Summary Basis of Decision for Padcev

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 Padcev is located below.

Recent Activity for Padcev

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 Padcev

Date SBD issued: 2022-02-04

The following information relates to the new drug submission for Padcev.

Enfortumab vedotin

Drug Identification Number (DIN):

  • DIN 02521903 - enfortumab vedotin 20 mg per vial, powder for solution, intravenous administration
  • DIN 02521911 - enfortumab vedotin 30 mg per vial, powder for solution, intravenous administration

Seagen Inc.

New Drug Submission Control Number: 251438

On October 29, 2021, Health Canada issued a Notice of Compliance to Seagen Inc. for the drug product Padcev.

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 Padcev is favourable for the treatment of adult patients with unresectable locally advanced or metastatic urothelial cancer who have previously received a platinum-containing chemotherapy and programmed death receptor‑1 (PD‑1) or programmed death‑ligand 1 (PD‑L1) inhibitor therapy.

1 What was approved?

Padcev, an antineoplastic agent, was authorized for the treatment of adult patients with unresectable locally advanced or metastatic urothelial cancer who have previously received a platinum-containing chemotherapy and programmed death receptor‑1 (PD‑1) or programmed death‑ligand 1 (PD‑L1) inhibitor therapy.

No data are available to Health Canada regarding the use of Padcev in patients younger than 18 years of age. Consequently, an indication for pediatric use has not been authorized.

Of the 748 patients treated with Padcev in clinical trials, 449 (60%) were 65 years of age or older and 142 (19%) were 75 years of age or older. No clinically relevant differences in the efficacy of Padcev were observed between these patients and those younger than 65 years of age. Evidence from clinical studies suggests the use of Padcev in the geriatric population may be associated with differences in safety when compared to the population younger than 65 years of age.

Padcev (20 mg and 30 mg of enfortumab vedotin) is presented as a powder for solution supplied in a single-dose vial. In addition to the medicinal ingredient, the powder contains histidine, histidine hydrochloride monohydrate, polysorbate 20, and trehalose dihydrate.

The use of Padcev 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.

Padcev was approved for use under the conditions stated in its product monograph taking into consideration the potential risks associated with its administration. The Padcev 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 Padcev approved?

Health Canada considers that the benefit-risk profile of Padcev is favourable for the treatment of adult patients with unresectable locally advanced or metastatic urothelial cancer who have previously received a platinum-containing chemotherapy and programmed death receptor‑1 (PD‑1) or programmed death‑ligand 1 (PD‑L1) inhibitor therapy.

Urothelial cancer can arise anywhere in the urinary tract, including the renal pelvis, ureter, bladder, and urethra, but it is usually found in the bladder. Bladder cancer occurs more commonly in men than in women and its incidence increases with age. Locally advanced or metastatic urothelial cancer is present in approximately 15% of patients at the time of diagnosis, leading to poor prognostic outcomes for these patients. Therapeutic options are limited for patients whose disease progresses despite platinum-based chemotherapy and especially for patients whose disease progresses despite both chemotherapy and immunotherapy.

Enfortumab vedotin, the medicinal ingredient in Padcev, is an antibody-drug conjugate directed against nectin‑4, an adhesion protein located on the surface of most urothelial cancer cells. The antibody-drug conjugate consists of a fully human immunoglobulin G1-kappa (IgG1-kappa) monoclonal antibody conjugated to the microtubule-disrupting agent, monomethyl auristatin E (MMAE), via a protease-cleavable linker. Non-clinical data suggest that the anticancer activity of enfortumab vedotin is due to its binding to nectin‑4‑expressing cells, followed by internalization of the conjugate‑nectin‑4 complex, and the release of MMAE via proteolytic cleavage. The released MMAE disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptotic cell death.

The market authorization of Padcev was based on the efficacy and safety results derived from one pivotal, randomized, open-label Phase III clinical trial, EV‑301, conducted in adult patients with unresectable locally advanced or metastatic urothelial cancer who had previously received a platinum-containing chemotherapy and PD‑1 or PD‑L1 inhibitor therapy. Patients received either Padcev (1.25 mg/kg on days 1, 8 and 15 of each 28‑day cycle) (number of patients [n] = 301) or a chemotherapy agent (docetaxel, paclitaxel or vinflunine, on the first day of every 21‑day cycle) (n = 307).

