Summary Basis of Decision for Entyvio
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 Entyvio is located below.
Recent Activity for Entyvio
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.
Post-Authorization Activity Table (PAAT) for Entyvio
Updated: 2024-06-11
The following table describes post-authorization activity for Entyvio, a product which contains the medicinal ingredient vedolizumab. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).
For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.
Drug Identification Number (DIN):
DIN 02436841 - 300 mg/vial, vedolizumab powder for solution, intravenous administration
DIN 02497867 - 108 mg/0.68 mL, vedolizumab, solution, subcutaneous administration, single-use pre-filled pen
DIN 02497875 - 108 mg/0.68 mL, vedolizumab, solution, subcutaneous administration, single-use pre-filled syringe
Post-Authorization Activity Table (PAAT)
|
Activity/Submission Type, Control Number |
Date Submitted |
Decision and Date |
Summary of Activities |
|
SNDS # 278897 |
2023-09-06 |
Issued NOC 2024-04-23 |
Submission filed as a Level I – Supplement to update the drug substance manufacturing process involving changes to the cell banks. The submission was reviewed and considered acceptable, and an NOC was issued. |
|
SNDS # 284745 |
2024-03-07 |
Cancellation Letter Received 2024-04-05 |
Submission filed as a Level II – Supplement (Safety) to update the PM. The changes were not in scope of a Level II SNDS but were considered to be Level I changes. The sponsor cancelled the submission administratively. |
|
NC # 283002 |
2024-01-22 |
Issued NOL 2024-03-22 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the cell banks. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
SNDS # 276382 |
2023-06-21 |
Issued NOC 2023-11-17 |
Submission filed as a Level II – Supplement (Safety) to revise text in the PM. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Storage, Stability and Disposal, section of the PM and to Part III: Patient Medication Information. An NOC was issued. |
|
NC # 275465 |
2023-05-17 |
Issued NOL 2023-09-14 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add an alternate drug substance manufacturing site. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
SNDS # 254300 |
2021-06-29 |
Issued NOC 2022-07-06 |
Submission filed as a Level I – Supplement for a change in dosing frequency. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Dosage and Administration section of the PM. An NOC was issued. |
|
NC # 264010 |
2022-05-12 |
Issued NOL 2022-07-04 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the shelf-life for the drug substance or for a stored intermediate of the drug substance and a change to reference standard qualification protocol. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
SNDS # 251229 |
2021-03-30 |
Issued NOC 2022-06-08 |
Submission filed as a Level I – Supplement to update the PM with new information, and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Adverse Reactions; Clinical Pharmacology; and Clinical Trials sections of the PM. An NOC was issued. |
|
NC # 259740 |
2021-12-29 |
Issued NOL 2022-02-24 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process. The submission was considered acceptable, and an NOL was issued. |
|
NC # 253541 |
2021-06-08 |
Issued NOL 2021-07-21 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change involving a drug product manufacturer/manufacturing facility and changes affecting the quality control testing of the drug product (release and stability).The submission was reviewed and considered acceptable, and an NOL was issued. |
|
NC # 245026 |
2020-10-13 |
Issued NOL 2020-12-03 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
Drug product (DIN 02497875) market notification |
Not applicable |
Date of first sale: 2020-11-20 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
SNDS # 233708 |
2019-12-11 |
Issued NOC 2020-11-19 |
Submission filed as a Level I – Supplement to seek approval for a subcutaneous route of administration of Entyvio for maintenance treatment of Crohn’s disease in patients who demonstrated clinical response to induction treatment administered by intravenous infusion of Entyvio, and for the addition of a drug product manufacturing site. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published. |
|
SNDS # 232127 |
2019-10-01 |
Issued NOC 2020-09-10 |
Submission filed as a Level I – Supplement to update the PM as a result of new information available in the pediatric population from Study MLN0002-2003. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Indications and Clinical Use; Warnings and Precautions; and Action and Clinical Pharmacology sections of the PM. Corresponding changes were made to the package insert. An NOC was issued. |
|
NC # 239712 |
2020-05-15 |
Issued NOL 2020-08-27 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the shelf-life for the drug product. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
NC # 238913 |
2020-05-15 |
Issued NOL 2020-07-20 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
Drug product (DIN 02497867) market notification |
Not applicable |
