Summary Basis of Decision for Mayzent

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 Mayzent is located below.

Recent Activity for Mayzent

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Summary Basis of Decision (SBD) for Mayzent

Date SBD issued: 2020-04-29

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

Siponimod

Drug Identification Number (DIN):

  • DIN 02496429 - 0.25 mg tablet, oral administration
  • DIN 02496437 - 2 mg tablet, oral administration

Novartis Pharmaceuticals Canada Inc.

New Drug Submission Control Number: 223225

On February 20, 2020, Health Canada issued a Notice of Compliance to Novartis Pharmaceuticals Canada Inc. for the drug product Mayzent.

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 Mayzent is favourable for the treatment of patients with secondary progressive multiple sclerosis with active disease evidenced by relapses or imaging features characteristic of multiple sclerosis inflammatory activity, to delay the progression of physical disability.

1 What was approved?

Mayzent, a sphingosine-1-phosphate receptor modulator, was authorized for the treatment of patients with secondary progressive multiple sclerosis with active disease evidenced by relapses or imaging features characteristic of multiple sclerosis inflammatory activity, to delay the progression of physical disability.

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

The efficacy and safety of Mayzent have not been evaluated in pediatric patients. Accordingly, Mayzent is not indicated for treatment of patients under 18 years of age.

Clinical studies of Mayzent did not include patients aged 65 years and over. Therefore, it is not known whether the safety and efficacy of Mayzent differ in elderly patients compared to younger adults. Physicians who choose to treat geriatric patients should consider that treatment with Mayzent warrants caution in the context of a greater frequency of reduced hepatic, renal, immune, pulmonary and cardiovascular functions, other concomitant diseases and concomitant drug therapy, and may necessitate additional or more frequent monitoring.

Mayzent is contraindicated in:

  • Patients who are hypersensitive to this drug, or to peanut or soya, or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
  • Patients with a CYP2C9*3*3 genotype.
  • 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.
  • Patients who in the last 6 months had myocardial infarction, unstable angina pectoris, stroke/transient ischemic attack, decompensated heart failure (requiring inpatient treatment), or New York Heart Association Class III/IV heart failure.
  • Patients with second-degree Mobitz type II atrioventricular (AV) block, third-degree AV block, or sick sinus syndrome, if they do not have a pacemaker.
  • Women (including female adolescents) who are pregnant or of childbearing potential not using effective contraception. Pregnancy must be excluded before start of treatment as Mayzent may cause fetal harm.

Mayzent 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.

Mayzent (0.25 mg and 2 mg siponimod) is presented as a tablet. In addition to the medicinal ingredient, the film-coated tablet contains colloidal silicon dioxide, crospovidone, glyceryl behenate, lactose monohydrate, and microcrystalline cellulose. The tablet coating consists of iron oxide (red and black iron oxides for the 0.25 mg strength and red and yellow iron oxides for the 2 mg strength), lecithin (soya), polyvinyl alcohol, talc, titanium dioxide, and xanthan gum.

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

2 Why was Mayzent approved?

Health Canada considers that the benefit-harm-uncertainty profile of Mayzent is favourable for the treatment of patients with secondary progressive multiple sclerosis (SPMS) with active disease evidenced by relapses or imaging features characteristic of multiple sclerosis (MS) inflammatory activity, to delay the progression of physical disability.

Multiple sclerosis is a serious, progressive and severely debilitating chronic autoimmune and neurodegenerative disease of the central nervous system (CNS) that affects approximately 2.3 million people worldwide. It is estimated that 1 in 385 Canadians live with MS. While MS most commonly affects adults aged 20 to 49 years, younger children and older adults may also be diagnosed with the disease. Approximately 85% of MS patients present initially with a relapsing-remitting disease course (RRMS), which is characterized by acute attacks or relapses of neurological disability caused by acute focal inflammatory lesions in the CNS white matter. The relapses are interspersed with periods of remission during which symptoms remain stable or may fully resolve. Within 10 to 15 years after an initial relapsing-remitting course, approximately 70% of patients will transition to SPMS. Acute relapses may or may not be superimposed on the progressive course but disability progression in SPMS is independent of a relapse. It is estimated that at least 1.3 million people worldwide have progressive MS (i.e., primary progressive MS [PPMS] or SPMS), with the majority (over 85%) of patients having SPMS. Disability accrues predominantly in patients with the progressive forms of the disease.

