Summary Basis of Decision for Ocrevus

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 Ocrevus is located below.

Recent Activity for Ocrevus

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 Ocrevus

Updated: 2024-02-23

The following table describes post-authorization activity for Ocrevus, a product which contains the medicinal ingredient ocrelizumab. 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 02467224 – 30 mg/mL, ocrelizumab, solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 272206

2023-02-09

Issued NOC 2023-08-21

Submission filed as a Level I – Supplement for the addition of a drug substance manufacturing facility. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 263006

2022-03-31

Cancellation Letter Received 2023-02-08

Submission filed as a Level I – Supplement to update the PM with new efficacy information. A number of issues were identified with the submission during review. The sponsor cancelled the submission before Health Canada completed the review.

SNDS # 266929

2022-08-12

Issued NOC 2023-01-09

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety 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 and Dosage and Administration sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

SNDS # 238774

2020-04-24

Issued NOC 2021-04-01

Submission filed as a Level I – Supplement for the introduction of an alternative, shorter (2-hour) infusion time for the second and subsequent doses of Ocrevus, in patients with multiple sclerosis who have not experienced a serious infusion-related reaction with any previous ocrelizumab infusion. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 234659

2019-12-20

Issued NOC 2020-07-31

Submission filed as a Level I – Supplement for the addition of a drug product manufacturing facility. The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 236896

2020-03-05

Issued NOL 2020-06-18

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes in the drug substance and drug product release or shelf-life specifications and changes affecting the quality control testing of the drug substance (release and stability). The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 236853

2020-03-06

Issued NOL 2020-06-10

Submission filed as a Level II (90 day) Notifiable Change to update the PM. As a result of the NC, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 226000

2019-03-22

Issued NOL 2019-07-05

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the controls (in‐process tests and/or acceptance criteria) applied during the drug product manufacturing process or on intermediates. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 215767

2018-04-27

Issued NOC 2019-04-09

Submission filed as a Level I – Supplement to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Adverse Reactions; and Drug Interactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

NC # 216281

2018-05-14

Issued NOL

2018-06-28

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacture of the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 213383

2018-02-02

Issued NOL

2018-04-27

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to extend the shelf-life of the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 197969

2016-08-29

Issued NOC under NOC/c Guidance 2018-02-14

Submission filed as a Level I – Supplement for a new indication. The submission was reviewed under the Priority Review of Drug Submissions Policy. The indication authorized was: Ocrevus is indicated for the management of adult patients with early primary progressive multiple sclerosis (PPMS) as defined by disease duration and level of disability, in conjunction with imaging features characteristic of inflammatory activity. The submission was reviewed and considered acceptable, and an NOC was issued under the Guidance Document: Notice of Compliance with Conditions (NOC/c). A Regulatory Decision Summary was published.

Drug product (DIN 02467224) market notification

Not applicable

Date of first sale: 2017-09-21

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 198094

2016-09-16

Issued NOC 2017-08-14

Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Ocrevus

Date SBD issued: 2017-10-19

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

Ocrelizumab
30 mg/mL, solution, intravenous

Drug Identification Number (DIN):

  • 02467224

Hoffmann-La Roche Ltd.

New Drug Submission Control Number: 198094

 

On August 14, 2017, Health Canada issued a Notice of Compliance to Hoffmann-La Roche Ltd. for the drug product Ocrevus.

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 assessment, the benefit-risk profile of Ocrevus is favourable for the treatment of adult patients with relapsing remitting multiple sclerosis (RRMS) with active disease defined by clinical and imaging features.

 

1 What was approved?

 

Ocrevus is a selective immunomodulator, a recombinant humanized monoclonal antibody that selectively targets CD20-expressing B cells. Ocrevus was authorized for the treatment of adult patients with relapsing remitting multiple sclerosis (RRMS) with active disease defined by clinical and imaging features.

Treatment with Ocrevus should be initiated and supervised by neurologists experienced in the treatment of patients with MS and who have fully familiarized themselves with the efficacy and safety profile of Ocrevus.

Specific premedication should be administered before injecting Ocrevus. In addition, resources for the treatment of hypersensitivity and anaphylactic reactions should be immediately available. Patients treated with Ocrevus must be informed about the risks of Ocrevus.

Ocrevus 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
  • with a history of life-threatening infusion reaction to Ocrevus
  • with active hepatitis B virus infection
  • with severe, active infections
  • who have or have had confirmed progressive multifocal leukoencephalopathy

The safety and efficacy of Ocrevus in patients ≥65 years of age, in children and adolescents (<18 years of age) have not been studied.

