If these are determined to be two separate diseases in the future, the authorization of Poteligeo for both SS and MF may need to be re-evaluated.
Overall, Study 0761-010 provided sufficient evidence that the use of Poteligeo prolonged PFS and improved ORR compared to vorinostat, an authorized treatment, in adult patients with relapsed or refractory MF or SS with at least one prior systemic therapy.
Indication
The New Drug Submission for Poteligeo was filed by the sponsor with the following indication:
- Poteligeo is indicated for the treatment of adult patients with mycosis fungoides (MF) or Sézary syndrome (SS) who have received at least one prior systemic therapy.
Health Canada revised the proposed indication to accurately reflect the patient population in the pivotal study (Study 0761-010). Accordingly, Health Canada approved the following indication:
- Poteligeo is indicated for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy.
For more information, refer to the Poteligeo Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The safety profile of Poteligeo was evaluated in an open-label, multicentre, randomized, one-way crossover Phase III study known as Study 0761-010 (see the Clinical Efficacy section).
The proportions of patients with treatment‑emergent adverse events (TEAEs) and serious adverse reactions were comparable between the Poteligeo arm (97.3% and 19.6%, respectively) and the vorinostat arm (99.5% and 16.1%, respectively).
The incidences (Poteligeo arm versus [vs.] vorinostat arm) of adverse drug reactions (84.8% vs. 95.7%), moderate to severe adverse reactions (25.5% vs. 34.9%), adverse reaction leading to death (1.1% vs. 1.6%), and adverse reaction leading to drug discontinuation (13.6% vs. 21.5%) were lower in the Poteligeo arm compared to the vorinostat arm.
The most frequently reported adverse reactions in the Poteligeo arm were infusion-related reaction (33.2%), drug eruption (22.8%), fatigue (18.5%), and diarrhea (10.3%). Moderate to severe adverse reactions included infusion-related reaction (1.6%) and drug eruption (4.3%). Two possible adverse reactions leading to death were sepsis and polymyositis.
Adverse events of special interest included infusion-related reactions, infections, dermatologic toxicity, autoimmune complications, stress cardiomyopathy, and graft-versus-host disease in allogeneic hematopoietic stem cell transplantation. In scientific and medical literature, cytomegalovirus and hepatitis were identified as potential risks associated with Poteligeo.
The duration of exposure between the Poteligeo crossover arm and the Poteligeo arm was comparable. However, the incidences of adverse reactions (72.8% vs. 84.8%), moderate to severe adverse reactions (15.4% vs. 25.5%), adverse reactions leading to death (0% vs. 1.1%), and serious adverse reactions (10.3% vs. 19.6%) were numerically lower in the crossover arm compared to the Poteligeo arm. No reason was identified to account for the differences in the incidences between the two Poteligeo arms.
Treatment with any therapeutic protein is accompanied by the risk of immunogenicity, i.e., the development of anti-drug antibodies, which have the potential to neutralize the biological activity of the drug. Among the 263 patients in Study 0761-010 with evaluable data, 37 (14.1%) tested positive for treatment-emergent (treatment-induced or treatment-boosted) anti-mogamulizumab antibodies detected by an electrochemiluminescent assay. There were no positive neutralizing antibody responses.
Supportive Studies
KW-0761-001
Study KW-0761-001 was an open-label, multicentre, dose-escalation Phase I/II study evaluating Poteligeo as monotherapy in patients with previously treated peripheral T‑cell lymphoma or cutaneous T‑cell lymphoma. Of the 42 patients enrolled, 22 patients were diagnosed with MF, 19 patients were diagnosed with SS, and 1 patient was diagnosed with peripheral T‑cell lymphoma. During the Phase I dose escalation, no dose-limiting toxicities or discontinuations were reported, and Poteligeo was tolerated up to and including 1.0 mg/kg by intravenous administration once per week. This study supported the safety of Poteligeo at the dosage regimen evaluated in Study 0761-010.
Nearly all patients (97.6%) included in the safety analysis set experienced a TEAE. Drug-related TEAEs were reported in 33 patients (78.6%) with the most common being nausea, infusion-related reaction, pyrexia, headache, and drug eruption. The majority (76.2%) of patients experienced mild to moderate TEAEs. Three deaths were reported; two resulting from disease progression and one resulting from bronchopneumonia. These deaths were not considered by the investigators to be related to the study drug; however, the death as a result from bronchopneumonia is associated with infection, a known risk associated with mogamulizumab treatment. The immunogenicity of Poteligeo was low in the study, with only one patient testing positive for anti-drug antibodies in screening and confirmatory assays. No neutralizing anti-drug antibodies were detected.
0761-004, 0761-007, and 0761-009
Studies 0761-004 (n = 37), 0761-007 (n = 38), and 0761-009 (n = 71) were Phase II studies performed to support the safety of Poteligeo. The dosing regimen used for studies 0761-007 and 0761-009 was the same as the recommended regimen for the administration of Poteligeo (1.0mg/kg by intravenous administration once a week for 4 weeks followed by every 2 weeks in subsequent cycles until disease progression). Study 0761-004 had a dosing regimen of 1.0 mg/kg by intravenous administration once a week for 8 weeks.
In studies 0761-004, 0761-007, and 0761-009, TEAEs were observed in 97.3%, 97.4%, and 97.9% of patients, respectively.
Overall, the safety profile from these supportive studies is consistent with the pivotal study (Study 0761-010).