The medicinal ingredient in Mayzent, siponimod, is a new chemical entity that acts as a 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-S1P5. Siponimod binds with high affinity to S1P1 and S1P5 receptors. The binding of siponimod to S1P1 receptors on lymphocytes prevents lymphocyte egress from lymph nodes. This reduces the number of lymphocytes in peripheral blood. The mechanism by which siponimod exerts its therapeutic effects in multiple sclerosis is not known, but may involve reduction of lymphocyte migration into the CNS.

Mayzent has been shown to be efficacious in the treatment of patients with SPMS with active disease evidenced by relapses or imaging features characteristic of MS inflammatory activity. The market authorization was based on the efficacy and safety data derived from a large, Phase III, randomized, placebo-controlled, time-to-event clinical trial (Study A2304).

The study enrolled patients who, following an initial course of RRMS, had documented evidence of a progressive increase in disability of at least a 6-month duration, in the absence or independent of relapses. Patients had documented evidence of disability progression in the prior 2 years, as measured by the Expanded Disability Status Scale (EDSS) (i.e., ≥1-point increase for an EDSS score <6.0 at screening and ≥0.5-point increase for an EDSS score ≥6.0 at screening). In addition, patients had no evidence of relapse in the 3 months prior to study enrollment and had an EDSS score of 3.0 to 6.5 at study entry. Overall, there were 1,105 patients randomized to Mayzent and 546 to placebo. The primary endpoint of the study was the time to 3-month confirmed disability progression (CDP), defined as an increase from baseline in the EDSS score of at least 1 point (0.5-point increase for patients with a baseline EDSS score of 5.5 or more), in the absence of relapse, sustained for 3 months.

In the overall study population, there was a statistically significant reduction of 21% in the risk of 3-month CDP with Mayzent compared to placebo. The risk of 6-month CDP was also reduced by 26% with Mayzent compared to placebo. Results for secondary endpoints were also favourable with Mayzent relative to placebo.

Subgroup analyses that were pre-planned in the study protocol were conducted to evaluate the extent to which the effect of Mayzent on disability progression may have been independent of the inflammatory disease processes (relapses, new lesion activity). These analyses showed that the effect of Mayzent on 3-month and 6-month CDP was greater in patients with pre-study evidence of active inflammatory disease processes superimposed on disability progression. Results support an indication for the treatment of patients with active SPMS, characterized by the presence of relapses and/or imaging features that are consistent with MS inflammatory activity.

During the Phase III clinical trial in patients with SPMS, the median duration of exposure to Mayzent was approximately 18 months (range 0-37 months); 884 patients had over 12 months of exposure and 322 patients had over 24 months of exposure. Of note, most of the safety concerns reported with Mayzent and described below have also been reported during the clinical experience with fingolimod (a sphingosine-1-phosphate receptor modulator indicated for the treatment of patients with RRMS). Appropriate contraindications and warnings are specified in the Mayzent Product Monograph to address the identified safety concerns.

