Summary Basis of Decision for Zinbryta

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 Zinbryta is located below.

Recent Activity for Zinbryta

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 Zinbryta

Updated:

2018-12-12

The following table describes post-authorization activity for Zinbryta, a product which contains the medicinal ingredient daclizumab beta. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

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

Drug Identification Numbers (DINs):

  • DIN 02459620 - 150 mg/mL, daclizumab beta, solution, subcutaneous (pre-filled syringe)
  • DIN 02459639 - 150 mg/mL daclizumab beta, solution, subcutaneous (pre-filled pen)

Post-Authorization Activity Table (PAAT)

Activity/submission type, control numberDate submittedDecision and dateSummary of activities
NC # 2205492018-09-28Issued NOL
2018-11-15		Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with safety-related changes. As a result of the NC, modifications were made to the Serious Warnings and Precautions Box, and Warnings and Precautions sections of the PM. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
DIN (02459639) cancelled (Pre-market)Not applicableDiscontinuation date
2018-05-30		The manufacturer notified Health Canada that sale of the drug has been discontinued pre-market. Health Canada cancelled the DIN pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations.
DIN (02459620) cancelled (Post-market)Not applicableDiscontinuation date:
2018-04-30		The manufacturer notified Health Canada that sale of the drug has been discontinued post-market. Health Canada cancelled the DIN pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations.
Dear Healthcare Professional LetterNot applicablePosted
2018-03-16		Dear Healthcare Professional Letter posted containing important safety information, product withdrawal, for healthcare professionals.
NC # 2135832018-02-09Issued NOL
2018-03-07		Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with safety-related changes. As a result of the NC, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 2077512017-07-21Issued NOL
2017-08-14		Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with safety-related changes. As a result of the NC, modifications were made to the. Serious Warnings and Precautions Box, Contraindications, Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DIN 02459620 market notificationNot applicableDate of first sale:
2017-03-30		The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 1904582015-12-21Issued NOC
2016-12-08		Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Zinbryta

Date SBD issued: 2017-02-09

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

Daclizumab beta
150 mg/mL, solution, subcutaneous

Drug Identification Number (DIN):

  • DIN 02459620 - 150 mg/mL solution (pre-filled syringe)
  • DIN 02459639 - 150 mg/mL solution (pre-filled pen)

Biogen Canada Inc.

New Drug Submission Control Number: 190458

On December 8, 2016, Health Canada issued a Notice of Compliance to Biogen Canada Inc. for the drug product Zinbryta.

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 Zinbryta is favourable for the treatment of adult patients with active relapsing remitting multiple sclerosis (RRMS) who have had an inadequate response to, or who are unable to tolerate, one or more therapies indicated for the treatment of multiple sclerosis (MS).

1 What was approved?

Zinbryta is an immunomodulator, a humanized monoclonal antibody of the human immunoglobulin G1 (IgG1) isotype that binds to CD25, the alpha subunit of the human high affinity interleukin-2 receptor (IL-2Rα), and modulates IL-2 signalling. Zinbryta was authorized for the treatment of adult patients with active relapsing remitting multiple sclerosis (RRMS) who have had an inadequate response to, or who are unable to tolerate, one or more therapies indicated for the treatment of multiple sclerosis (MS).

The safety and efficacy of Zinbryta have not been established in patients with primary and secondary progressive MS.

Because of the risks of hepatic injury, Zinbryta can be used only if regular hepatic assessments are made, as specified in the Warnings and Precautions section of the Zinbryta Product Monograph.

Zinbryta is only available through a controlled distribution program called Biogen ONE Support Program. Under this program, only prescribers and pharmacies registered with the program are able to prescribe and dispense the product. In addition, Zinbryta can only be dispensed as one injection per month, to patients who are registered and informed about the risks of Zinbryta and meet all the conditions of the Biogen ONE Support Program, including compliance with monthly monitoring and assessment of liver enzymes before the next dose of Zinbryta.

Zinbryta is contraindicated in patients with:

  • Pre-existing hepatic disease or hepatic impairment, including alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at least 2 times the upper limit of normal (ULN), because Zinbryta could exacerbate existing liver dysfunction.
  • A history of autoimmune hepatitis or other autoimmune condition involving the liver.
  • A history of severe hypersensitivity to daclizumab beta, or any of the components of the product. Use in such patients may result in anaphylaxis or life-threatening multi-organ hypersensitivity.