The primary efficacy endpoint of the trial was overall survival. At a preplanned interim analysis, the prespecified efficacy boundary for overall survival was crossed and the EV‑301 trial was stopped on the recommendation of an independent data monitoring committee because of the observed overall survival benefit in favour of Padcev. The results demonstrated that overall survival in the Padcev arm was statistically significantly improved compared to the chemotherapy arm, with a hazard ratio of 0.70 (95% confidence interval [CI]: 0.56, 0.89; one-sided p = 0.0014) and a median overall survival benefit of 3.9 months (12.9 months [95% CI: 10.6, 15.2] versus 9.0 months [95% CI: 8.1, 10.7]).

In the pivotal trial, 296 patients received at least one dose of Padcev. Serious adverse events, regardless of causality, occurred in 47% (139/296) of patients treated with Padcev. Adverse events resulting in death, regardless of causality, occurred in 7% (21/296) of patients, and included malignant neoplasm progression (3%), multiple organ dysfunction syndrome (1%), pneumonia (0.7%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis, and pelvic abscess (0.3% each). Adverse events leading to discontinuation were reported in 17% of patients, while adverse events leading to dose interruption and dose reduction were observed in 61% and 34% of patients, respectively.

The risks of hyperglycemia, peripheral neuropathy, pneumonitis, ocular disorders, and skin reactions following infusion site extravasation have been included in the Warnings and Precautions section of the Padcev Product Monograph. Notably, severe cutaneous adverse reactions, including fatalities, were reported during the post-approval use of Padcev in the United States. Consequently, a Serious Warnings and Precautions Box highlights the reported occurrences of severe cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, with fatal outcomes. Also included in this box is a warning about the occurrences of hyperglycemia and diabetic ketoacidosis, including fatal events, that have been reported in patients with and without pre-existing diabetes mellitus.

A Risk Management Plan (RMP) for Padcev was submitted by Seagen Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

The submitted inner and outer labels, package insert, and Patient Medication Information section of the Padcev 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 Padcev was accepted.

Overall, the safety profile of Padcev is considered acceptable for the intended patient population. The identified safety issues can be managed through labelling, adequate monitoring, and dose modifications. Appropriate warnings and precautions are in place in the Padcev 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 Padcev?

The sponsor requested a priority review status for the New Drug Submission for Padcev. Following review of the information in the submitted clinical assessment package, Health Canada determined that the sponsor’s request fulfilled the criteria set out in the Priority Review Policy. Specifically, sufficient information was provided to conclude that locally advanced or metastatic urothelial cancer represents a serious, life-threatening and severely debilitating disease, and that the overall benefit-risk profile of Padcev is improved over the existing therapies for this disease.

Additionally, the sponsor requested participation in the Project Orbis, an initiative of the United States Food and Drug Administration (FDA) Oncology Center of Excellence. The project is an international partnership of drug regulatory agencies designed to give cancer patients faster access to promising cancer treatments. It provides a framework for concurrent submission and review of oncology products among international partners. The submission for Padcev was classified as a Project Orbis Type B (Modified Orbis) submission. This type of Project Orbis submissions refers to marketing applications submitted to Project Orbis partners more than 30 days after filing with the FDA and it allows Project Orbis partners to receive FDA review reports, exchange or receive requests for clarification, and observe and participate in some multicountry meetings.

During the review, Health Canada collaborated with the FDA and Australia’s Therapeutic Goods Administration. The Canadian regulatory decision on the Padcev submission was made independently and was based on a critical assessment of the data package submitted to Health Canada.

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

Submission Milestones: Padcev

Submission MilestoneDate
Pre-submission meeting2021-01-11
Request for priority status filed2021-01-19
Request for priority status accepted by Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics2021-02-17
New Drug Submission filed2021-04-06
Screening
Screening Acceptance Letter issued2021-05-06
Review
Review of Risk Management Plan completed2021-10-01
Non-clinical evaluation completed2021-10-22
Quality evaluation completed2021-10-25
Labelling review completed2021-10-27
Clinical/medical evaluation completed2021-10-28
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate2021-10-29

4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

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

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.