Mayzent induces a reduction in the number of lymphocytes in peripheral blood to approximately 20% to 30% of baseline counts, which persists throughout treatment and can increase the risk of infections, including serious and life-threatening infections. For example, herpes zoster infections were more frequently reported in SPMS patients treated with Mayzent (2.5%) compared to placebo (0.7%). Therefore, prior to initiating treatment, the varicella zoster virus (VZV) antibody status should be determined and vaccination of VZV antibody-negative patients is recommended. Serious opportunistic infections reported with Mayzent during clinical development included one patient with a disseminated herpes zoster infection (herpes zoster meningitis) and one patient with cryptococcal meningitis. Lymphocyte counts can return to the normal range within 10 days after stopping treatment with Mayzent but residual effects on the immune system may persist for an additional 3 to 4 weeks after the last dose. Consequently, patients may continue to be at an increased risk of infections for up to 1 month after stopping Mayzent.

Reduced immune surveillance associated with Mayzent may increase the risk of cancer but such an increased risk cannot be well characterized due to the duration of clinical trials. During the Phase III study in SPMS patients, basal cell carcinoma was reported at a similar rate with Mayzent and placebo. Other types of skin cancer (e.g., malignant melanoma, squamous cell carcinoma) and non-cutaneous cancers (seminoma) were reported only in patients treated with Mayzent (0.1%-0.2%). Healthcare professionals and patients are advised to monitor for suspicious skin lesions before starting treatment and regularly during treatment with Mayzent.

Upon treatment initiation, Mayzent causes a marked transient reduction in heart rate, which manifests as bradycardia, and/or may cause conduction delays resulting in first- or second-degree atrioventricular block (Mobitz I). When treatment was initiated using the recommended 6-day titration procedure the effect on heart rate and conduction was gradual and less pronounced, and serious or symptomatic events were largely mitigated. However, based on the known effects on heart rate and atrioventricular conduction, the results from the Phase III trial and the thorough QTc study, it is recommended that all patients have pre-treatment assessments of cardiovascular status including an electrocardiogram (ECG) and review of medications, and, if deemed necessary, a cardiologist's evaluation. For patients with sinus bradycardia (heart rate lower than 55 beats per minute), first- or second-degree atrioventricular block (Mobitz I), or a history of myocardial infarction or heart failure, the first dose of Mayzent should be administered in a clinical setting where the patient's heart rate and blood pressure can be monitored hourly for at least 6 hours.

Other types of adverse events that occurred more frequently with Mayzent relative to placebo included macular edema, increases in blood pressure or new hypertension, and decreases in pulmonary function tests. Additionally, vascular events such as cerebrovascular accidents, ischemic stroke, and peripheral occlusive arterial disease were reported only in patients treated with Mayzent (0.5%).

Mayzent has not been studied in pregnant women. Reproductive toxicology studies in rats and rabbits clearly demonstrated teratogenic effects of siponimod. Furthermore, an increased risk in congenital malformations has been seen with fingolimod in the post-market setting. Consequently, a contraindication during pregnancy and in women of childbearing potential not using effective contraception has been implemented for Mayzent.

Seizures, elevations in liver transaminases, an imbalance in suicidal ideation, and suicidal behaviour also occurred more frequently with Mayzent relative to placebo in the Phase III study.

The metabolism of siponimod is attributed mainly to cytochrome P450 (CYP) 2C9 (79.3%) and to a lesser extent to CYP3A4 (18.5%). Given that CYP2C9 is a polymorphic enzyme, patients have to be genotyped prior to initiating treatment to determine their CYP2C9 metabolizer status. This is important for determining whether or not a patient can be treated with siponimod or whether a lower dose may be needed. As stated in the Mayzent Product Monograph, the sponsor will offer CYP2C9 genotyping through its Patient Support Program.

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

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

Based on the available data, the overall benefit-harm-uncertainty profile of Mayzent is considered acceptable for the treatment of patients with SPMS with active disease evidenced by relapses or imaging features characteristic of MS inflammatory activity, when used under the conditions provided in the Mayzent Product Monograph.

Appropriate warnings and precautions are in place in the Mayzent 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 Mayzent?