Date of first sale: 2020-07-08 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
SNDS # 226874 |
2019-04-23 |
Issued NOC 2020-04-07 |
Submission filed as a Level I – Supplement to seek approval for a subcutaneous route of administration of Entyvio for maintenance treatment of ulcerative colitis in patients who demonstrated clinical response to initial vedolizumab treatment administered by intravenous infusion, and for the addition of a drug product manufacturing site. The submission was reviewed and considered acceptable, and an NOC was issued. Two new DINs (02497867, 02497875) were issued for the new presentation. A Regulatory Decision Summary was published. |
|
NC # 231841 |
2019-09-20 |
Issued NOL 2019-12-03 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the parameters of an approved holding step or addition of a new holding step. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
SNDS # 220394 |
2018-09-21 |
Issued NOC 2019-05-06 |
Submission filed as a Level I – Supplement to add drug substance and drug product manufacturing and testing sites. The submission was reviewed and considered acceptable, and an NOC was issued. |
|
NC # 222309 |
2018-11-26 |
Issued NOL 2019-03-11 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change testing procedures for the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
NC # 221384 |
2018-10-25 |
Issued NOL 2019-01-28
|
Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM to reflect revisions in the company core data sheet. As a result of the NC, modifications were made to the Serious Warnings and Precautions, Adverse Reactions, Dosage and Administration, Action and Clinical Pharmacology, Storage and Stability, and Toxicology sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
SNDS # 204351 |
2017-03-31 |
Issued NOC 2017-11-10 |
Submission filed as a Level I – Supplement to change the specifications for the drug substance and drug product. The data were reviewed and considered acceptable, and an NOC was issued. |
|
NC # 206107 |
2017-05-30 |
Cancellation Letter Received 2017-08-02 |
Submission filed as a Level II - (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacture of the drug product. The changes were not in scope of an NC but were considered to be Level III changes. The submission was cancelled by the sponsor. |
|
SNDS # 201287 |
2016-12-19 |
Issued NOC 2017-07-14 |
Submission filed as a Level I – Supplement to add an alternate manufacturing site for the production of the drug substance. The stability profiles of the drug substance and drug product remain unchanged. The information was reviewed and considered acceptable. An NOC was issued. |
|
NC # 198758 |
2016/09/28 |
Issued No Objection Letter 2016/12/29 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacture of the drug substance. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
|
SNDS # 194054 |
2016/04/08 |
Issued NOC 2016/11/08 |
Submission filed as a Level I – Supplement for the approval of an alternate manufacturing site of the drug product. Drug product manufactured at the new site is comparable to product manufactured at the current site. The data were reviewed and considered acceptable, and an NOC was issued. |
|
NC # 196332 |
2016/06/27 |
Issued No Objection Letter 2016/10/25 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacturing of the drug product. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
|
NC # 195566 |
2016/05/27 |
Issued No Objection Letter 2016/08/30 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to fulfill several quality-related post-authorization commitments. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
|
SNDS # 183836 |
2015/04/24 |
Issued NOC 2016/03/22 |
Submission filed as a Level I – Supplement for a new indication: the treatment of adult patients with moderately to severely active Crohn’s disease who have had an inadequate response with, lost response to, or were intolerant to a tumour necrosis factor-alpha (TNFα) antagonist or immunomodulators, or had inadequate response, intolerance, or demonstrated dependence on corticosteroids. The safety and efficacy of vedolizumab in support of the indication was based mainly on two Phase III pivotal trials (Study C13007 and C13011) and one open-label, on-going, long-term extension safety report (Study C13008). The benefit of vedolizumab in the treatment of Crohn’s disease was demonstrated by the totality of efficacy from combined data for achieving induction and maintenance clinical response. The safety data provided in this SNDS included a substantial number of patients who had received vedolizumab treatment. The benefit outweighs the risks associated with the vedolizumab product. The data were considered acceptable, and the product offers another treatment option for patients with Crohn’s Disease. An NOC was issued. |
|
Drug product (DIN 02436841) market notification |
Not applicable |
Date of first sale: 2015/04/21 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
NDS # 169414 |
2013/10/29 |
Issued NOC 2015/01/29 |
Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Entyvio
Date SBD issued: 2015-04-28
The following information relates to the New Drug Submission for Entyvio.
