Summary Basis of Decision for Zeposia

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 Zeposia is located below.

Recent Activity for Zeposia

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.

The following table describes post-authorization activity for Zeposia, a product which contains the medicinal ingredient ozanimod (supplied as ozanimod hydrochloride). 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 AnchorAnchorManagement of Drug Submissions and Applications Guidance.

Updated: 2023-08-30

Drug Identification Number (DIN):

  • DIN 02506009 – 0.23 mg ozanimod, capsule and 0.46 mg ozanimod, capsule, oral administration
  • DIN 02505991 – 0.92 mg ozanimod, capsule, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 248992 2021-01-29 Issued NOC 2022-04-08 Submission filed as a Level I – Supplement for a new indication. The indication authorized was: the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response, loss of response, or were intolerant to either conventional therapy or biologic agent. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 253417 2021-06-04 Issued NOC 2021-10-29 Submission filed as a Level II – Supplement (Safety) 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 Dosage and Administration sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
Drug product (DINs 02505991, 02506009) market notification Not applicable Date of first sale: 2020-11-12 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 232761 2019-10-25 Issued NOC 2020-10-02 NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Zeposia

Date SBD issued: 2020-12-02

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

Ozanimod (supplied as ozanimod hydrochloride)

Drug Identification Number (DIN):

  • DIN 02506009 - 0.23 mg ozanimod, capsule and 0.46 mg ozanimod, capsule, oral administration
  • DIN 02505991 - 0.92 mg ozanimod, capsule, oral administration

Celgene Inc.

New Drug Submission Control Number: 232761

 

On October 2, 2020, Health Canada issued a Notice of Compliance to Celgene Inc. for the drug product Zeposia.

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-harm-uncertainty profile of Zeposia is favourable for the treatment of patients with relapsing remitting multiple sclerosis to decrease the frequency of clinical exacerbations.

 

1 What was approved?

 

Zeposia, a sphingosine 1-phosphate receptor modulator, was authorized for the treatment of patients with relapsing remitting multiple sclerosis to decrease the frequency of clinical exacerbations.

Zeposia should only be prescribed by neurologists who are experienced in the treatment of multiple sclerosis, have knowledge of the efficacy and safety profile of Zeposia, and are able to discus the benefits and harms of the drug with patients.

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

In addition, Health Canada has not authorized an indication for geriatric use, as no data are available for patients aged 65 years and over. Physicians who choose to treat geriatric patients should consider that treatment with Zeposia in the context of a greater frequency of reduced hepatic, renal, immune, pulmonary and cardiovascular functions, other concomitant diseases and concomitant drug therapy warrants caution and may necessitate additional or more frequent monitoring.

The use of Zeposia is contraindicated in the following patient populations:

  • Patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
  • Patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization or New York Heart Association class III or IV heart failure.
  • Patients with a history or presence of second-degree atrioventricular (AV) block type II or third-degree AV block, sick sinus syndrome, or sinoatrial block, unless the patient has a functioning pacemaker.
  • Patients with increased risk of opportunistic infections, including those who are immunocompromised due to treatment (e.g., antineoplastic, immunosuppressive or immunomodulating therapies, total lymphoid irradiation or bone marrow transplantation) or disease (e.g., immunodeficiency syndrome).
  • Patients with severe active infections including active bacterial, fungal or viral infections (e.g., hepatitis, tuberculosis), until resolution of the infection.
  • Patients with known active malignancies, except localized basal cell carcinoma of the skin.
  • Women (including female adolescents) who are pregnant or of childbearing potential not using effective contraception. Pregnancy must be excluded before start of treatment as Zeposia may cause fetal harm.

Additionally, the concomitant use of Zeposia with other monoamine oxidase (MAO) inhibitors is contraindicated because of the increased risk of non-selective MAO inhibition that may lead to a hypertensive crisis.

Zeposia 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.