Clinical studies of Zinbryta did not include patients over 65 years of age to determine whether they respond differently than younger patients.

The safety and efficacy of Zinbryta in patients below 18 years of age have not been studied.

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

Zinbryta (150 mg/mL daclizumab beta) is presented as a solution for subcutaneous injection in 1 mL pre-filled single-use syringes and 1 mL pre-filled single-use pens. In addition to the medicinal ingredient, the solution contains sodium succinate (anhydrous), succinic acid, sodium chloride, polysorbate 80 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 Zinbryta Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Zinbryta approved?

Health Canada considers that the benefit/risk profile of Zinbryta is favourable for the treatment of adult patients with active relapsing remitting multiple sclerosis (RRMS) who have had an inadequate response to, or who are unable to tolerate, one or more therapies indicated for the treatment of multiple sclerosis.

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 is 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 (referred to as relapses, exacerbations, or attacks) which include weakness, sensory loss, visual loss, and 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) and alemtuzumab (Lemtrada).

The market authorization of Zinbryta was based on data derived from two pivotal studies and their extensions, three Phase I studies, one Phase II dose-finding study, and supportive studies conducted to support its different presentations (a pre-filled pen and a pre-filled syringe), its dose, and its formulation.

In clinical trials conducted in adult patients with RRMS, Zinbryta demonstrated a significant reduction of annualized relapse rate (ARR) in comparison to either placebo or Avonex (IFN β-1a). In addition, Zinbryta demonstrated a superior effect on brain magnetic resonance imaging (MRI) measures (the number of new or newly enlarging T2 hyperintense lesions and the number of new gadolinium [Gd]-enhancing lesions) as compared to either placebo or Avonex. The effect of Zinbryta on disability, measured by Expanded Disability Status Scale (EDSS) score was numerically in favour of Zinbryta over Avonex (a drug known to reduce disability progression in MS), but it did not reach a statistically significant level.

The primary safety concern associated with the use of Zinbryta is severe liver injury including life-threatening events, liver failure, and autoimmune hepatitis. In clinical trials, one patient died due to autoimmune hepatitis. Liver injury, including autoimmune hepatitis, can occur at any time during treatment with Zinbryta, with cases reported up to four months after the last dose of Zinbryta. These serious safety concerns are highlighted in a Serious Warnings and Precautions box of the Zinbryta Product Monograph. In addition, obtaining serum transaminases (alanine aminotransferase, ALT and aspartate aminotransferase, AST) and bilirubin levels prior to starting Zinbryta is required. As Zinbryta could exacerbate existing liver dysfunction, it is contraindicated in patients with pre-existing hepatic disease or hepatic impairment and in patients with a history of autoimmune hepatitis or other autoimmune conditions involving the liver. Furthermore, the Serious Warnings and Precautions box of the Zinbryta Product Monograph specifies the need for regular monthly monitoring of transaminase levels and total bilirubin, which should also be assessed before the next dose of Zinbryta, and followed for six months after the last dose of Zinbryta. In case of elevation, treatment interruption or discontinuation may be required.

In addition to autoimmune hepatitis, other immune-mediated disorders such as skin reactions, lymphadenopathy, autoimmune hemolytic anemia and gastrointestinal disorders can occur in patients treated with Zinbryta. These serious safety concerns have also been specifically addressed in the Serious Warnings and Precautions box of the Zinbryta Product Monograph.

Other reported adverse events included infections, acute hypersensitivity, depression (including suicidal ideation or suicide attempt), seizures and malignancies (breast cancer).

Due to the serious safety concerns, Zinbryta will only be available through a controlled distribution program called Biogen ONE Support Program, information of which is included in the Zinbryta Product Monograph.

As part of the marketing authorization for Zinbryta, Health Canada requested that the sponsor agree to several commitments to be addressed post-marketing (see What follow-up measures will the company take?). Commitments include (but are not limited to) providing a Canadian Risk Management Plan (RMP) for Zinbryta. 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 Zinbryta was accepted.

Overall, the benefits of Zinbryta therapy are considered to outweigh the potential risks, taking into consideration the limitations required by its conditions of use. The identified safety issues are managed through labelling, educational material for health care professionals and patients, adequate monitoring, and the controlled distribution program (Biogen ONE Support Program). Appropriate warnings and precautions are in place in the Zinbryta 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 Zinbryta?