At this time, no PAAT is available for Padcev. When available, the PAAT will be incorporated into this SBD.

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

Enfortumab vedotin, the medicinal ingredient in Padcev, is an antibody-drug conjugate directed against nectin‑4, an adhesion protein located on the surface of most urothelial cancer cells. The antibody-drug conjugate consists of a fully human immunoglobulin G1-kappa (IgG1-kappa) monoclonal antibody conjugated to the microtubule-disrupting agent, monomethyl auristatin E (MMAE), via a protease-cleavable linker. Upon binding to nectin‑4, enfortumab vedotin is internalized and the linker is cleaved by lysosomal proteases, leading to the intracellular release of MMAE. The released MMAE binds to microtubules and kills dividing cells by inhibiting cell division and inducing apoptosis.

The clinical pharmacology profile of enfortumab vedotin was characterized based on data derived from Phase I, II, and III clinical studies, and a validated modelling and simulation analysis. A stand-alone pharmacokinetic study was not conducted. In patients with locally advanced or metastatic urothelial carcinoma, a dose-dependent increase in exposure for both enfortumab vedotin and the MMAE payload was demonstrated at enfortumab vedotin doses ranging from 0.5 mg/kg to 1.25 mg/kg administered as an intravenous infusion over 30 minutes on days 1, 8, and 15 of a 28-day cycle.

Based on the data provided, the mean values (± standard deviation [SD]) for maximum plasma concentration (Cmax) of enfortumab vedotin and MMAE were 28 (± 6.1) µg/mL and 5.5 (± 3.0) ng/mL, respectively. The area under the concentration-time curve from time zero to 28 days (AUC0 -28d) was determined to be 110 (± 26) µg·d/mL for enfortumab vedotin and 85 (± 50) ng·d/mL for MMAE. In addition, the derived median time to reach maximum plasma concentration (tmax) for enfortumab vedotin ranged from 0.53 hours to 1.06 hours. As the MMAE is released following proteolytic cleavage of the antibody-drug conjugate, the median tmax for MMAE ranged from 24.50 hours to 67.68 hours. Moreover, at the proposed 1.25 mg/kg dose (up to a maximum of 125 mg for patients weighing 100 kg and over) administered as an intravenous infusion over 30 minutes on days 1, 8, and 15 of a 28-day cycle, minimal intracycle accumulation was observed not only for enfortumab vedotin but also for MMAE. Therefore, given that no significant intracycle accumulation was observed in pharmacokinetic analyses, the proposed weight-based dosing regimen for Padcev is considered acceptable.

The sponsor further characterized the effect of various covariates on the pharmacokinetic parameters of enfortumab vedotin. Data from population pharmacokinetic analyses showed that race and age (range: 24 to 90 years), as covariates, did not have a clinically meaningful impact on the pharmacokinetic parameters of enfortumab vedotin. In addition, there was no significant effect of renal impairment on exposure to the antibody‑drug conjugate or MMAE in patients with mild, moderate or severe renal impairment following administration of 1.25 mg/kg of enfortumab vedotin. These data suggest that dose adjustment is not required in patients with renal insufficiency.

However, available data showed that mild hepatic impairment resulted in a 37% increase in exposure to unconjugated MMAE, which was associated with an increased incidence of serious treatment-emergent adverse events. These events were experienced by 53.6% of patients with mild hepatic impairment versus 45.3% of patients with normal hepatic function. There are insufficient data to characterize the impact of moderate or severe hepatic impairment on exposure to enfortumab vedotin or MMAE in patients treated with Padcev. As patients with moderate or severe hepatic impairment are likely to have increased exposure to MMAE, the use of Padcev in these patients should be avoided.

While drug-drug interaction studies have not been conducted with enfortumab vedotin, previously conducted drug-drug interaction studies with a similar antibody-drug conjugate, brentuximab vedotin (containing the same vedotin payload), demonstrated that exposure to MMAE is increased following concomitant administration with inhibitors of cytochrome P450 (CYP) 3A4/5 enzymes, e.g., ketoconazole. Therefore, given the same MMAE payload in enfortumab vedotin, concomitant administration of Padcev with ketoconazole may increase MMAE concentrations after proteolytic cleavage of the antibody-drug conjugate. These increased MMAE levels may be associated with increased rates and severity of adverse events following the administration of Padcev. Therefore, close monitoring of patients may be necessary to mitigate occurrences of serious adverse events when Padcev is administered concomitantly with any CYP3A4 inhibitory agent.