Zeposia (0.23 mg, 0.46 mg, and 0.92 mg ozanimod, supplied as ozanimod hydrochloride) is presented as a capsule. In addition to the medicinal ingredient, the capsule contains colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The capsule shell contains black iron oxide (E172), gelatin, pharmaceutical ink, red iron oxide (E172), titanium dioxide (E171), and yellow iron oxide (E172).

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

 

2 Why was Zeposia approved?

 

Health Canada considers that the benefit-harm-uncertainty profile of Zeposia is favourable for the treatment of patients with relapsing remitting multiple sclerosis to decrease the frequency of clinical exacerbations.

Multiple sclerosis is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system that affects approximately 55,000 to 75,000 Canadians. Canada has one of the highest prevalence rates of multiple sclerosis in the world (around 240 cases per 100,000 people in 2005). Multiple sclerosis is associated with irreversible progression of disability that includes physical and cognitive impairments, fatigue, pain, depression, and bladder dysfunction. Relapsing remitting multiple sclerosis is the most common clinical presentation of the disease, affecting about 85% of multiple sclerosis patients. It is characterized by acute attacks of neurological disability (relapses) caused by acute inflammatory lesions in the central nervous system, followed by full recovery or residual effects. The acute inflammatory lesions that cause relapses are generally thought to be related to aberrant (autoimmune) immune responses. The residual effects of the inflammatory lesions on the central nervous system tissue (axonal loss, tissue loss, and atrophy) contribute to the neurodegenerative aspects of the disease and the accumulation of disability over time. Within 20 years, approximately two-thirds of patients will eventually develop secondary progressive multiple sclerosis, which is characterized by progressive neurological decline.

The current therapeutic approach involves symptomatic treatment, treatment of acute relapses, and disease modifying therapies, which aim to prevent relapses and diminish accumulation of disability.

The medicinal ingredient in Zeposia, ozanimod, is a potent, orally bioavailable sphingosine 1-phosphate (S1P) receptor modulator. Sphingosine 1-phosphate regulates a variety of physiological processes, including lymphocyte recirculation and cardiac function, via five G-protein-coupled S1P receptor subtypes (referred to as S1P1, S1P2, S1P3, S1P4, and S1P5). Ozanimod binds with high affinity and selectivity to S1P1 and S1P5 receptors. The binding of ozanimod and its metabolites to S1P1 receptors on lymphocytes prevents the lymphocyte egress from lymph nodes, thereby reducing the number of lymphocytes in peripheral blood. The mechanism by which ozanimod and its active metabolites exert their therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.

The market authorization of Zeposia was based on clinical efficacy data derived from two pivotal Phase III studies in patients with relapsing remitting multiple sclerosis (Study RPC01-301 and Study RPC01-201B). The overall safety evaluation of Zeposia was based on data derived from 24 clinical studies, including seven Phase II and III studies, and 17 clinical pharmacology studies.

The pivotal studies were multicentre, randomized, double-blind, double-dummy, active-controlled, parallel-group studies of similar design and endpoints. In both studies, the active comparator treatment was interferon beta-1a (30 µg administered intramuscularly once weekly). Zeposia was given orally once daily, with a starting dose of 0.23 mg on days 1 to 4, an escalation to 0.46 mg on days 5 to 7, followed by the assigned dose, 0.92 mg or 0.46 mg, on day 8 and thereafter. The duration of treatment was 24 months in Study RPC01-201B and up to approximately 22 months (mean duration of 13.6 months) in Study RPC01-301, in which the treatment continued for all patients until the last enrolled patient completed one year of treatment. Following baseline brain magnetic resonance imaging (MRI) assessments at screening, further brain MRI assessments were conducted at months 6 and 12 in Study RPC01-301, and at months 12 and 24 in Study RPC01-201B.