The sponsor requested a priority review status under the Priority Review Policy for the review of the new drug submission (NDS) for Mayzent. Following review of the submitted clinical assessment package, it was determined that the sponsor's request did not fulfill the criteria set out in the Priority Review Policy. Subsequently, the submission was filed and reviewed as a regular NDS.

Submission Milestones: Mayzent

Submission MilestoneDate
Pre-submission meeting:2017-06-27
Submission filed:2018-12-21
Screening
Screening Acceptance Letter issued:2019-02-07
Review
Biopharmaceutics Evaluation complete:2019-10-30
Review of Risk Management Plan complete:2020-02-04
Quality Evaluation complete:2020-02-12
Labelling Review complete, including Look-alike Sound-alike brand name assessment:2020-02-19
Clinical/Medical Evaluation complete:2020-02-20
Notice of Compliance issued by Director General, Therapeutic Products Directorate:2020-02-20

The Canadian regulatory decision on the review of Mayzent 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 Mayzent?

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

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

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

6 What other information is available about drugs?

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

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

Clinical Pharmacology

Siponimod, the medicinal ingredient in Mayzent, is a sphingosine-1-phosphate (S1P) receptor modulator that binds with high affinity to S1P1 and S1P5 receptors. The binding of siponimod to S1P1 receptors on lymphocytes prevents lymphocyte egress from lymph nodes, thereby reducing the number of lymphocytes in peripheral blood. The mechanism by which siponimod exerts its therapeutic effects in multiple sclerosis is not known, but may involve reduction of lymphocyte migration into the central nervous system.

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

Clinical pharmacology studies conducted in healthy subjects characterized the pharmacokinetics of single and multiple doses of siponimod, its disposition (absorption, distribution, metabolism and excretion), drug interactions, dose titration and cardiovascular safety. The pharmacokinetic properties of siponimod were also evaluated in subjects with hepatic impairment or renal impairment.

The absolute oral bioavailability following a single oral dose of siponimod 0.25 mg is 84%. Exposure to siponimod appeared to increase dose proportionally in a single ascending (0.1 mg to 75 mg) dose study (Study A2101) and in a multiple ascending dose study, in which subjects received doses from 0.3 mg/day to 20 mg/day for 28 days (Study A2105). Steady-state plasma concentrations were reached after approximately 6 days and the median time to maximum concentration observed (Tmax) at steady state was between 3 hours and 4 hours post-dose (Tmax after single dose was 3 hours to 6 hours). A high level (>99.9%) of plasma protein binding was observed consistently across all species evaluated as well as in subjects with hepatic or renal impairment.

Siponimod is primarily metabolized by cytochrome P450 (CYP) 2C9 (79.3%) and to a lesser extent by CYP3A4 (18.5%). Notably, CYP2C9 is a polymorphic enzyme, and the CYP2C9 genotype influences the contributions of the two metabolism pathways (CYP2C9 and CYP3A4) to the overall elimination of siponimod. Therefore, CYP2C9 genotyping is required prior to initiating treatment with siponimod to determine the patient's CYP2C9 metabolizer status, since this can affect dosing and the potential for interactions with other drugs. Clinical drug-drug interaction studies and evaluation of the drug interaction potential using physiologically based pharmacokinetic modelling have informed the recommendations included in the Mayzent Product Monograph regarding the co-administration of Mayzent with CYP2C9 and CYP3A4 inhibitors and inducers.

The primary pharmacodynamic effect of siponimod is lowering of the absolute lymphocyte count. This effect has been adequately characterized in the single and multiple ascending dose clinical pharmacology studies. The nadir absolute lymphocyte count achieved with siponimod at steady state is estimated to be 20% to 30% of the baseline levels. Results of a dedicated study investigating the effects of siponimod on the immune response of selected vaccines support a recommendation to pause treatment with siponimod 1 week prior to until 4 weeks after vaccination, due to the risk of reduced vaccine efficacy with shorter duration interruptions.