Any antibody therapy has the potential for inducing an immunogenic response. Data provided showed the formation of anti-drug antibody (ADA) in a low percentage (2%) of exposed subjects.

The sponsor also evaluated the effect of enfortumab vedotin infusion on the duration of cardiac ventricular repolarization. Administration of enfortumab vedotin (up to 1.25 mg/kg) did not result in a clinically meaningful prolongation (i.e., over 20 ms) of the QT interval corrected for heart rate according to the Fridericia formula (QTcF).

In addition, the clinical response to enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer was assessed in relation to the expression level of nectin‑4 in the tumour samples. Notably, clinical responses to enfortumab vedotin were observed in patients irrespective of the presence of high or low levels of nectin‑4 expression. These results suggest that patient selection for treatment with enfortumab vedotin based on nectin‑4 expression levels is not warranted.

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

Clinical Efficacy

The clinical efficacy of Padcev was evaluated in EV‑301, a randomized, open-label, multicentre Phase III trial of Padcev versus chemotherapy in adult patients with inoperable locally advanced or metastatic urothelial cancer previously treated with both platinum-based chemotherapy and immunotherapy (a programmed death receptor‑1 [PD‑1] or programmed death‑ligand 1 [PD‑L1] inhibitor). The chemotherapy agent used in the comparator arm was docetaxel, paclitaxel or vinflunine (which is not currently authorized for use in Canada).

Randomization (1:1) was stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1), regions (Western Europe versus the United States versus the rest of the world) and liver metastasis (Yes versus No).

Patients received intravenous infusions of either Padcev (1.25 mg/kg on days 1, 8 and 15 of each 28-day cycle) (number of patients [n] = 301) or chemotherapy (docetaxel, paclitaxel or vinflunine on the first day of every 21-day cycle) (n = 307). In the comparator arm, the chemotherapies were administered as follows:

  1. docetaxel at 75 mg/m2 on the first day of every 21-day cycle, or
  2. paclitaxel at 175 mg/m2 on the first day of every 21-day cycle, or
  3. vinflunine at 320 mg/m2 on the first day of every 21-day cycle.

Study participants (n = 608) were treated until death, disease progression, discontinuation due to adverse events or withdrawal of consent. All patients were assessed by computed tomography (CT) and/or magnetic resonance imaging (MRI) and/or bone scintillation for response (using Response Evaluation Criteria in Solid Tumours version 1.1 [RECIST v1.1]) starting at baseline and every 56 days. The conduct and safety of the study were overseen by an independent data monitoring committee.

The study arms were balanced in terms of region, age distribution, race, disease histology type, metastasis, and prior therapies. The study population was predominantly male (77.3%) with a median age of 68.0 years, which is representative of the patient population with advanced urothelial cancer. An area of potential uncertainty pertains to race, since the majority of patients were White (52%) or Asian (33%) and only 0.7% were Black.

The primary efficacy endpoint of EV‑301 was overall survival. Secondary endpoints included progression-free survival, overall response rate, duration of response, and disease control rate, all assessed by investigator as per RECIST v1.1. At a preplanned interim analysis, the prespecified efficacy boundary for overall survival was crossed with a median follow-up of 11.1 months. On the recommendation of the independent data monitoring committee, the EV‑301 trial was stopped because of the observed overall survival benefit in favour of Padcev.

The results demonstrated that overall survival in the Padcev arm was statistically significantly improved compared to the chemotherapy arm, with a hazard ratio (HR) of 0.70 (95% confidence interval [CI]: 0.56, 0.89; one-sided p = 0.0014) and a median overall survival benefit of 3.9 months (12.9 months [95% CI: 10.6, 15.2] versus 9.0 months [95% CI: 8.1, 10.7]). Progression-free survival was also statistically significantly improved in comparison to the chemotherapy arm (HR = 0.62; 95% CI: 0.51, 0.75; p<0.0001) with the median progression-free survival benefit of 1.9 months (5.6 months [95% CI: 5.3, 5.8] compared to 3.7 months [95% CI: 3.5, 3.9]). Of note, in the Padcev arm, the overall response rate was 40.6% (95% CI: 34.9, 46.5) compared to 17.9% [95% CI: 13.7, 22.8) in the chemotherapy arm (p<0.001). The efficacy results were consistent across all of the stratified patient subgroups. Overall, these results are clinically significant in this target population.