The primary endpoint was the annualized relapse rate over 12 months (for Study RPC01-301) and the annualized relapse rate over 24 months (for Study RPC01-201B). Statistically significant reductions in the annualized relapse rate were demonstrated for Zeposia 0.92 mg and Zeposia 0.46 mg compared to interferon beta-1a. In Study RPC01-301, the reduction in the annualized relapse rate at the end of the treatment period was 48% with Zeposia 0.92 mg and 31% with Zeposia 0.46 mg relative to the treatment with interferon beta-1a. The reduction in the annualized relapse rate at month 24 in Study RPC01-201B was approximately 38% with Zeposia 0.92 mg and 21% with Zeposia 0.46 mg compared to interferon beta-1a.

The safety profile of Zeposia was evaluated in 2,787 patients with relapsing multiple sclerosis, with over 7,200 person-years of follow-up. This patient population included 2,491 patients treated with Zeposia 0.92 mg for more than 1 year, 1,069 patients treated for more than 2 years, and 521 patients treated for more than 3 years.

In the pivotal Phase III clinical studies, adverse drug reactions assessed by the sponsor to be related to Zeposia 0.92 mg included nasopharyngitis, increased alanine aminotransferase, increased gamma glutamyltransferase, urinary tract infection, hypertension, pharyngitis, viral respiratory tract infection, bradycardia, herpes zoster, rash, and urticaria.

Important risks associated with Zeposia have been identified based on integrated and trial-specific safety analyses, known pharmacokinetic and pharmacodynamic properties, and the mechanism of action of ozanimod and other S1P receptor modulators. These risks include reduction in heart rate, elevations in hepatic enzymes, infections (e.g., herpetic infections, cryptococcal infections, progressive multifocal leukoencephalopathy), posterior reversible encephalopathy syndrome, macular edema, embryo-fetal toxicity, and serotonin toxicity due to potential interaction between the monoamine oxidase inhibitory activity of the major metabolites of ozanimod and serotonergic drugs or opioid drugs (although no events of serotonin toxicity/serotonin syndrome have been reported in subjects concomitantly exposed to opoids and/or serotonergic medications and Zeposia in clinical studies) (see Clinical Safety).

Risk mitigation measures encompassing appropriate contraindications, warnings, guidance, dosage considerations, screening and monitoring recommendations have been outlined in the Zeposia Product Monograph to address the identified risks. Nevertheless, uncertainties remain with respect to long-term risks of malignancies, cardiovascular morbidity, and effects following withdrawal of Zeposia (considering the long half-life of the active metabolites).

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

The submitted inner and outer labels, package insert and Patient Medication Information section of the Zeposia Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

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

Zeposia 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 Zeposia 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 Zeposia?

 

Submission Milestones: Zeposia

Submission Milestone Date
Pre-submission meeting 2019-07-31
Submission filed 2019-10-25
Screening  
Screening Acceptance Letter issued 2019-12-09
Review  
Biopharmaceutics Evaluation complete 2020-07-23
Biostatistics Evaluation complete 2020-09-10
Quality Evaluation complete 2020-09-29
Labelling Review complete, including Look-alike Sound-alike brand name assessment 2020-10-01
Clinical/Medical Evaluation complete 2020-10-02
Review of Risk Management Plan complete 2020-10-02
Notice of Compliance issued by Director General, Therapeutic Products Directorate 2020-10-02

 

The Canadian regulatory decision on the review of Zeposia was based on a critical assessment of the data package submitted to Health Canada. 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?

 

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

 

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

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

The PAAT for Zeposia 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

Ozanimod, the medicinal ingredient in Zeposia, is a sphingosine 1-phosphate (S1P) receptor modulator. The clinical pharmacology of ozanimod has been characterized in healthy subjects in 17 Phase I studies. Additionally, sparse samples for population pharmacokinetic and exposure-response analyses were collected from patients with relapsing multiple sclerosis in one Phase II study and two Phase III studies.