Reduced immune surveillance associated with siponimod may increase the risks of infections and cancers. Accordingly, contraindications and warnings relevant to the immune effects of siponimod and recommendations for adequate monitoring have been included in the Mayzent Product Monograph.

Studies were conducted to evaluate the major secondary pharmacodynamic effects of transient reduced heart rate and atrioventricular conduction delays. The results of these studies indicated that a 6-day titration regimen evoked a more gradual reduction in heart rate and attenuated the pronounced decrease in heart rate occurring after administration of siponimod without titration. Use of the titration regimen also avoided most symptomatic or clinically relevant events of bradycardia or atrioventricular conduction delay (there were mainly asymptomatic first- or second-degree [Mobitz I] atrioventricular blocks). The thorough QT study showed a QT prolonging effect with siponimod (steady state) that did not appear to be an indirect effect of the heart rate lowering effect. The Mayzent Product Monograph includes extensive warnings and recommendations related to the heart rate lowering effects and atrioventricular conduction delays that can occur during treatment initiation, the QT interval prolongation associated with siponimod and the use of this drug in patients with pre-existing cardiac conditions (including pre-existing significant QT prolongation) or risk factors.

A Phase II randomized, double-blind, placebo-controlled trial was conducted in patients with relapsing-remitting multiple sclerosis to evaluate safety, tolerability and efficacy on magnetic resonance imaging (MRI) lesion parameters, and to determine the dose-response curve of siponimod based on MRI lesion parameters (Study A2201). The primary efficacy analysis demonstrated a statistically significant dose-response relationship among five doses of siponimod (10 mg, 2 mg, 1.25 mg, 0.5 mg, and 0.25 mg) and placebo during 3 months of treatment in patients with relapsing-remitting multiple sclerosis as measured by the number of combined unique active lesions (p = 0.0001 for the maximal effect [Emax] model). The reduction in combined unique active lesions was near maximum at the 2 mg dose and this dose was selected for use in the Phase III clinical trial (described in the Clinical Efficacy section).

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

Clinical Efficacy

The efficacy of Mayzent for the treatment of patients with secondary progressive multiple sclerosis (SPMS) was evaluated in a Phase III, multicentre, randomized, double-blind, placebo-controlled, variable treatment duration clinical trial (Study A2304). The trial enrolled patients who, following an initial course of relapsing-remitting multiple sclerosis, had documented evidence of a progressive increase in disability of at least a 6-month duration, in the absence or independent of relapses. Patients also had documented evidence of disability progression in the prior 2 years, as measured by the Expanded Disability Status Scale (EDSS) (i.e., ≥1-point increase for an EDSS score <6.0 at screening and ≥0.5-point increase for an EDSS score ≥6.0 at screening); no evidence of relapse in the 3 months prior to study enrollment; and an EDSS score of 3.0 to 6.5 at study entry.

The primary objective of the study was to demonstrate the efficacy of Mayzent, compared with placebo, in delaying progression of disability. To reduce exposure to placebo, patients were randomized in a ratio of 2:1 to receive Mayzent 2 mg/day or placebo. Treatment was initiated with a 6-day dose titration starting with 0.25 mg on Days 1 and 2, 0.5 mg on Day 3, 0.75 mg on Day 4, 1.25 mg on Day 5, and 2 mg (maintenance dose) on Day 6.

The primary endpoint of the study was the time to 3-month confirmed disability progression (CDP), defined as an increase from baseline in the EDSS score of at least 1 point (0.5-point increase for patients with a baseline EDSS score of 5.5 or more), sustained and confirmed at 3 months in the absence of relapse.

Key secondary endpoints were time to 3-month confirmed worsening of at least 20% from baseline in the timed 25-foot walk test (T25FW) and change from baseline in T2 lesion volume. The primary endpoint and two key secondary endpoints were analyzed according to a pre-specified hierarchical order. Additional secondary endpoints, including time to 6-month CDP, percent brain volume change, measures of inflammatory disease activity (annualized relapse rate, MRI lesions), were analyzed without correction for multiplicity or hierarchical testing.