Indication

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

  • Padcev (enfortumab vedotin) is indicated for the treatment of patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor‑1 (PD‑1) or programmed death‑ligand 1 (PD‑L1) inhibitor and who:
    • have received a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting or
    • are not eligible for cisplatin-containing chemotherapy

Upon review of the submitted information, Health Canada approved the following indication:

  • Padcev (enfortumab vedotin for injection) is indicated for the treatment of adult patients with unresectable locally advanced or metastatic urothelial cancer who have previously received a platinum-containing chemotherapy and programmed death receptor‑1 (PD‑1) or programmed death‑ligand 1 (PD‑L1) inhibitor therapy.

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

Clinical Safety

The characterization of the safety profile of Padcev was primarily based on data derived from the pivotal clinical trial EV‑301 (described in the Clinical Efficacy section). In the trial, 296 patients received at least one dose of Padcev. The median duration of exposure to Padcev was 5 months (range: 0.5 to 19.4 months) and the median duration of exposure to chemotherapy was 3.5 months (range: 0.2 to 15 months).

The most commonly reported treatment-emergent adverse events (in over 10% of patients treated with Padcev) included: alopecia, decreased appetite, fatigue, diarrhea, peripheral sensory neuropathy, pruritus, nausea, constipation, dysgeusia, pyrexia, anemia, dry skin, maculopapular rash, decreased weight, asthenia, musculoskeletal pain, abdominal pain, vomiting, increased aspartate aminotransferase, hematuria, urinary tract infection, decreased neutrophil count, hyperglycemia, insomnia, dry eye, and increased lacrimation.

Serious adverse events, regardless of causality, occurred in 47% (139/296) of patients treated with Padcev. Adverse events resulting in death, regardless of causality, occurred in 7% (21/296) of patients and included malignant neoplasm progression (3%), multiple organ dysfunction syndrome (1%), pneumonia (0.7%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis, and pelvic abscess (0.3% each). Adverse events leading to discontinuation were reported in 17% of patients, while adverse events leading to dose interruption and dose reduction were observed in 61% and 34% of patients, respectively.

The risks of hyperglycemia, peripheral neuropathy, pneumonitis, ocular disorders, and skin reactions following infusion site extravasation have been included in the Warnings and Precautions section of the Padcev Product Monograph. Notably, severe cutaneous adverse reactions, including fatalities, were reported during the post-approval use of Padcev in the United States. Therefore, a Serious Warnings and Precautions Box underscores the reported occurrences of severe cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, with fatal outcomes. Also included in this box is a warning about the occurrences of hyperglycemia and diabetic ketoacidosis, including fatal events, that have been reported in patients with and without pre-existing diabetes mellitus.

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

7.2 Non-Clinical Basis for Decision

Enfortumab vedotin, the medicinal ingredient in Padcev, is an antibody-drug conjugate (ADC), composed of a human anti‑nectin‑4 antibody linked to the cytotoxic microtubule-disrupting agent monomethyl auristatin E (MMAE).

The non-clinical data submitted for Padcev included the results of various studies undertaken to elucidate the mechanism of action, pharmacodynamics, pharmacology, and toxicology of enfortumab vedotin.

The expression of the transmembrane adhesion protein nectin‑4 was demonstrated in a variety of human cancer tissues including urothelial, breast, lung, pancreatic, and ovarian cancer. Binding of the ADC to nectin‑4 on the tumour cell surface was shown to initiate internalization of the ADC‑nectin‑4 complex, followed by trafficking to the lysosomal compartment and release of MMAE via proteolytic cleavage of the linker. The released MMAE was reported to disrupt tubulin polymerization, resulting in G2/M cell cycle arrest and apoptosis of tumour cells. Binding of enfortumab vedotin to target cells mediated antibody-dependent cellular phagocytosis but did not trigger antibody-dependent cytotoxicity or complement-dependent cytotoxicity.