In humans, ozanimod is extensively metabolized to form a number of circulating active metabolites, including two major active metabolites, CC112273 and CC1084037. Ozanimod and its active metabolites have similar activity and selectivity for the S1P receptor subtypes, S1P1 and S1P5. The binding of ozanimod and its metabolites to S1P1 receptors on lymphocytes prevents the lymphocyte egress from lymph nodes, thereby reducing the number of lymphocytes in peripheral blood. The mechanism by which ozanimod and its active metabolites exert their therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.

Following multiple-dose administration of ozanimod in healthy subjects, approximately 94% of circulating total active drug exposure is represented by ozanimod (6%) and its two major active metabolites, CC112273 (73%) and CC1084037 (15%). The remaining 6% of circulating total active drug exposure is represented by other minor active metabolites. Following oral administration, the median time to reach maximum plasma concentration of ozanimod was approximately 6 to 8 hours. The mean elimination half-life values for ozanimod were approximately 19 to 22 hours. Steady-state concentrations for ozanimod were reached within 5 to 7 days of daily administration of ozanimod. At steady state, approximately twofold drug accumulation for ozanimod was observed. The metabolites CC112273 and CC1084037 exhibited similar mean half-life values of approximately 10 days following single oral doses in healthy subjects. In patients with relapsing multiple sclerosis, the estimated mean half-life of CC112273 was approximately 11 days following multiple dosing. After oral administration of a single dose of radiolabelled ozanimod, approximately 26% and 37% of the administered radioactivity was recovered from urine and feces, respectively. The recovered radioactivity was primarily composed of inactive metabolites.

An increased exposure of intermediate metabolites of ozanimod was seen with coadministration of an inhibitor of the breast cancer resistance protein (BCRP). This may potentially lead to increases in the major active metabolites, CC112273 and CC1084037. An increased exposure of the major active metabolites, which may increase the risk of adverse reactions, was seen when ozanimod was coadministered with a strong inhibitor of CYP2C8. On the other hand, the coadministration of a strong CYP2C8 inducer with ozanimod led to a reduced exposure of major active metabolites, which may decrease the efficacy of ozanimod.

The potential for clinical interaction with monoamine oxidase (MAO) inhibitors has not been studied. However, the coadministration with monoamine oxidase B (MAO-B) inhibitors may decrease exposure of the major active metabolites. In addition, CC112273 and CC1084037 inhibited MAO-B in vitro (half-maximal inhibition [IC50] values of 5.72 nM and 58 nM, respectively) with more than 1,000-fold selectivity over monoamine oxidase A (MAO-A). Therefore, the concomitant use of drugs in the MAO inhibitor class or other drugs that are potent inhibitors of MAO is contraindicated due to the likely reduction in active metabolite concentration leading to reduced therapeutic effect and risk of non-selective MAO inhibition, which may lead to hypertensive crisis.

Interaction with food items containing high amounts of tyramine could cause severe hypertension due to potential risk of non-selective MAO-A inhibition in the gastrointestinal tract.

There were no clinically meaningful differences in systemic exposure of ozanimod and CC112273 in subjects with end-stage renal disease compared with their matched healthy subjects.

A single-dose study investigating the pharmacokinetics of ozanimod and its metabolites in participants with mild to moderate hepatic impairment did not address the accumulation potential of the major active metabolites in patients who will be taking frequent and higher doses of ozanimod. In addition, the pharmacokinetic characteristics of ozanimod and its metabolites were not evaluated in individuals with severe hepatic impairment. Therefore, the use of Zeposia is not recommended in patients with hepatic impairment.

Results of a thorough QT study of ozanimod did not reveal prolongation effects on the corrected QT (QTc) interval. The duration of this study was not sufficient to achieve steady-state plasma concentrations of the major active metabolites, CC112273 and CC1084037.