Vedolizumab, 300 mg/vial, powder for solution, intravenous
Drug Identification Number (DIN):
- 02436841
Takeda Canada Inc.
New Drug Submission Control Number: 169414
On January 29, 2015, Health Canada issued a Notice of Compliance to Takeda Canada Inc. for the drug product Entyvio.
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 Entyvio is favourable for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response, loss of response to, or were intolerant to either conventional therapy or infliximab, a tumor necrosis factor-alpha (TNF-α) antagonist.
1 What was approved?
Entyvio, a selective immunosuppressant, was authorized for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response, loss of response to, or were intolerant to either conventional therapy or infliximab, a tumor necrosis factor-alpha (TNF-α) antagonist.
Clinical studies for Entyvio did not include sufficient numbers of patients aged 65 and over (in Phase III clinical studies 26 patients 65 years of age or older were evaluated) to determine whether they respond differently from younger patients. The efficacy and safety of Entyvio should therefore be interpreted with caution in patients older than 65 years of age.
The safety and efficacy of Entyvio have not been established in pediatric patients less than 18 years of age.
Entyvio is contraindicated for patients who are hypersensitive to vedolizumab or to any ingredient in the formulation or component of the container. Entyvio is also contraindicated for patients with active severe infections or opportunistic infections. Entyvio was approved for use under the conditions stated in the Entyvio Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Entyvio (300 mg/vial, vedolizumab) is presented as lyophilized powder for solution for intravenous infusion. In addition to the medicinal ingredient, the single-use vial also contains the following non-medicinal ingredients, L-histidine, L-histidine monohydrochloride, L-arginine hydrochloride, sucrose, and polysorbate 80.
For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Entyvio Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Entyvio approved?
Health Canada considers that the benefit/risk profile of Entyvio is favourable for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response, loss of response to, or were intolerant to either conventional therapy or infliximab, a tumor necrosis factor-alpha (TNF-α) antagonist.
Ulcerative colitis is a relapsing, remitting, inflammatory disease of the colonic mucosa and submucosa characterized by large numbers of lymphocytes and histiocytes in the mucosa and submucosa, and a variable degree of neutrophils.
Clinical manifestations include diarrhea (typically bloody), abdominal pain, fecal urgency and incontinence. Systemic features such as fever, weight loss, malaise, and fatigue are indicators of a more extensive disease. Extra-intestinal manifestations such as uveitis, peripheral arthritis, ankylosing spondylitis, or primary sclerosing cholangitis may also be observed in conjunction with ulcerative colitis.
Entyvio has been shown to be efficacious in patients with moderate to severe active ulcerative colitis (Mayo score 6 to 12 with endoscopic sub-score ≥2). The market authorization was predominantly based on a Phase III, multicentre, randomized, placebo-controlled, 52-week study (C13006) which investigated Entyvio treatment versus placebo for both induction and maintenance of remission in patients with moderate to severe active ulcerative colitis who previously failed conventional treatment or TFNa antagonist therapy. The C13006 study had two primary efficacy endpoints, patients who achieved a clinical response to Entyvio therapy at Week 6 (induction) and patients who achieved clinical remission at Week 52 (maintenance). Study results demonstrated that a significantly greater percentage of patients treated with Entyvio compared to patients treated with placebo achieved clinical response at Week 6 and clinical remission at Week 52. In addition, a significantly greater percentage of patients treated with Entyvio demonstrated an improvement in the endoscopic appearance of mucosa at Week 6. The beneficial effect of Entyvio on clinical response, remission and improvement of endoscopic appearance of the mucosa was observed in patients naïve to a TNFα antagonist as well as in those who had failed prior TNFα antagonist therapy. However, a lower magnitude of benefit with Entyvio treatment was noted in patients previously treated with infliximab compared to infliximab naïve patients.