Zinbryta contains the active substance daclizumab beta. Daclizumab was previously marketed as Zenapax, with Notice of Compliance issued on January 4, 2000, as an adjunct agent for prophylaxis of acute organ rejection in patients receiving renal transplants. Zenapax was removed from the Canadian market on October 17, 2011, due to non-safety related issues. Zinbryta (daclizumab beta, also referred to as daclizumab high yield process [DAC HYP]) is a unique substance, as the molecular structure, nature of the source material used in cell culture, manufacturing process, and biological properties are different from the previously approved daclizumab. Accordingly, on June 17, 2016, daclizumab beta was classified as a new active substance by Health Canada.

Submission Milestones: Zinbryta

Submission MilestoneDate
Pre-submission meeting:2015-05-27
Submission filed:2015-12-21
Screening
Screening Acceptance Letter issued:2016-02-12
Review
Quality Evaluation complete:2016-12-06
Clinical Evaluation complete:2016-12-07
Labelling Review complete:2016-12-07
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate:2016-12-08

The Canadian regulatory decision on the non-clinical and clinical review of Zinbryta was based on a critical assessment of the Canadian data package. The foreign reviews completed 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 Zinbryta, Health Canada requested and the sponsor agreed to several commitments to be addressed post-marketing. 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 that occurred in all clinical trials with Zinbryta. These serious adverse events should include: hepatic injury, other serious immune-mediated disorders (for example [e.g.], skin reactions, lymphadenopathy, colitis), malignancies (e.g., breast cancer), infections, hypersensitivity reactions, depression, etc.
  • Submitting to Health Canada, prior to the launch of Zinbryta:
    • the full Zinbryta controlled distribution program plan: Biogen ONE Support Program and its associated registry;
    • the Zinbryta medical educational materials and communication plan for review and comments;
    • a revised Canadian Risk Management Plan (RMP) that will:
      • integrate the parameters/elements of the Biogen ONE Support Program and its associated registry;
      • reflect the Canadian labelling for Zinbryta, the post-approval commitments to Health Canada and the international status.
  • Providing Health Canada with Periodic Safety Update Reports (PSURs)/Periodic Benefit Risk Evaluation Reports (PBRERs) for Zinbryta every six months for the first three years following market authorization and annually thereafter (upon request by Health Canada). Each PSUR/PBRER should include an analysis of all adverse drug events as per the pharmacovigilance plan and safety updates from all ongoing clinical trials with Zinbryta.
  • Providing Health Canada with concise safety reports every six months for the first three years following market authorization and annually thereafter (upon request by Health Canada), including copies of reports provided to other regulatory agencies, once the product is launched (in addition to the PSURs/PBRERs).
  • Informing Health Canada, in a timely manner, of all suspected cases of hepatic injury, other serious immune-mediated disorders (e.g., skin reactions, lymphadenopathy, colitis), malignancies (e.g., breast cancer), etc.
  • 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. This will include reports on studies 3084-1, 3084-2, and 3084-3 (committed to the FDA).
  • Including Canadian patients in the planned registry for pregnancies (study 3084-4, committed to the FDA) and providing Health Canada, as appropriate, with regular safety updates from this study. This should be indicated in the updated RMP.

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

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 decision was negative or positive. The PAAT will continue to be updated during the product's life cycle.

The PAAT for Zinbryta 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

Daclizumab beta, the medicinal ingredient of Zinbryta, is a humanized monoclonal antibody that binds to CD25 (interleukin-2 receptor α, IL-2Rα), and prevents IL-2 binding to CD25. Daclizumab beta modulates IL-2 signalling by selectively blocking CD25-dependent, high-affinity IL-2 receptor signalling (a receptor that is up-regulated on the surface of activated lymphocytes), resulting in higher levels of IL-2 available for signalling through the CD25-independent intermediate-affinity IL-2 receptor. The precise mechanism by which daclizumab beta exerts therapeutic effects in multiple sclerosis is unknown.

The pharmacokinetics and pharmacodynamics of daclizumab beta have been evaluated in four Phase I studies in healthy volunteers, one study in subjects with multiple sclerosis, and by using sparse sampling from Phase II and Phase III studies in subjects with multiple sclerosis.