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

Ocrevus (30 mg/mL ocrelizumab) is supplied as a preservative-free, sterile solution in a single-use glass vial. In addition to the medicinal ingredient, the solution contains sodium acetate, α,α trehalose dihydrate, polysorbate 20, glacial acetic acid, and water for injection.

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

 

2 Why was Ocrevus approved?

 

Health Canada considers that the benefit-risk profile of Ocrevus is favourable for the treatment of adult patients with relapsing remitting multiple sclerosis (RRMS) with active disease defined by clinical and imaging features.

Multiple sclerosis is a chronic autoimmune and neurodegenerative disorder of the central nervous system (CNS) that is characterized by inflammation, demyelination, and neuronal loss. Multiple sclerosis affects approximately 2.5 million people worldwide and represents the most common cause of neurological disability among young adults. It is usually diagnosed between the ages of 20 to 40 years, with twice as many women affected as men. Relapsing remitting multiple sclerosis (RRMS) is the most common clinical presentation of the disease. Patients with RRMS experience discrete episodes of neurological dysfunction which result in a range of multiple sclerosis-associated symptoms including chronic pain, weakness, spasticity, sensory loss, vision loss, depression, fatigues and/or imbalance. Early in the course of the disease (RRMS phase), the physical symptoms of relapse tend to subside completely after each attack. However, the CNS inflammatory process that accompanies the clinical relapses during the RRMS phase results in lasting brain injury that predisposes individuals to long-term disability.

Commonly used RRMS therapies include the interferon beta (IFN β) therapies (Avonex, Rebif, Betaseron and Plegridy) and glatiramer acetate (Copaxone). Other disease-modifying therapies authorized in Canada for RRMS include dimethyl fumarate (Tecfidera), fingolimod (Gilenya), teriflunomide (Aubagio), natalizumab (Tysabri), alemtuzumab (Lemtrada), and daclizumab beta (Zinbryta).

Ocrevus (ocrelizumab) is a recombinant humanized monoclonal antibody that selectively targets CD20-expressing B cells. The precise mechanisms through which ocrelizumab exerts its therapeutic clinical effects in multiple sclerosis are not fully elucidated, but it is presumed to involve immunomodulation through the reduction in the number and function of CD20+ B cells.

Ocrevus has been shown to be efficacious in patients with RRMS. The market authorization of Ocrevus was based on efficacy and safety data derived from two 96-week, randomized, double-blind, double-dummy, active comparator-controlled clinical trials with identical designs (Study WA21092 and Study WA21093). The active comparator drug used in both studies was Rebif (interferon beta-1a). The primary outcome of both studies was the annualized relapse rate (ARR). Additional outcome measures included the proportion of patients with confirmed disability progression, the mean number of magnetic resonance imaging (MRI) T1 gadolinium (Gd)-enhancing lesions at Weeks 24, 48, and 96, and new or enlarging MRI T2 hyperintense lesions.

The primary endpoint was met in both studies. As compared to Rebif, Ocrevus reduced the ARR by 46% in Study WA21092 (rate ratio [RR] = 0.536, 95% confidence interval [CI]: 0.400, 0.719, p<0.0001), and by 47% in Study WA21093 (RR = 0.532, 95% CI: 0.397, 0.714, p<0.0001).

The major safety concerns associated with the use of Ocrevus in RRMS patients include infusion-related reactions, infections and malignancies.

Infusion-related reactions were the most common adverse events and occurred more frequently in the Ocrevus group (34%) compared to the Rebif group (10%). There were no fatal infusion reactions, but 0.3% of Ocrevus-treated MS patients experienced infusion reactions that were serious, some requiring hospitalization. The risk of infusion-related reactions and management recommendations for infusion-related reactions are highlighted in the Warnings and Precautions, and Dosage and Administration sections of the Ocrevus Product Monograph. Specific premedication is recommended prior to each Ocrevus infusion.

The proportion of patients who experienced infections was higher in the Ocrevus group (58%) compared to the Rebif group (52%). Ocrevus increased the risk of upper respiratory tract infections, lower respiratory tract infections, and herpes-related infections.