The coadministration of a starting dose of ozanimod (0.23 mg) and steady-state long-acting propranolol (80 mg) or steady-state extended-release diltiazem (240 mg) did not result in any additional clinically meaningful changes in heart rate, mean arterial blood pressure, and PR interval compared to propranolol or diltiazem alone. However, concomitant administration of beta-blockers and calcium channel blockers have not been studied in the context of the maintenance dosing of ozanimod.

A dedicated Phase I study demonstrated that the magnitude of the negative chronotropic and adverse conduction effects of S1P receptor modulation may be exposure dependent and could be mitigated by a gradual increase of the exposure. Based on these data, a 7-day dose escalation regimen was implemented in a placebo-controlled Phase II study (Study RPC01-201A) and two active-controlled Phase III studies (Study RPC01-301 and Study RPC01-201B, described in the Clinical Efficacy section). Two dose levels (0.46 mg and 0.92 mg) for once daily oral dosing of ozanimod were selected for the Phase II study. Both doses showed roughly equivalent efficacy on the endpoints evaluated by brain magnetic resonance imaging (MRI). However, the ozanimod 0.92 mg dose showed a numerically better effect than the 0.46 mg dose on the adjusted annualized relapse rate at week 24 and the number of new or enlarging hyperintense T2-weighted brain MRI lesions from week 12 to week 24, with no meaningful differences in safety. These two doses of ozanimod (0.46 mg and 0.92 mg) were further investigated in the active-controlled Phase III studies (see Clinical Efficacy).

The clinical pharmacology data support the use of Zeposia for the recommended indication.

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

Clinical Efficacy

The clinical efficacy of Zeposia was evaluated in two pivotal Phase III studies conducted in patients with relapsing remitting multiple sclerosis (Study RPC01-301 and Study RPC01-201B).

The pivotal studies were multicentre, randomized, double-blind, double-dummy, active-controlled, parallel-group studies of similar design and endpoints. In both studies, the active comparator treatment was interferon beta-1a (30 µg administered intramuscularly once weekly). Zeposia was given orally once daily, with a starting dose of 0.23 mg on days 1 to 4, an escalation to 0.46 mg on days 5 to 7, followed by the assigned dose (0.92 mg or 0.46 mg) on day 8 and thereafter. The duration of treatment was 24 months in Study RPC01-201B and up to approximately 22 months (mean duration of 13.6 months) in Study RPC01-301, in which the treatment continued for all patients until the last enrolled patient completed one year of treatment. Following baseline brain MRI assessments at screening, further brain MRI assessments were conducted at months 6 and 12 in Study RPC01-301, and at months 12 and 24 in Study RPC01-201B.

The primary endpoint was the annualized relapse rate over 12 months, for Study RPC01-301, and the annualized relapse rate over 24 months, for Study RPC01-201B. The key secondary outcome measures included the number of new or enlarging MRI T2 hyperintense lesions over 12 and 24 months, the number of MRI T1 gadolinium-enhancing lesions at 12 and 24 months, and the time to confirmed disability progression, defined as at least a 1-point increase from baseline Expanded Disability Status Scale (EDSS) score sustained for 12 weeks. Confirmed disability progression was prospectively evaluated in a pooled analysis of both studies. An additional MRI outcome measure was the mean percentage change from baseline in normalized brain volume.

Statistically significant reductions in the annualized relapse rate were demonstrated for Zeposia 0.92 mg and Zeposia 0.46 mg compared to interferon beta-1a. In Study RPC01-301, the reduction in the annualized relapse rate at the end of the treatment period was 48% with Zeposia 0.92 mg and 31% with Zeposia 0.46 mg relative to the treatment with interferon beta-1a. The reduction in the annualized relapse rate at month 24 in Study RPC01-201B was approximately 38% with Zeposia 0.92 mg and 21% with Zeposia 0.46 mg compared to interferon beta-1a.

Similarly, treatment with Zeposia 0.92 mg led to reductions of 48% and 42% in the mean number of new or enlarging hyperintense T2-weighted brain MRI lesions per brain scan over 12 and 24 months, respectively, compared to the treatment with interferon beta-1a. Treatment with Zeposia 0.46 mg resulted in reductions of 25% and 34% over 12 and 24 months, respectively, relative to treatment with interferon beta-1a.