In total, 1,651 patients were randomized: 1,105 to Mayzent and 546 to placebo. Mean (median) age of the randomized population was 48.0 (49.0) years, 95% of patients were white and 60% were female. The median disease duration was 16.0 years and the median EDSS score was 6.0 at baseline (56% of patients had a baseline EDSS score of 6.0 or 6.5). Approximately 36% of patients had at least one relapse in the 2 years prior to study entry, with the mean number of relapses in the year prior to study entry being 0.2 to 0.3, and 22% of patients had at least one active inflammatory lesion on their baseline MRI scan. As this was a time-to-event study, the study duration was variable for individual patients (median study duration was 21 months; range 1 day to 37 months).

Results for the entire study population indicated that for the primary endpoint there was a statistically significant reduction of 21% in the risk of 3-month CDP progression with Mayzent compared to placebo.

Other endpoints showing a nominally significant effect of treatment with Mayzent included:

  • the change from baseline in T2 lesion volume (overall lesion burden) averaged over Month 12 and Month 24, which showed a smaller increase in lesion volume in the Mayzent group compared to the placebo group (nominal p<0.0001);
  • 6-month CDP, which showed a 26% reduction in the risk of 6-month CDP;
  • annualized relapse rate and the MRI endpoints (e.g., mean numbers of contrast-enhancing lesions, new/newly enlarging lesions, percent brain volume).

The effect of Mayzent on these endpoints is indicative of a strong effect on active focal inflammatory disease processes.

Mayzent did not significantly reduce the risk of the time to 3-month confirmed worsening of at least 20% from baseline in the T25FW (one of the two key secondary endpoints).

The effect of Mayzent on 3-month and 6-month CDP was greater in patients with pre-study evidence of active inflammatory disease processes superimposed on progression. For the combined subgroup of patients with relapses in the 2 years prior to study entry and/or contrast-enhancing T1 lesions at baseline, the reduction in risk of 3-month CDP with Mayzent was 31%.

The results from the planned subgroup analyses and the effect on relapses and MRI endpoints suggest that the efficacy of Mayzent on delaying disability progression in patients with SPMS may be dependent on an effect on the inflammatory disease activity. Accordingly, the results of Study A2304 could only be considered to support an indication for treatment of patients with active SPMS, characterized by the presence of relapses and/or imaging features that are consistent with MS inflammatory activity.

Three databases were used to ensure that study personnel would have access only to the data relevant to their role in the study in order to maintain the study blinding. A Good Clinical Practice inspection identified many instances of misassigned access to study databases that resulted in inappropriate dual database access for several study personnel involved in Study A2304, which could have potentially unblinded these study personnel. Several sensitivity analyses, conducted to assess the effect of potential unblinding, confirmed the efficacy of Mayzent demonstrated by the primary analysis.

Indication

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

  • Mayzent (siponimod) is indicated for the treatment of patients with secondary progressive multiple sclerosis (SPMS).

  • Mayzent should only be prescribed by neurologists who are experienced in the treatment of multiple sclerosis, and are knowledgeable of the efficacy and safety profile of Mayzent.

Health Canada revised the proposed indication to reflect the patient population in Study A2304. Accordingly, Health Canada approved the following indication:

  • Mayzent (siponimod) is indicated for the treatment of patients with secondary progressive multiple sclerosis (SPMS) with active disease, evidenced by relapses or imaging features characteristic of multiple sclerosis inflammatory activity, to delay the progression of physical disability.

  • Mayzent should only be prescribed by neurologists who are experienced in the treatment of multiple sclerosis, and are knowledgeable of the efficacy and safety profile of Mayzent and are able to discuss benefits/harms with patients.