Fatal infections have been observed in clinical trials in patients treated with Ocrevus and other anti-CD20 antibodies. Notably, clinical trials of Ocrevus in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and lupus nephritis (LN) were terminated due to an increased incidence of serious and opportunistic infections, and insufficient efficacy. No fatal infections were reported in the placebo groups, however, among the Ocrevus-treated patients who experienced serious infections, 6% (6/93), 17% (8/46), and 67% (2/3) of the patients died from serious infections/opportunistic infections in the RA, LN, and SLE clinical trials, respectively.

A fatal outcome of serious infections is a concern associated with a B-cell depleting therapy. Consequently, Ocrevus is contraindicated in patients with active hepatitis B infection, patients with severe, active infections, and patients who have or have had confirmed progressive multifocal leukoencephalopathy.

Hepatitis B virus reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, and progressive multifocal leukoencephalopathy, a rare opportunistic viral infection of the brain, have been reported in patients treated with anti-CD20 antibodies.

An increased risk of malignancy with Ocrevus may exist. Two (0.4%) female patients who received Ocrevus developed breast cancer, whereas no breast cancer was reported in the Rebif group. This information has been included in the Warnings and Precautions section of the Ocrevus Product Monograph.

Other safety concerns included depression, cardiovascular events, hepatic/biliary/pancreatic events, neutropenia, and decrease in serum immunoglobulins.

The lack of long-term exposure data does not allow sufficient evaluation of the risks of malignancies, cardiovascular disorders and rare infections, such as progressive multifocal leukoencephalopathy. In addition, the risk of adverse outcomes in pregnancy has not been well characterized.

As part of the marketing authorization for Ocrevus, Health Canada requested that the sponsor agree to several commitments to be addressed post-market (What follow-up measures will the company take?). Commitments include (but are not limited to) monitoring closely all serious adverse events in the clinical trials and in the post-marketing setting, as well as conducting two post-marketing safety studies to assess the use of Ocrevus during pregnancy.

A Risk Management Plan (RMP) for Ocrevus was submitted by Hoffmann-La Roche Ltd. 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. The sponsor has committed to provide, following approval, a revised Canadian RMP aligned with the revised Canadian Product Monograph information, applicable post-approval commitments to Health Canada, and updated international status of Ocrevus.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Ocrevus was accepted.

Overall, the benefits of Ocrevus therapy in patients with RRMS are considered to outweigh the potential risks. Ocrevus 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 when applicable. Appropriate warnings and precautions are in place in the Ocrevus 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 Ocrevus?

 

Submission Milestones: Ocrevus

Submission Milestone Date
Pre-submission meeting: 2016-05-25
Submission filed: 2016-09-16
Screening  
Screening Acceptance Letter issued: 2016-10-18
Review  
On-Site Evaluation: 2017-01-30 - 2017-02-03
Quality Evaluation complete: 2017-08-10
Clinical Evaluation complete: 2017-08-10
Review of Risk Management Plan complete: 2017-08-04
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2017-08-14
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2017-08-14

 

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

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

 

4 What follow-up measures will the company take?

 

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

  • Submitting to Health Canada, in accordance with Canadian regulations, all serious adverse events (SAEs) that occur following market authorization in Canada, in all clinical trials with Ocrevus. These SAEs should include but are not limited to: malignancies (e.g., breast cancer), serious/opportunistic infections, hepatitis B virus reactivation, progressive multifocal leukoencephalopathy, infusion reactions, hypersensitivity reactions, depression/suicide, intervertebral disc protrusion, abnormal liver function tests, amylase or lipase increase, decreased white blood cells/neutropenia, and decrease in serum immunoglobulins. Also, submitting class-related anti-CD20 SAEs such as mucocutaneous reactions (toxic epidermal necrolysis and Stevens-Johnson syndrome), as well as cardiovascular events, and any other events as appropriate.
  • Providing Health Canada with all reports/correspondence pertaining to post-approval commitments from major regulatory authorities (e.g., the United States Food and Drug Administration [FDA], European Medicines Agency [EMA], Australia's Therapeutic Goods Administration [TGA], etc.), including clinical and non-clinical reports.
  • Providing Health Canada with Periodic Safety Update Reports (PSURs)/Periodic Benefit Risk Evaluation Reports (PBRER) for Ocrevus every six months for the first three years and annually thereafter (upon request). Each PSUR/PBRER should include an analysis of all adverse drug events as per the pharmacovigilance plan, an analysis of increased immunosuppressive effects (e.g., infections, opportunistic infections, etc.) with concomitant use of other immunosuppressants, and safety updates from all ongoing clinical trials with Ocrevus.
  • Submitting to Health Canada a revised Canadian Risk Management Plan that will:
    • reflect a revised Canadian labelling for Ocrevus, the post-approval commitments to Health Canada, and the international status;
    • include a specific component to evaluate the use and safety in elderly patients in the proposed Post-Authorization Safety Study (PASS) within the pharmacovigilance plan.
  • Providing Health Canada with regular safety updates from a planned registry for pregnancies committed to the FDA.
  • Providing copies of the Pharmaceutical Advertising Advisory Board (PAAB)-approved educational programs and materials for health care providers for review by Health Canada, once available.