The mean number of brain MRI T1 gadolinium-enhancing lesions at 12 and 24 months was also reduced with Zeposia treatment relative to interferon beta-1a treatment. The observed relative reductions with Zeposia 0.92 mg were 63% at 12 months and 53% at 24 months. Zeposia 0.46 mg led to reductions of 34% and 47% at 12 and 24 months, respectively, compared to interferon beta-1a.

In prespecified pooled analyses, disability progression, as measured by the percent reduction in time to onset of disability progression (EDSS worsening of at least 1-point increase, confirmed after 3 and 6 months, CDP-3M and CDP-6M), was similar between the Zeposia and the interferon beta-1a treatment groups.

Indication

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

  • Zeposia (ozanimod) is indicated for the treatment of patients with relapsing remitting multiple sclerosis (RRMS) to decrease the frequency of clinical exacerbations.

To ensure safe and effective use of the product, Health Canada revised the proposed indication to include a caveat statement related to the prescription of treatment with Zeposia. Accordingly, Health Canada approved the following indication:

  • Zeposia (ozanimod) is indicated for the treatment of patients with relapsing remitting multiple sclerosis (RRMS) to decrease the frequency of clinical exacerbations.
     
  • Zeposia should only be prescribed by neurologists who are experienced in the treatment of multiple sclerosis, are knowledgeable of the efficacy and safety profile of Zeposia and are able to discuss benefits/harms with patients.

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

Clinical Safety

The safety of Zeposia (ozanimod) was evaluated in 2,787 patients with relapsing multiple sclerosis, with over 7,200 person-years of follow-up. This patient population included 2,491 patients treated with Zeposia 0.92 mg for more than 1 year, 1,069 patients treated for more than 2 years, and 521 patients treated for more than 3 years.

In the Phase III clinical studies (described in the Clinical Efficacy section), adverse drug reactions assessed by the sponsor to be related to Zeposia 0.92 mg included nasopharyngitis, increased alanine aminotransferase, increased gamma glutamyltransferase, urinary tract infection, hypertension, pharyngitis, viral respiratory tract infection, bradycardia, herpes zoster, rash, and urticaria.

Important risks associated with Zeposia have been identified based on integrated and trial-specific safety analyses, known pharmacokinetic and pharmacodynamic properties, and the mechanism of action of ozanimod. These risks include reduction in heart rate, elevations in hepatic enzymes, infections, posterior reversible encephalopathy syndrome, macular edema, embryo-fetal toxicity, and serotonin toxicity due to potential interaction between the MAO inhibitory activity of the major metabolites of ozanimod and serotonergic drugs or opioid drugs.

Bradycardia was reported in 0.5% of patients treated with Zeposia versus 0% of those treated with interferon beta-1a on the day of treatment initiation. Heart rates below 40 beats per minute were not observed. A dose escalation schedule attenuates the magnitude of heart rate reductions. Nevertheless, in patients with certain pre-existing cardiac conditions, i.e., sinus bradycardia (heart rate lower than 55 beats per minute), first or second-degree (Mobitz type) atrioventricular block, or a history of myocardial infarction or heart failure, first-dose monitoring for signs and symptoms of bradycardia is recommended for a period of at least 6 hours after the first dose of Zeposia. Furthermore, contraindications for the use of Zeposia in patients with specific pre-existing cardiac conditions are included in the Zeposia Product Monograph.

Zeposia is associated with elevations in alanine aminotransferase and gamma glutamyltransferase. Most hepatic-related events were mild to moderate in intensity, and resolved while continuing treatment. Liver function tests should be obtained before initiation of Zeposia. Patients who develop symptoms suggestive of hepatic dysfunction should have liver enzymes checked and the treatment with Zeposia should be discontinued if significant liver injury is confirmed. The use of Zeposia is not recommended in patients with hepatic impairment since the effect of hepatic impairment on the pharmacokinetics of the major active metabolites of ozanimod has not been established.