The pharmacokinetic characteristics determined after multiple subcutaneous administrations of daclizumab beta indicated a slow absorption (approximately 7 days following the first dose), and a long elimination half-life (approximately 21 days). The pharmacokinetics of daclizumab beta is well described by a two-compartment model with first-order absorption and elimination. Multiple studies demonstrated similar pharmacokinetics of daclizumab beta for healthy volunteers and patients with multiple sclerosis (MS).

In the Phase I study 1014, saturation of CD25 on peripheral CD4+ T cells was observed within 4 hours of dosing in the majority of subjects, despite the slow absorption of daclizumab beta. Moreover, the CD25 saturation was sustained throughout the dosing period (16 weeks) despite the interruption in dosing.

During Zinbryta treatment, mean cell counts for the major immune subsets (T, B, and natural killer [NK] cells) remained within normal ranges. Total lymphocyte, T and B cell counts decreased on average ≤10% from baseline during the first year of treatment. Total lymphocyte counts returned to baseline levels approximately 8-12 weeks after the last dose of Zinbryta (150 mg).

The clinical pharmacological data support the use of Zinbryta for the specified indication.

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

Clinical Efficacy

The efficacy of Zinbryta was evaluated in two randomized, double-blind, controlled studies; the active comparator-controlled Phase III Study 205MS301 (DECIDE) and the placebo-controlled Phase II Study 205MS201 (SELECT). The active-controlled study, DECIDE, was the main focus of the clinical review of Zinbryta.

The DECIDE study was a double-blind, randomized, active-controlled study, which compared Zinbryta 150 mg administered subcutaneously every 4 weeks (number of patients [n] = 919) with Avonex (IFN β-1a) 30 µg administered intramuscularly once weekly (n = 922), for a minimum of 96 weeks to a maximum of 144 weeks. At baseline, the mean age of the patients was 36 years, the mean disease duration since diagnosis was 4.2 years, the mean Expanded Disability Status Scale (EDSS) score was 2.5, and the mean number of relapses in the prior year was 1.6.

The primary efficacy endpoint in the DECIDE study was the annualized relapse rate (ARR). The secondary endpoints included the number of new or newly enlarging T2 hyperintense magnetic resonance imaging (MRI) lesions, the proportion of patients who experienced confirmed disability progression, and the proportion of patients who relapsed. Confirmed disability progression was defined as an increase of at least 1 point from baseline EDSS (or an increase of 1.5 points for patients with baseline EDSS of 0) sustained for 12 weeks.

The study met its primary efficacy endpoint; Zinbryta reduced the ARR by 45% as compared to Avonex, rate ratio (RR) = 0.55 (95% confidence interval [CI], 0.469-0.645, p<0.0001). A number of sensitivity analyses supported the primary analysis.

In addition, Zinbryta significantly reduced the number of new, or newly enlarging T2 hyperintense lesions by 54% (95% CI, 47%-61%, p<0.0001) compared to Avonex. The 12-week sustained disability progression measured by increase in EDSS did not reach statistical significance. The hazard ratio for Zinbryta versus Avonex was 0.84 (95% CI, 0.66-1.07), indicating that Zinbryta reduced the risk of disability progression by 16% (p = 0.1575) compared with Avonex.

The SELECT study was a double-blind, randomized, placebo-controlled study, which compared Zinbryta 150 mg (n = 208), or Zinbryta 300 mg (n = 209) administered subcutaneously every 4 weeks with placebo (n = 204) for 52 weeks. At baseline, the mean age of patients was 36 years, the mean disease duration since diagnosis was 4.1 years, the mean EDSS score was 2.8, and the mean number of relapses in the prior year was 1.4.

The primary efficacy endpoint in the SELECT study was the ARR at Week 52. The secondary endpoints included the number of new T1 gadolinium (Gd)-enhancing lesions between Week 8 and Week 24, the number of new or newly enlarging T2 hyperintense MRI lesions at Week 52, and the proportion of patients who relapsed. The proportion of patients who experienced 12-week confirmed disability progression (as defined in the DECIDE study) was a tertiary endpoint.

In the SELECT study, treatment with Zinbryta 150 mg every 4 weeks versus placebo significantly reduced the ARR by 54% (95% CI, 33%-68%, p<0.0001).

Zinbryta impacted the MRI endpoints, including a reduction in the mean number of new or newly enlarging T2 hyperintense MRI lesions at Week 52 and the mean number of new T1 Gd-enhancing lesions between 8 and 24 weeks compared to placebo.