Adverse events were reported in 80% of Entyvio-treated patients versus 77% of placebo-treated patients. Over 52 weeks, 12% of patients treated with Entyvio experienced serious adverse events compared to 11% of patients treated with placebo. The most common adverse reactions were headache, nasopharyngitis, arthralgia, upper respiratory tract infection, cough, abdominal pain, fatigue, and influenza.
A Risk Management Plan (RMP) for Entyvio was submitted by Takeda Canada 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.
A Look-alike Sound-alike brand name assessment was performed and the proposed name Entyvio has been deemed appropriate and acceptable.
Overall, the therapeutic benefit seen in the pivotal and supplemental studies is promising and the benefits of Entyvio therapy are considered to outweigh the risks. Entyvio 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 Entyvio 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 Entyvio?
Submission Milestones: Entyvio
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2013-04-08 |
| Submission filed: | 2013-10-29 |
| Screening | |
| Screening Deficiency Notice issued: | 2014-01-13 |
| Response filed: | 2014-02-11 |
| Screening Acceptance Letter issued: | 2014-04-04 |
| Review | |
| Quality Evaluation complete: | 2015-01-29 |
| Clinical Evaluation complete: | 2015-01-29 |
| Labelling Review complete: | 2015-01-29 |
| Notice of Compliance issued by Director General: | 2015-01-29 |
The Canadian regulatory decision on the non-clinical, clinical and quality review of Entyvio was based on a critical assessment of the Canadian data package. Parts of foreign regulatory information from the European Union's centralized procedure European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were also provided and used as an added reference.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
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 and have been market notified (that is, the company has told Health Canada the product is being marketed).
- 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
Entyvio is classed as a gut-selective anti-inflammatory biologic. It is a humanized monoclonal antibody that binds exclusively to the alpha 4 beta 7 (a4ß7) integrin on pathogenic gut-homing lymphocytes and selectively inhibits adhesion of these cells to mucosal addressin cell adhesion molecule 1 (MAdCAM-1), but not vascular cell adhesion molecule 1 (VCAM 1). By specifically inhibiting the a4ß7/MAdCAM-1 pathway, Entyvio alleviates gastrointestinal inflammation without affecting immune responses to dermal antigenic challenge and immune surveillance of the central nervous system.
The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacological data support the use of Entyvio for the specified indication.
For further details, please refer to the Entyvio Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The efficacy of Entyvio for the treatment of adult patients with moderate to severe active ulcerative colitis (Mayo score 6 to 12 with endoscopic sub-score ≥2) was evaluated predominately in a Phase III study (C13006, also known as GEMINI I). This study was a randomized, double-blind, placebo-controlled study which investigated Entyvio treatment versus a placebo for both induction and maintenance of remission in patients with moderate to severe active ulcerative colitis.
Patients enrolled in the C13006 study had failed at least one conventional therapy, including corticosteroids, immunomodulators, and/or infliximab, a tumor necrosis factor-alpha (TNF-α) antagonist. Infliximab failure patients included those with inadequate response (primary non-responders), loss of response (secondary non-responders) or those who were intolerant to infliximab. Approximately 40% of the overall population in the C13006 study had failed prior infliximab therapy.
Patients enrolled from the United States had over the previous five-year period an inadequate response or intolerance to immunomodulator therapy [that is (i.e.), azathioprine or 6-mercaptopurine] and/or an inadequate response, loss of response, or intolerance to a TNFα antagonist therapy. Outside the United States, prior treatment with corticosteroids was sufficient for study entry if over the previous five-year period the patients were corticosteroid dependent (i.e. unable to successfully taper corticosteroids without a return of the symptoms of ulcerative colitis) or had an inadequate response or intolerance to corticosteroids.