Zeposia causes a mean reduction in peripheral blood lymphocyte count to approximately 43% to 47% of baseline values at the 0.92 mg dose and may therefore increase the susceptibility to infections, including serious and life-threatening infections (e.g., herpes simplex encephalitis, varicella zoster meningitis, cryptococcal meningitis, disseminated cryptococcal infections, progressive multifocal leukoencephalopathy). Accordingly, the use of Zeposia is contraindicated in patients with an increased risk of opportunistic infections and patients with severe active bacterial, fungal or viral infections, until resolution of the infection. There are no clinical data on the efficacy and safety of vaccinations in patients taking Zeposia. The use of live attenuated vaccines during and for 3 months after treatment with Zeposia should be avoided. Varicella zoster virus vaccination of patients without documented immunity to the virus is recommended prior to initiating treatment with Zeposia.

Rare cases of posterior reversible encephalopathy syndrome have been reported in patients receiving a S1P receptor modulator. In controlled clinical trials with Zeposia, one case of posterior reversible encephalopathy syndrome was reported in a patient with Guillain-Barré syndrome.

Macular edema occurred infrequently in the active-controlled Phase III studies, as confirmed by an external macular edema review panel (1 case [0.1%] with Zeposia 0.92 mg and 3 cases [0.3%] with Zeposia 0.46 mg). No cases of macular edema were observed in patients treated with interferon beta-1a. Patients with risk factors for macular edema such as a history of uveitis or diabetes mellitus should have an ophthalmologic evaluation prior to initiating treatment with Zeposia.

There are no adequate and well-controlled studies of Zeposia in pregnant women. In animal studies, findings encompassed embryo-fetal death, abnormal/delayed ossification, and abnormalities of the viscera and large blood vessels of the offspring. Based on these data, females of childbearing potential are advised to use effective contraception during and for 3 months after stopping treatment with Zeposia. Moreover, Zeposia is contraindicated in women (including female adolescents) who are pregnant or of childbearing potential and not using effective contraception.

The potential for clinical interaction with MAO inhibitors has not been studied. However, the coadministration of Zeposia and MAO-B inhibitors may decrease exposure of the major active metabolites (CC112273 and CC1084037). In addition, CC112273 and CC1084037 inhibited MAO-B in vitro with more than 1000-fold selectivity over MAO-A. Therefore, the concomitant use of Zeposia with drugs in the MAO inhibitor class (e.g., selegiline, phenelzine, rasagiline, safinamide) or other drugs that are potent inhibitors of MAO (including the antibiotic linezolid and the dye methylene blue) is contraindicated due to the likely reduction in active metabolite concentration leading to reduced therapeutic effect and risk of non-selective MAO inhibition, which may lead to hypertensive crisis. Additionally, the concomitant use of Zeposia with serotonergic or opioid drugs is not recommended.

Treatment with immunosuppressive or immunomodulating drugs, including S1P receptor modulators, may increase the risk of malignancies. Malignancies, such as melanoma, basal cell carcinoma, breast cancer, and seminoma, were reported with Zeposia in clinical trials. Numerically more malignancies were reported in the Zeposia groups (5 patients per dose group, 0.6%) than in the interferon beta-1a group (2 subjects, 0.2%) in the active-controlled Phase III trials. Basal cell carcinoma was reported with a similar incidence in patients treated with Zeposia (3 patients, 0.2%) and patients who received interferon beta-1a (1 patient, 0.1%). Other skin malignancies, including malignant melanoma in situ (1 patient, <0.1%) and keratoacanthoma (1 patient, <0.1%,) were reported only in patients treated with Zeposia.