Indication

The original New Drug Submisssion (NDS) for Zinbryta was filed with the following proposed indication:

  • Zinbryta is indicated for the treatment of relapsing forms of multiple sclerosis (MS).

Health Canada revised the proposed indication to restrict the targeted patient population due to the serious safety concerns associated with Zinbryta, and approved the following indication:

  • Zinbryta (daclizumab beta) is indicated for the treatment of adult patients with active relapsing remitting multiple sclerosis (RRMS) who have had an inadequate response to, or who are unable to tolerate, one or more therapies indicated for the treatment of multiple sclerosis (MS).

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

Clinical Safety

The clinical safety of Zinbryta was evaluated from a safety database that encompassed data obtained in the Phase II placebo-controlled study SELECT (with treatment duration of 1 year), the Phase III active-controlled study DECIDE (with treatment duration of up to 3 years), their extensions, the Phase III open-label study 205MS302, and the 120-day safety update report. A total of 2,236 adult patients with RRMS were treated with Zinbryta. Of these patients, 1,576 received Zinbryta for at least 1 year, 1,259 for at least 2 years, and 888 for at least 3 years. The size of the safety database was considered acceptable. Notably, there were only two patients older than 55 years in two clinical trials.

The primary safety concern identified in the submitted information refers to the fact that Zinbryta can cause life-threatening severe liver injury, including liver failure and autoimmune hepatitis. In controlled studies, serious drug-related hepatic injury occurred in 0.7% of Zinbryta-treated patients compared with 0.4% of Avonex-treated patients (the DECIDE study) and in 1.0% of Zinbryta-treated patients compared with no injury in placebo-treated patients (the SELECT study). Across all clinical studies (controlled and open-label), serious drug-related hepatic injury occurred in 1% of Zinbryta-treated patients, with monthly monitoring of transaminases and total bilirubin. The incidence of discontinuation due to drug-related hepatic injury was 5% in Zinbryta-treated patients and 4% in Avonex-treated patients.

In a clinical study, one patient died due to autoimmune hepatitis. The case prompted changes to the protocol to increase monitoring. Subsequently, additional changes were made to mandate assessment of laboratory values prior to monthly dosing of Zinbryta.

Furthermore, the incidence of increases in hepatic transaminases was greater in patients receiving Zinbryta than in those receiving Avonex or placebo. The incidence of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations above 5 times the upper limit of normal (ULN) was 6% in Zinbryta-treated patients compared with 3% in Avonex-treated patients (the DECIDE study), and 4% in Zinbryta-treated patients compared with 1% in patients treated with placebo (the SELECT study). The serum transaminase elevations occurred during treatment and up to four months after the last dose of Zinbryta.

In addition to autoimmune hepatitis, Zinbryta was also associated with other immune mediated disorders including skin reactions, lymphadenopathy, autoimmune hemolytic anemia and gastrointestinal disorders. Across all clinical studies (controlled and open label), immune-mediated disorders occurred in 28% of patients receiving Zinbryta. Serious skin reactions occurred in 2% of patients treated with Zinbryta compared with 0.1% of patients treated with Avonex (the DECIDE study), and in 1% of patients treated with Zinbryta compared with 0% of patients treated with placebo (the SELECT study). One death resulted from infectious complications following a serious cutaneous reaction. Autoimmune hemolytic anemia was reported in <1% of patients treated with Zinbryta. Also, an increased incidence of serious colitis (<1%) was reported in Zinbryta-treated patients.

Other reported adverse events included infections, hypersensitivity, depression (including suicidal ideation or suicide attempt), seizures and malignancies (breast cancer).

The serious safety concerns associated with the use of Zinbryta have been specifically addressed in the Serious Warnings and Precautions box of the Zinbryta Product Monograph.

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

7.2 Non-Clinical Basis for Decision

The non-clinical development program of daclizumab beta, the medicinal ingredient of Zinbryta, included a total of 24 studies.