In vivo, AGS-22M6E (a hybridoma-derived ADC, biologically equivalent to enfortumab vedotin) exhibited antitumour activity in patient-derived bladder cancer cell xenografts AG-B1 and AG-B8 in severe combined immunodeficient (SCID) mice, resulting in over 75% tumour growth inhibition.

The metabolism of MMAE depends primarily on cytochrome P450 (CYP) enzymes. In vitro, in cultured rat, monkey, and human hepatocytes, the metabolism of MMAE was found to be similar. Additionally, MMAE was shown to inhibit CYP3A4/5, but it did not induce CYP1A2, CYP2B6, or CYP3A4/5 enzymes.

Monomethyl auristatin E was genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism. This effect is consistent with the pharmacological effect of MMAE as a microtubule-disrupting agent.

Loss of human pancreatic islet viability was reported following incubation with MMAE under high glucose conditions at concentrations lower than the maximum observed concentration (Cmax) at the recommended clinical dose of enfortumab vedotin.

Repeat-dose toxicity studies with recovery periods were conducted in rats (up to 13 weeks) and in monkeys (up to 4 weeks). The studies showed comparable toxicity profiles in the two species. Mortality was observed in both rats and monkeys at exposure levels that were at least 6-fold higher than the human exposure at the recommended clinical dose. The main target organs of toxicity in both species were skin (including injection site), bone marrow, liver, and eye. Additional target organs of toxicity reported only in rats included sex organs (testis, epididymis, and mammary gland). Gastrointestinal tract toxicity was only observed in monkeys.

A 4-week study in rats assessing the testicular toxicity of enfortumab vedotin found decreased testes and epididymis weights at the end of the dosing period, along with spermatocyte depletion and the presence of cell debris in the epididymis. The male organ toxicity did not reverse during the study.

Enfortumab vedotin was found to be a teratogen. In rats, the administration of doses leading to exposures comparable to the clinical exposure at the recommended dose induced maternal toxicity and embryo-fetal lethality as well as structural malformations and skeletal abnormalities in the embryos.

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

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

7.3 Quality Basis for Decision

Characterization of the Drug Substance

The drug substance, enfortumab vedotin, is an antibody-drug conjugate. It is composed of an anti‑nectin‑4 fully human immunoglobulin G1-kappa (IgG1-kappa) monoclonal antibody (AGS‑22C3) conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker, maleimidocaproyl valine-citrulline (vc).

Detailed characterization studies were performed to provide assurance that the drug substance 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

Drug Substance

Enfortumab vedotin is produced by chemical conjugation of the monoclonal antibody intermediate AGS‑22C3 to the drug-linker intermediate SGD‑1006 (vcMMAE) at an average drug-to-antibody ratio of approximately four.

The commercial manufacturing process of the monoclonal antibody intermediate starts with the thawing of a vial of working cell bank of a Chinese hamster ovary (CHO) cell line genetically engineered to express the AGS‑22C3. Cell numbers are increased successively in shake flasks, culture bags, and seed bioreactors, prior to the initiation of production culture and expression of the recombinant protein in a production bioreactor. The cell culture fluid is clarified through depth filtration, and the monoclonal antibody is captured and purified by chromatography steps, followed by viral removal and inactivation steps. The final monoclonal antibody bulk solution is filtered through a bioburden reduction filter into high-density polyethylene (HDPE) bottles and stored at or below -60 °C.

The AGS‑22C3 manufacturing process was successfully validated through the manufacture of three consecutive batches. Data provided by the sponsor indicate that all predefined action ranges and acceptance criteria were met for all process parameters and controls. All release and stability specifications were met, demonstrating that the manufacturing process at the proposed facility is capable of consistently manufacturing AGS‑22C3 of appropriate quality. All additional validation studies (e.g., studies of process hold times, studies of extractables and leachables) were appropriately conducted, and found acceptable.