The study evaluated efficacy at two primary endpoints, Week 6 which evaluated the proportion of patients who achieved a clinical response (induction phase) and Week 52 which evaluated the proportion of patients who achieved clinical remission (maintenance phase). For the induction phase, clinical response at Week 6 was defined as a reduction in complete Mayo score of ≥3 points and ≥30% decrease from baseline, with an accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point. As for the maintenance phase, clinical remission at Week 52 was defined as a complete Mayo score of ≤2 points and no individual subscore >1 point.
Secondary efficacy endpoints included were durable clinical response, mucosal healing (improvement of endoscopic appearance of the mucosa), durable clinical remission and corticosteroid-free clinical remission. Corticosteroid-free remission was assessed in the subset of patients taking corticosteroids at baseline.
For the evaluation of the Week 6 endpoint (induction phase), 374 patients were randomized in a double-blind fashion (3:2) to receive Entyvio 300 mg or a placebo at Week 0 and Week 2. Concomitant medications were permitted, and patients received corticosteroids (54%), immunomodulators (30%), and aminosalicylates (74%).
In the study, two cohorts of patients received Entyvio at Week 0 and Week 2: Cohort 1 patients were randomized to receive either Entyvio 300 mg or placebo in a double-blind fashion (induction phase), Cohort 2 patients were treated with open-label Entyvio 300 mg. For the evaluation of efficacy at Week 52, patients from Cohort 1 and 2, who were treated with Entyvio and had achieved clinical response at Week 6 (373 patients), were randomized in a double blind fashion (1:1:1) to one of the following regimens beginning at Week 6: Entyvio 300 mg every eight weeks, Entyvio 300 mg every four weeks, or placebo every four weeks.
Concomitant medications were permitted, and patients received corticosteroids (61%), immunomodulators (32%) and aminosalicylates (75%). Concomitant immunomodulators (azathioprine or 6-mercaptopurine) were permitted outside the United States but were not permitted beyond Week 6 in the United States. Beginning at Week 6, patients who had achieved clinical response and were receiving corticosteroids were required to begin a corticosteroid tapering regimen.
Study results from the induction phase at Week 6 demonstrated that 47% of Entyvio-treated patients compared to 26% placebo-treated patients achieved a clinical response. In addition, 17% of Entyvio-treated patients compared to 5% of placebo-treated patients achieved clinical remission at Week 6. Furthermore, 41% of Entyvio-treated patients compared to 25% of placebo-treated patients demonstrated an improvement in the endoscopic appearance of mucosa at Week 6.
Study results observed from the maintenance phase demonstrated that 42% percent of patients in the Entyvio treatment group receiving the Entyvio every 8 weeks achieved clinical remission compared to 16% of placebo-treated patients. In addition, 52% of Entyvio-treated patients compared with 20% of placebo-treated patients demonstrated improvement of endoscopic appearance of the mucosa. Furthermore, 31% of Entyvio-treated patients compared to 14% of placebo-treated patients achieved corticosteroid-free clinical remission at Week 52.
Additionally, 57% of Entyvio-treated patients compared with 24% of placebo-treated patients demonstrated a durable clinical response, and 20% compared to 9% demonstrated durable clinical remission, respectively.
However, no additional clinical benefit was demonstrated when comparing the every four-week treatment regimen to that of the every eight-week treatment regimen. Therefore, the only authorized treatment regimen is that of every eight weeks.
Indication
During the original filing of the Entyvio submission, the sponsor had proposed its use for two indications: the treatment of adult patients with moderately to severely active ulcerative colitis or Crohn's disease who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a tumour necrosis factor-alpha (TNF-α) antagonist. During the clinical review of the submission, Health Canada requested that the sponsor withdraw the indication for Crohn's disease. The sponsor agreed to withdraw this indication, and the resulting indication approved by Health Canada for Entyvio is as follows:
- Ulcerative Colitis (Adults ≥18 years)
Entyvio (vedolizumab) is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response, loss of response to, or were intolerant to either conventional therapy or infliximab, a TNFα antagonist.
For more information, refer to the Entyvio Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety of Entyvio was evaluated primarily in 620 Entyvio-treated patients based on the clinical safety data provided from the Phase III C13006 study, previously described in the Clinical Efficacy section. In this study, patients were exposed to Entyvio for a mean duration of 259 days.