Non-clinical safety studies were conducted in cynomolgus monkeys due to the species specificity of daclizumab beta binding only to human or primate CD25. In cynomolgus monkeys, subcutaneous administration of daclizumab beta for up to 39 weeks at doses ranging from 10 mg/kg to 200 mg/kg every two weeks, increased the incidence of skin findings, including dry, red raised patchy areas of the skin that correlated microscopically with acanthosis/hyperkeratosis and subacute to chronic inflammation. In addition, a dose-dependent increase in microglial aggregates was observed in the brain and spinal cord of monkeys administered with ≥35 mg/kg daclizumab beta, corresponding to plasma exposure (the area under the curve [AUC]) approximately 27 times higher than would be expected clinically. Studies demonstrated a no-effect level of 10 mg/kg (AUC approximately 7 times higher than would be expected clinically) for microglial aggregates. However, dose levels between 10 mg/kg and 35 mg/kg were not evaluated. Following a recovery period of up to 12 weeks, there was evidence of reversibility. Microglial aggregates were associated with microhemorrhage in some animals, but were not associated with neuronal damage or neurobehavioral effects. The clinical relevance of microglial aggregates is unknown and aggregate monitoring in human patients is not feasible. These findings have been carefully considered in the benefit/risk evaluation of daclizumab beta and incorporated in the Zinbryta Product Monograph.

Other studies in cynomolgus monkeys showed that daclizumab beta crosses the placental barrier. An increase in fetal loss was observed in animals administered subcutaneously 200 mg/kg daclizumab beta every week during the period of organogenesis (gestation days 20 to 50). The no-effect dose of 50 mg/kg resulted in plasma exposure (AUC) that was approximately 30 times greater than would be expected clinically. The clinical significance of these findings is not known. These findings have been highlighted in the Special Populations section of the Zinbryta Product Monograph.

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

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

7.3 Quality Basis for Decision

Daclizumab beta, the medicinal ingredient of Zinbryta, is a recombinant humanized immunoglobulin G1 (IgG1) monoclonal antibody expressed in murine myeloma NS0 cells. It binds to CD25, the alpha subunit of the high-affinity interleukin-2 receptor, IL 2Rα, which is expressed on the surface of activated lymphocytes. The antibody consists of human constant regions and engineered variable regions composed of human frameworks and murine complementarity-determining regions.

Zinbryta is formulated as a liquid at a concentration of 150 mg/mL in 40 mM sodium succinate, 100 mM sodium chloride, 0.03% polysorbate 80, pH 6.0.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that daclizumab beta 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 of the Drug Substance and Drug Product

The drug substance, daclizumab beta, is produced by recombinant deoxyribonucleic acid (DNA) technology in murine myeloma NS0 cells.

The cell culture is expanded using a series of shake flasks and seed bioreactors to generate a sufficient amount of viable cells to inoculate a production bioreactor. The conditioned medium is clarified by centrifugation followed by depth filtration and purification steps. The drug substance manufacturing process also includes a low pH virus inactivation and neutralization step and a virus reduction filtration step. The resulting drug substance is formulated and dispensed in ultra-low density polyethylene bags, stored at 2°C to 8°C.

The sponsor has demonstrated that daclizumab beta is manufactured by a process that is robust and capable to consistently produce a high quality product that meets specifications.

The Zinbryta drug product is a colourless to slightly yellow, clear to slightly opalescent liquid, which is essentially free of visible particles and is supplied in a 1 mL sterile, Type 1 glass pre-filled syringe for subcutaneous administration. Two presentations are available for subcutaneous administration: a pre-filled syringe that consists of the syringe assembled with a finger flange and plunger rod, and a pre-filled pen which encloses the pre-filled syringe container closure inside the final assembled pre-filled pen.

The manufacturing process for the drug product Zinbryta consists of receipt and storage of drug substance, sterile filtration to the filling line, aseptic syringe filling and plunger placement, visual inspection, and storage at 2°C to 8°C.

The sponsor has demonstrated that the drug product manufacturing process is under adequate control and can yield a product with consistent quality.

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 daclizumab beta with the excipients was demonstrated.

Control of the Drug Substance and Drug Product

Through Health Canada's lot release testing and evaluation program, consecutively manufactured drug 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-month shelf life at 2°C to 8°C for Zinbryta, and its 30-day in-use shelf life at room temperature are considered acceptable.

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 daclizumab beta (drug substance) was not warranted since the facility was recently evaluated in good standing. An OSE of the facility involved in the manufacture and testing of Zinbryta (drug product) could not be undertaken during the drug review period.

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

Adventitious Agents Safety Evaluation

The daclizumab beta manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. The purification process employs adequately validated viral clearance and viral inactivation steps, and demonstrates a high level of viral clearance for a variety of virus types.

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