 

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

 

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's life cycle.

The PAAT for Ocrevus is found above.

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

 

6 What other information is available about drugs?

 

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

 

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

 

Clinical Pharmacology

The medicinal ingredient in Ocrevus, ocrelizumab, is a recombinant humanized monoclonal antibody that selectively targets CD20-expressing B cells. The precise mechanisms through which ocrelizumab exerts its therapeutic clinical effects in multiple sclerosis (MS) are not fully elucidated, but it is presumed to involve immunomodulation through the reduction in the number and function of CD20-expressing B cells. Following cell surface binding, ocrelizumab selectively depletes CD20-expressing B cells through antibody-dependent cellular phagocytosis, antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and apoptosis.

The clinical pharmacology data included reports on the human pharmacodynamic and pharmacokinetic studies conducted in patients with multiple sclerosis. No dedicated clinical pharmacology studies were performed in healthy subjects. The clinical pharmacological data support the use of Ocrevus for the specified indication.

B-cell counts are determined by assays for CD19+ B cells as the presence of Ocrevus interferes with the CD20 assay. Treatment with Ocrevus leads to depletion of CD19+ B cells in blood by 14 days post treatment. In the Phase III studies, between each dose of Ocrevus, up to 5% of patients showed B-cell repletion, above the lower limit of normal (LLN) or above baseline counts, at least at one time point. The median time to B-cell repletion (counts returned to baseline or to LLN, whichever occurred first) was 72 weeks (range 27-175 weeks). In 90% of patients, B-cell repletion to LLN or baseline was observed by approximately two and a half years after the last infusion.

The pharmacokinetics of ocrelizumab in the MS studies was described by a two-compartment model with time-dependent clearance.

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

Clinical Efficacy

The efficacy of Ocrevus was assessed in two 96-week, randomized, double-blind, double-dummy, active comparator-controlled clinical trials with identical designs, in patients with relapsing remitting multiple sclerosis (Study WA21092 and Study WA21093). The dose of Ocrevus was 600 mg every 24 weeks. The initial treatment was given as two 300 mg intravenous infusions administered two weeks apart, and subsequent doses were administered as a single 600 mg intravenous infusion. Placebo subcutaneous injections were given three times per week. The dose of Rebif (interferon beta-1a), the active comparator, was 44 µg given as subcutaneous injections three times per week, and placebo intravenous infusions were given every 24 weeks. Both studies included patients who had experienced at least one relapse within the prior year, or two relapses within the prior two years, and had an Expanded Disability Status Scale (EDSS) score from 0 to 5.5. Patients with primary progressive forms of multiple sclerosis were excluded. Neurological evaluations were performed every 12 weeks and at the time of a suspected relapse. Brain magnetic resonance imaging (MRI) was performed at baseline and at Weeks 24, 48, and 96.

Based on both studies, the mean age of patients was 37 years, the mean disease duration since multiple sclerosis diagnosis was 4 years, the mean EDSS score was 2.8, and the mean number of relapses in the prior year was 1.3.

The primary outcome of both Study WA21092 and Study WA21093 was the annualized relapse rate (ARR). Additional outcome measures included the proportion of patients with confirmed disability progression, the mean number of MRI T1 gadolinium (Gd)-enhancing lesions at Weeks 24, 48, and 96, and new or enlarging MRI T2 hyperintense lesions. Progression of disability was defined as an increase of 1 point or more from the baseline EDSS score attributable to multiple sclerosis when the baseline EDSS score was 5.5 or less, or 0.5 points or more when the baseline EDSS score was above 5.5. Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit 12 weeks after the initial documentation of neurological worsening.

The primary endpoint was met in both studies. As compared to Rebif, Ocrevus reduced the ARR by 46% in Study WA21092 (rate ratio [RR] = 0.536, 95% confidence interval [CI]: 0.400, 0.719, p<0.0001), and by 47% in Study WA21093 (RR = 0.532, 95% CI: 0.397, 0.714, p<0.0001).