The drug-linker SGD‑1006 (also known as vcMMAE and vedotin) is a commercial-grade synthetic small molecule, which is used as the drug-linker intermediate for further processing into vedotin-containing antibody-drug conjugates. The release specification for SGD‑1006 drug-linker intermediate constitutes one critical element of the overall control strategy implemented to ensure product quality and consistency. The tests and acceptance criteria chosen to confirm the quality of SGD‑1006 are consistent with the principles and guidance outlined in the relevant International Council for Harmonisation (ICH) guideline.

For manufacturing of the drug substance, the monoclonal antibody intermediate is thawed and mixed if more than one batch is to be used. After pH adjustment, a reducing agent is added to initiate reduction of the monoclonal antibody. Reduced AGS‑22C3 is then mixed with SGD‑1006. The conjugation reaction is stopped after a specified time, and the resulting conjugate is purified through a series of filtration steps. The drug substance is formulated, filtered, filled into polycarbonate bottles, and stored at or below -60 °C.

The drug substance manufacturing process was validated through the production of three consecutive batches. All predefined acceptance criteria and ranges for process parameters and controls, and specifications for release and stability testing, were met for all three batches, demonstrating that the manufacturing process can consistently generate enfortumab vedotin drug substance of sufficient quality.

Drug Product

The drug substance is thawed, pooled (if necessary), and mixed. After mixing, the bulk drug product is sterilized by filtration, filled into glass vials, and lyophilized. The drug product undergoes 100% visual inspection, and acceptable quality limit testing is performed for each lot. Vials are stored at 2 °C to 8 °C.

Validation of the drug product manufacturing process was performed by the manufacture of three consecutive drug product lots (one 20 mg/vial lot and two 30 mg/vial lots). All predefined limits and acceptance criteria for process parameters and controls were met, and all results for release and stability testing were within specifications. This demonstrates that the proposed drug product manufacturing process is able to consistently manufacture enfortumab vedotin drug product (20 mg/vial and 30 mg/vial) of acceptable quality. Media fill studies support the proposed maximum aseptic processing time.

A multi-level control strategy as part of the overall process performance and product quality monitoring system assures consistent manufacture of an acceptable product and mitigates risk of failures in the process performance.

Control of the Drug Substance and Drug Product

All in-house analytical methods were appropriately validated in accordance with the relevant ICH guideline. The validation data support the release and stability specifications for the critical quality attributes of the antibody intermediate, drug substance, and drug product.

The reference standards have been well characterized and an appropriate program is in place to qualify new primary and working reference materials in the future.

Each specification considers historical release and stability batch data, clinical experience, manufacturing capability, assay variability, regulatory expectations, and compendial requirements for protein-based products, where appropriate. The justifications for the acceptance criteria are based on the release and long-term stability data from antibody intermediate, drug substance or drug product lots, which are representative of the commercial process. All release and stability acceptance criteria were met for the antibody intermediate, drug substance, and drug product.

Padcev is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program as per Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs. Health Canada conducted testing of three manufactured lots of Padcev using a subset of release methods. All consistency test results were similar to those indicated on the certificates of analysis.

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 stability data support the proposed shelf life of 36 months for the drug product, when stored at 2 °C to 8 °C.

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

An on-site evaluation of the facility that manufactures the monoclonal antibody intermediate was recommended as per the risk assessment score determined by Health Canada. However, it could not be performed due to the coronavirus disease 2019 (COVID‑19) pandemic and travel restrictions at the time of the submission review. To mitigate the risk of not conducting an on-site evaluation of this facility, Health Canada reviewed the pre-license inspection reports prepared by the United States Food and Drug Administration and provided through the Project Orbis.

Based on risk assessment scores, on-site evaluations for the drug substance and drug product manufacturing sites were not deemed necessary.

Overall, the design, operations, and controls of the facilities and equipment involved in the production are considered suitable for the activities and products manufactured. The production sites are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The drug substance manufacturing process incorporates adequate control measures to ensure freedom from adventitious microorganisms (bacteria, fungi, mycoplasma, and viruses). Purification process steps designed to remove and inactivate any potential viral contaminants from the cell culture process are adequately validated.

Materials of biological origin are properly sourced and tested. Accordingly, the risk of contamination of the drug product with bovine spongiform encephalopathy and transmissible spongiform encephalopathy agents is considered negligible.

No excipients of human or animal origin are used in the formulation of Padcev.

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