Appropriate contraindications, warnings, guidance, dosage considerations, screening and monitoring recommendations have been included in the Zeposia Product Monograph as mitigation measures for management of the identified risks. Uncertainties remain with respect to long-term risks of malignancies, cardiovascular morbidity, and effects following withdrawal of Zeposia (considering the long half-life of the active metabolites).

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical toxicology evaluation of ozanimod (the medicinal ingredient in Zeposia) included general toxicology, genotoxicity, carcinogenicity, reproductive and developmental studies, and other special toxicology studies. There are substantial differences between the animal species and humans in terms of the contribution of the parent drug and its metabolites to the total drug exposure. Thus, particularly in rodents and rabbits, exposures in toxicology studies to one of the major active metabolite of ozanimod, CC112273, are lower than the exposure in humans. Direct oral administration of CC112273 resulted in poor and inconsistent absorption and it was not a viable option to characterize the toxicity of the CC112273.

Oral administration of ozanimod resulted in lymphopenia and depletion of lymphocytes in the thymus and spleen of mice, rats, and monkeys, representing the expected effects of a sphingosine 1-phosphate receptor 1 (S1P1) agonist. Increased lung weights and increased incidence of mononuclear alveolar infiltrates in rat and monkey studies were observed at systemic exposures to ozanimod as low as 3.7 times the exposure at the maximum recommended human dose (MRHD), while the exposure to major human metabolites was at a subtherapeutic level. The pulmonary changes were not associated with any observable clinical signs in the rats or monkeys, did not increase in severity with long term dosing, and were reversible.

Carcinogenicity potential of ozanimod was evaluated in a six-month bioassay in rasH2 transgenic mice and a two-year bioassay in rats. In the mouse study, hemangiosarcomas were seen across multiple organs at all dose levels. The hemangiosarcomas occurred at systemic exposures that were about 1,680 times, 106 times, and 97 times the exposure at the MRHD for ozanimod, its major inactive human metabolite, and total S1P1 agonists (ozanimod plus its major active human metabolites), respectively. In the two-year rat bioassay, no incidence of any tumour type was increased at systemic exposures up to 126 times, 212 times, and 7.6 times the exposure at the MRHD for ozanimod, its major inactive human metabolite, and total S1P1 agonists (ozanimod plus its major active metabolites), respectively. Based on published data on the pharmacologically similar S1P1 modulating drug siponimod, it was suggested that siponimod-induced hemangiosarcomas in mice may be a species-specific response to the induced sustained production of placental growth factor 2 (PlGF2) and the subsequent persistent vascular endothelial cell mitoses. In contrast, rat and human vascular endothelial cells did not release PlGF2 or only transiently released PlGF2 in response to siponimod. It is not known whether the same phenomena are induced by ozanimod.

Ozanimod had no effect on fertility in rats. Embryo-fetal toxicity, which appears to be related to the mechanism of action of ozanimod, occurred in rabbits and rats at total active drug and metabolite levels below or close to clinical exposure at the MRHD. The Zeposia Product Monograph includes a contraindication for use of Zeposia during pregnancy and in women of childbearing potential not using effective contraception.

Ozanimod and its metabolites are excreted in the milk of lactating rats, at levels greater than those in the maternal plasma. Because of the potential for adverse reactions to ozanimod and its metabolites in nursing infants, the Zeposia Product Monograph indicates that women receiving Zeposia should not breastfeed their infants.

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

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

 

 

7.3 Quality Basis for Decision

 

The Chemistry and Manufacturing information submitted for Zeposia has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored at room temperature (15ºC to 30ºC).

Proposed limits of drug-related impurities are considered adequately qualified, i.e., within International Council for Harmonisation limits and/or qualified from toxicological studies.

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

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. No excipients of human origin are used in the formulation of Zeposia. The only excipient of animal origin is the gelatin component of the capsule shell. Satisfactory information has been provided to establish that this excipient does not pose a risk of contamination with transmissible spongiform encephalopathy agents.

 

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