Adverse events were reported in 80% of patients treated with Entyvio and 77% of patients treated with a placebo. Over 52 weeks, 12% of patients treated with Entyvio experienced serious adverse events compared to 11% of patients treated with placebo. The proportion of patients who discontinued treatment due to adverse events was 6% for patients treated with Entyvio compared to 11% for patients treated with placebo.
The most common adverse reactions reported by Entyvio-treated ulcerative colitis patients were headache (13%), nasopharyngitis (13%), arthralgia (9%), upper respiratory tract infection (8%), cough (6%), abdominal pain (6%), fatigue (5%), and influenza (5%).
Topics of Special Interest
Infusion-Related Reactions
Infusion-related reactions were reported in 5% of patients treated with Entyvio and <1% of patients treated with a placebo. The most frequently observed events assessed as infusion-related reaction in the patients treated with Entyvio were arthralgia, fatigue, headache, pruritus, tinnitus, urticaria, vomiting, and infusion site irritation. The majority of infusion-related reactions were mild or moderate in intensity, and <1% resulted in discontinuation of study treatment. Observed infusion-related reactions generally resolved with no or minimal intervention following the infusion. Most infusion-related reactions occurred within the first two hours. One serious infusion-related reaction was reported by a Crohn's disease patient during the second infusion (symptoms reported were dyspnea, bronchospasm, urticaria, flushing, rash and increased blood pressure and heart rate) and was successfully managed with discontinuation of infusion and treatment with antihistamine and intravenous hydrocortisone. In patients who received Entyvio at Weeks 0 and 2 followed by a placebo, no increase in the rate of infusion-related reaction was seen upon retreatment with Entyvio after loss of response.
Infections
Infections were reported in 42% of patients treated with Entyvio and 31% of patients treated with placebo. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, and influenza. Most patients did not require discontinuation of Entyvio.
Serious infections were reported in 2% of patients treated with Entyvio and 3% of patients treated with placebo. Over time, there was no significant increase in the rate of serious infections.
In controlled- and open-label long-term extension studies in adults with Entyvio, serious infections have been reported, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis, and cytomegaloviral colitis.
Sepsis was reported in one of 620 (0.2%) patients treated with Entyvio and in one of 149 patients treated with placebo (0.7%). During the placebo-controlled studies, two Crohn's disease patients treated with Entyvio died due to reported sepsis or septic shock. Both of these patients had significant comorbidities and a complicated hospital course that contributed to their death. Additional cases of sepsis (some fatal), including bacterial sepsis and septic shock, were reported in the open-label long-term extension study. The incidence density rate of sepsis in patients with ulcerative colitis receiving Entyvio was 0.20 per 100 person-years.
Malignancies
Malignancies (excluding dysplasia and basal cell carcinoma) were reported in three of 620 (0.5%) patients treated with Entyvio, including colon cancer [patient number (n) = 2] and transitional cell carcinoma (n = 1). Malignancy was reported in one of 149 (0.7%) patients treated with placebo (squamous cell carcinoma).
Malignancies (excluding dysplasia and basal cell carcinoma), observed during the ongoing open-label long-term extension study included B-cell lymphoma, breast cancer, colon cancer, hepatic neoplasm malignant, lung neoplasm malignant, malignant melanoma, neuroendocrine carcinoma, renal cancer, and squamous cell carcinoma. Overall, results from the non-clinical and clinical programs to date do not suggest an increased risk of malignancy with Entyvio treatment; however, this should be interpreted with caution due to the small number of malignancies in the clinical studies and limited long-term exposure.
Immunogenicity
Entyvio showed an immunogenicity rate of 4% (23 of 620 patients who received continuous treatment with Entyvio were anti-Entyvio antibody-positive at any time during treatment). Six of 23 patients were persistently positive (antibody-positive at two or more study visits) and 17 of 23 patients developed neutralizing antibodies.
The frequency of antibodies detected in patients 16 weeks after the last dose of study drug (approximately five half-lives after last dose) was approximately 9%. Three of 28 (11%) of the patients who had an adverse event assessed by the investigator as an infusion-related reaction were persistently antibody-positive.