Appropriate warnings and precautions are in place in the approved Poteligeo Product Monograph to address the identified safety concerns.
For more information, refer to the Poteligeo Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Mogamulizumab, the medicinal ingredient in Poteligeo, was evaluated in cynomolgus monkeys using single- and repeat-dose toxicity studies of up to 26 weeks and a reproductive and developmental toxicity study to evaluate effects on embryo-fetal development. No adverse effects were observed at doses of up to 40 mg/kg/week. The no-observed-adverse-effect level (NOAEL) exposures ranged from 26.9-fold higher (in pregnant dams) to 94.6-fold higher (in single- and repeat-dose toxicity studies) than the exposures in subjects administered mogamulizumab at the recommended clinical dose of 1.0 mg/kg.
In fetuses, plasma concentrations at the end of the study were approximately 60% of that measured in dams. This indicates that mogamulizumab readily crosses the placenta, similarly to endogenous immunoglobulin G4 (IgG4).
Anti-mogamulizumab antibodies were detected in some animals receiving a single- or repeat-dose intravenous injection of mogamulizumab. In animals in which anti-mogamulizumab antibodies were observed, plasma mogamulizumab concentrations decreased more rapidly than the plasma concentration in animals that did not develop anti-mogamulizumab antibodies. No anti-mogamulizumab antibody-related toxicological findings were noted in the animals in which the production of anti-mogamulizumab antibodies occurred.
Based on observations of skin-related side effects in human patients treated with mogamulizumab, weekly doses of mogamulizumab were administered for up to 8 weeks in aged female cynomolgus monkeys. No clear relationship was observed between the development of mild dermatitis and changes in lymphocyte subsets.
Mogamulizumab did not bind to platelets, induce platelet aggregation, or result in platelet reduction in the whole blood. Mogamulizumab induced cytokine release from human whole blood and human peripheral blood mononuclear cells. While this is unlikely to pose a risk to humans in terms of effects on platelet count or function, it does have the potential to lead to cytokine release which could manifest in the clinical setting.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Poteligeo Product Monograph. In view of the intended use of Poteligeo, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Poteligeo Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
Characterization of the Drug Substance
Detailed characterization studies were performed to provide assurance that mogamulizumab, the medicinal ingredient in Poteligeo, consistently exhibits the desired characteristic structure and biological activity.
The drug substance manufacturing process has been optimized and scaled up during development. The process changes introduced at each generation of the process were adequately described and comparatively addressed. Lot release, stability, and characterization data have also been used to support the comparability assessment.
Manufacturing Process of the Drug Substance and Drug Product and Process Controls
The mogamulizumab drug substance is manufactured using a two-tiered cell banking system. The master and working cell banks are derived from a Chinese hamster ovary parental cell line. The manufacturing process for the drug substance is initiated with the thawing of working cell bank cells which are then expanded and used to inoculate the production bioreactor that is operated in fed-batch mode. Following the production bioreactor step, the cell culture fluid is harvested, centrifuged, clarified, and further processed using a series of chromatographic viral inactivation/removal steps. The resulting solution is concentrated prior to being filtered, dispensed into Teflon bottles, and stored frozen.
Performance validation and ancillary studies have shown that the manufacturing process is capable of consistently manufacturing the drug substance. All results from process parameters, in-process controls, and release testing have met their acceptance criteria.
Poteligeo is supplied as a single-use, sterile, preservative-free solution (4 mg mogamulizumab/mL) for intravenous infusion. The single-use 10 mL glass vial presentation contains 5 mL of solution.
The Poteligeo drug product manufacturing process consists of seven steps: drug substance thawing, formulation, sterile filtration, filling into vials, stoppering and capping with an aluminum seal, visual inspection, and labeling and packaging.
In-process controls and lot release tests for the drug product were established and validated, and demonstrated that the manufacturing process can consistently produce drug product that meets all critical quality attributes and release specifications.
None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of mogamulizumab with the excipients is supported by the stability data provided.
Control of the Drug Substance and Drug Product
An appropriate control strategy has been established, which includes in-process controls and parameters, control of raw materials, and specifications. This control strategy is expected to ensure the consistent production of high quality drug product and drug substance. The Poteligeo specifications were harmonized with those agreed on by the United States Food and Drug Administration and include validated assays for identity, quantity, purity, potency, impurities, and safety. The non-compendial analytical methods were validated according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines at the appropriate testing facilities, and the compendial methods were qualified in compliance with the respective Pharmacopeia (European Pharmacopoeia, United States Pharmacopeia, and Japan Pharmacopoeia). A two-tiered reference standard program has been established. Renewal working cell banks will be prepared and qualified in accordance with the qualification protocol provided as part of the New Drug Submission review package.
Poteligeo is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the 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 of 36 months is acceptable when the drug product is stored at 5 ± 3 ºC and protected from light. The in-use shelf life for Poteligeo diluted with normal saline in an infusion bag is no more than 24 hours when stored at 5 ± 3 ºC.
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 the production are considered suitable for the activities and products manufactured.
Based on risk assessment scores determined by Health Canada, on-site evaluations of the drug substance and drug product manufacturing facilities were not deemed necessary.
Adventitious Agents Safety Evaluation
The 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.
None of the excipients used in the production of Poteligeo drug substance or drug product are of human or animal origin.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| POTELIGEO | 02527715 | KYOWA KIRIN, INC. | MOGAMULIZUMAB 4 MG / ML |