For the secondary endpoint of 12-week confirmed disability progression (CDP) measured by increase in the EDSS in the pooled population from Studies WA21092 and WA21093, the hazard ratio for Ocrevus/Rebif was 0.60 (95% CI: 0.45, 0.81), indicating that Ocrevus significantly reduced the risk of disability progression by 40% (p = 0.0006) compared to Rebif.

For the MRI endpoints, Ocrevus significantly reduced the number of new, or newly enlarging T2 lesions by 77% (Study WA21092) and 83% (Study WA21093) compared to Rebif: RR = 0.229 (95% CI: 0.174, 0.3, p<0.0001) and RR = 0.171 (95% CI: 0.130, 0.225, p<0.0001), respectively.

Indication

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

  • Ocrevus (ocrelizumab) is indicated as monotherapy for the treatment of adult patients with relapsing forms of multiple sclerosis (RMS) to suppress relapses and disease progression (clinical and subclinical disease activity).

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

  • Ocrevus (ocrelizumab) is indicated for the treatment of adult patients with relapsing remitting multiple sclerosis (RRMS) with active disease defined by clinical and imaging features.

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

Clinical Safety

The safety of Ocrevus has been evaluated in 1,311 patients across multiple sclerosis clinical studies, including 825 patients with RRMS in two active comparator-controlled clinical trials (Study WA21092 and Study WA21093, described in the Clinical Efficacy section).

The major safety concerns associated with the use of Ocrevus in RRMS patients include infusion reactions, infections and malignancies.

Infusion-related reactions were the most common adverse events and occurred more frequently in the Ocrevus group (34%) compared to the Rebif group (10%). Two serious infusion-related reactions (one each in the Ocrevus and the Rebif group) were reported. None of the infusion-related reactions had a fatal outcome. There were several potential anaphylactic reactions (e.g., circulatory collapse, acute prerenal failure, asthma, dyspnea, and allergic pruritus) in the Ocrevus group.

The proportion of patients who experienced infections was higher in the Ocrevus group (58%) compared to the Rebif group (52%), mainly due to upper respiratory tract infections (15% vs. 11%), including nasopharyngitis (15% vs. 10%). There were 2 (0.2%) Grade 4 infections in the Ocrevus group, and no Grade 4 infections in the Rebif group. Opportunistic infections (e.g., herpes and candida infections) occurred more frequently in the Ocrevus group (7.0%) compared with the Rebif group (4.1%).

Notably, clinical trials of Ocrevus in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and lupus nephritis (LN) were terminated due to an increased incidence of serious and opportunistic infections, and insufficient efficacy. There were no fatal infections in the placebo groups, however, among the patients who experienced serious infections, 6% (6/93), 17% (8/46) and 67% (2/3) died from serious infections/opportunistic infections in the RA, LN, and SLE clinical trials, respectively.

An increased risk of malignancy with Ocrevus may exist. Two (0.4%) female patients who received Ocrevus developed breast cancer, whereas no breast cancer was reported in the Rebif group.

Other safety concerns included depression, cardiovascular events, hepatic/biliary/pancreatic events, neutropenia and decrease in serum immunoglobulins.

The lack of long-term exposure data does not allow sufficient evaluation of the risks of malignancies, cardiovascular disorders and rare infections, such as progressive multifocal leukoencephalopathy, which has been observed in patients treated with other anti-CD20 antibodies. In addition, the risk of adverse outcomes in pregnancy has not been well characterized.

Appropriate warnings and precautions are in place in the approved Ocrevus Product Monograph to address the identified safety concerns.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The toxicology program included a total of 13 studies, designed to evaluate and characterize the non-clinical safety profile of ocrelizumab, the medicinal ingredient in Ocrevus. The cynomolgus monkey was considered the most appropriate model for conducting non-clinical safety studies, as ocrelizumab is only known to bind to human and non-human primate CD20.

Genotoxicity, mutagenicity, and carcinogenicity studies were not conducted (which is in line with the International Council for Harmonisation [ICH] guideline S6 for drugs of biological origin).

Ocrelizumab was administered to cynomolgus monkeys by intravenous injections at doses ranging from 0 to 100 mg/kg and dose regimens including weekly, every two weeks, and every three weeks, for up to 24 weeks.