Overall, there was no apparent correlation of anti-vedolizumab antibody development to clinical response or adverse events. However, the number of patients who developed antibodies was too limited to make a definitive assessment.
For more information, refer to the Entyvio Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Vedolizumab (the medicinal ingredient of Entyvio) has been evaluated in a comprehensive program of non-clinical studies which included pharmacology, pharmacokinetics, acute intravenous toxicology (monkey), repeated dose intravenous toxicology (14-day, 13-week, 26-week) in monkeys and rabbits (3-month), reproductive toxicology (single-dose intravenous embryofetal development in rabbits and pre- and postnatal development in monkeys), local tolerance and special toxicology studies.
Chronic toxicology studies in monkeys (10, 30 and 100 mg/kg) intravenous, every two weeks, 3 and 6 month durations) showed alterations in gut histopathology including mild lymphoid depletion in Peyer's patches and increased stomach epithelial regeneration as compared to vehicle-treated animals, but no significant changes in clinical observations and measurements. Chronic repeat-dosing in rabbits (30 and 100 mg/kg every two weeks, 3 months + 1 month recovery) showed mild histopathological changes in the spleen and ileum (lymphoid hyperplasia).
Conventional carcinogenicity studies were not been performed; proxy markers in animal models did not indicate increased risk.
For more information, refer to the Entyvio Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
Characterization of the Drug Substance
Extensive characterization of the physicochemical, biological, and immunological properties of vedolizumab (medicinal ingredient of Entyvio), as well as confirmation of its purity was performed using methods selected in accordance with International Conference on Harmonisation (ICH) Q6B. The manufacturing process used to produce the drug substance has undergone two major changes during development, from the initial Process A to Process B, and from Process B to Process C. Analytical comparability consisted of comparison of in-process testing and parameters, side-by-side batch release testing, and additional characterization. Non-clinical and clinical studies using the different process material also supported the analytical comparability. Data from product quality assessments, non-clinical studies, and clinical studies demonstrated that vedolizumab produced by different manufacturing process versions during development is comparable and that there has been no significant impact on quality observed due to the associated process changes.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
The drug substance is produced in a fed-batch process, using a suspension-adapted Chinese Hamster Ovary cell line. After vial thaw, the manufacturing process consists of a series of steps which include cell culture, harvest, purification stages, including viral inactivation/removal steps, and formulation.
The Entyvio drug product is provided as a sterile preservative-free lyophilized powder for solution for infusion. Each single-use 20 mL vial contains 300 mg (target fill weight = 331.2 mg) vedolizumab for reconstitution with 4.8 mL sterile water for injection, followed by dilution in 250 mL of normal saline (sterile 0.9% sodium chloride) prior to intravenous administration. The drug product is formulated as 60 mg/mL vedolizumab in histidine, L-arginine hydrochloride, sucrose, and polysorbate 80.
Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review.
The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are valid 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 vedolizumab 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 Conference on Harmonisation (ICH) guidelines.
Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated, and found to meet the specifications of the drug product and demonstrate consistency in manufacturing.
Stability of the Drug Substance and Drug Product
Based on the stability data submitted, the proposed shelf-life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 36-months shelf-life for the Entyvio drug product when stored at 5°C ± 3°C, and protected from light 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 facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.
An On-Site Evaluation (OSE) was not required for this submission as the sites involved in the manufacturing of vedolizumab drug substance and drug product have previously been evaluated and found acceptable by Health Canada.
Adventitious Agents Safety Evaluation
The vedolizumab manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses). Purification process steps designed to remove and inactivate viruses are adequately validated.
All excipients are compendial and are tested to appropriate specifications by the excipient manufacturers and/or the drug product manufacturer.
The excipients used in the drug product formulation are not of animal or human
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| ENTYVIO | 02436841 | TAKEDA CANADA INC | VEDOLIZUMAB 300 MG / VIAL |
| ENTYVIO | 02497867 | TAKEDA CANADA INC | VEDOLIZUMAB 108 MG / 0.68 ML |