No effects on reproductive organs were observed in male monkeys, following intravenous administration of ocrelizumab (three loading doses of 15 or 75 mg/kg, followed by weekly doses of 20 or 100 mg/kg) for 8 weeks.

Following intravenous administration of Ocrevus to pregnant monkeys during the period of organogenesis (loading doses of 15 or 75 mg/kg on gestation days 20, 21, and 22, followed by weekly doses of 20 or 100 mg/kg), depletion of B lymphocytes in lymphoid tissues (spleen and lymph nodes) was observed in fetuses at both doses.

Intravenous administration of Ocrevus (three daily loading doses of 15 or 75 mg/kg, followed by weekly doses of 20 or 100 mg/kg) to pregnant monkeys throughout the period of organogenesis and continuing through the neonatal period resulted in two perinatal deaths (some associated with bacterial infections), renal toxicity (glomerulopathy and inflammation), lymphoid follicle formation in the bone marrow, and severe decreases in circulating B lymphocytes in neonates. The cause of the neonatal deaths was recorded as uncertain; however, both affected neonates were found to have bacterial infections.

Ocrelizumab was excreted in the milk of ocrelizumab-treated female monkeys. Human immunoglobulin G (IgG) is excreted in human milk; however, the potential for absorption of ocrelizumab to lead to B-cell depletion in the infant is unknown.

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

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

 

 

7.3 Quality Basis for Decision

 

Ocrelizumab, the medicinal ingredient in Ocrevus, is a recombinant, humanized, immunoglobulin G1 (IgG1) monoclonal antibody that selectively targets CD20-expressing B cells. It is based on the human IgG1 framework that contains heavy chain VHIII and light chain VκI subgroup sequences. The recombinant antibody consists of two identical 213 residue light chains and two identical 451 or 452 residue heavy chains.

In vitro, binding of ocrelizumab to CD20 on target cells induces immune effector function mechanisms such as antibody-dependent cell-mediated phagocytosis, antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and apoptosis. In vivo, ocrelizumab selectively and effectively depletes CD20+ B cells presumably through one or more of the aforementioned mechanisms.

Characterization of the Drug Substance

Ocrelizumab has been developed using a quality by design approach to establish a comprehensive risk-based control strategy.

Extensive characterization of the physicochemical, biological, and immunological properties of ocrelizumab and confirmation of its purity were performed using methods selected in accordance with the ICH guidelines. Critical quality attributes of ocrelizumab were identified by evaluating the potential impact of quality attributes on its bioactivity, pharmacokinetics, immunogenicity and safety, using a risk ranking and filtering procedure.

 

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

The drug substance, ocrelizumab, is produced by recombinant deoxyribonucleic acid (DNA) technology in a Chinese hamster ovary (CHO) mammalian cell expression system. Ocrelizumab is harvested from the cell culture fluid via centrifugation and filtration, and then subjected to a series of purification and virus inactivation and removal steps.

The manufacturing process of the drug product (Ocrevus) consists of thawing and mixing of the drug substance, dilution, sterile filtration, filling and capping, followed by visual inspection and container closure integrity testing. The manufacturer has demonstrated the ability of the drug product manufacturing site to consistently produce drug product of acceptable quality.

Ocrevus is supplied as a single-use vial containing 10 mL sterile, preservative-free, clear to slightly yellow opalescent and colourless to pale brown solution, at a concentration of 30 mg/mL for dilution for intravenous infusion. Each vial of Ocrevus contains a total of 300 mg ocrelizumab. Non-medicinal ingredients include: glacial acetic acid, α , α trehalose dihydrate, polysorbate 20, sodium acetate, and water for injection.

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.

Control of the Drug Substance and Drug Product

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

Three lots of the drug product were provided for Health Canada's in-house purity and potency consistency testing. The testing results were within the manufacturer's specifications and were considered acceptable.

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 18-month shelf life for Ocrevus is considered acceptable when the product is stored at 2°C-8°C and protected from light and freezing.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

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

An On-Site Evaluation (OSE) of the facility involved in the manufacture and testing of the drug substance was waived, as a successful OSE had been recently performed for another drug substance whose manufacturing process was similar.

An On-Site Evaluation (OSE) of the facility involved in the manufacture and testing of the drug product was conducted with a satisfactory rating.

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

Adventitious Agents Safety Evaluation

The ocrelizumab manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Purification process steps designed to remove and inactivate viruses are adequately validated.

 

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