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

Clinical Safety

The safety of Mayzent for the treatment of patients with SPMS was evaluated in a Phase III, multicentre, randomized, double-blind, placebo-controlled, variable treatment duration clinical trial (Study A2304, described in the Clinical Efficacy section ).

The median duration of exposure to Mayzent in Study A2304 was approximately 18 months (range 0-37 months). There were 884 patients with over 12 months of exposure and 322 patients with over 24 months of exposure, indicating that there was adequate duration of exposure to characterize many aspects of the safety profile of Mayzent.

All or most of the following safety concerns that were reported with Mayzent, have also been reported during clinical experience with fingolimod (a sphingosine-1-phosphate receptor modulator indicated for the treatment of patients with the relapsing-remitting form of multiple sclerosis).

Mayzent induces a reduction in the number of lymphocytes in peripheral blood to approximately 20% to 30% of baseline counts, which persists throughout treatment and can increase the risk of infections, including serious and life-threatening infections. The overall rates of infection were similar for Mayzent and placebo (49% in each group). Herpes zoster infections were more frequently reported in SPMS patients treated with Mayzent (2.5%) compared to placebo (0.7%). One patient had a disseminated herpes zoster infection (herpes zoster meningitis). A case of cryptococcal meningitis was reported in the development program of Mayzent in a patient who was treated with Mayzent for approximately 2.5 years.

Although reduced immune surveillance caused by Mayzent has the potential to increase the risk of cancer, an increase in this risk cannot be adequately characterized in the context of a placebo-controlled clinical trial. During Study A2304, basal cell carcinoma was reported at a similar rate with Mayzent and placebo (1%). However, other types of skin cancers (e.g., malignant melanoma, squamous cell carcinoma) and non-cutaneous cancers (seminoma) were reported only in patients treated with Mayzent (0.1%-0.2%).

When treatment was initiated using the recommended 6-day titration procedure, the reduction in heart rate was gradual over the titration period. The presence or history of most types of cardiovascular/vascular conditions or risk factors may preclude treatment with Mayzent (i.e., the treatment is contraindicated), or require evaluation by a cardiologist to determine the patient's suitability for treatment. Based on results from Study A2304, it is recommended that all patients undergo pre-treatment assessments of cardiovascular status including an electrocardiogram (ECG) and review of medications, and, if deemed necessary, a cardiologist's evaluation. For patients with sinus bradycardia (heart rate lower than 55 beats per minute), first- or second-degree atrioventricular block (Mobitz I), or a history of myocardial infarction or heart failure, the first dose of Mayzent should be administered in a clinical setting, where the patient can be monitored (hourly heart rate and blood pressure, pre- and post-dose ECG) for signs and symptoms of bradycardia for at least 6 hours, and where symptomatic bradycardia can be managed.

Other types of adverse events that occurred more frequently with Mayzent relative to placebo included macular edema, increases in blood pressure or new hypertension, and decreases in pulmonary function tests, suggesting a small effect on airway resistance. Macular edema was reported in 1.8% of patients treated with Mayzent compared to 0.2% of patients who received placebo. Most cases were reported within the first 3 to 4 months of treatment. Macular edema was more frequent in patients with risk factors (i.e., pre-existing uveitis, history of macular edema or diabetes mellitus). Hypertension was reported in 12.6% of patients treated with Mayzent and 9% of placebo-treated patients. A small mean increase in blood pressure that started early after treatment initiation reached a maximum effect after 6 to 12 months of treatment. Vascular events such as cerebrovascular accidents, ischemic stroke, and peripheral occlusive arterial disease were reported only in patients treated with Mayzent (<0.5%) and not in placebo-treated patients.

Adverse events occurring more frequently with Mayzent as compared to placebo also included seizures (1.7% Mayzent, 0.4% placebo), elevations in liver transaminases (mainly asymptomatic alanine aminotransferase [ALT] and aspartate aminotransferase [AST] elevations; no case met Hy's law criteria) (11.3% Mayzent, 3.1% placebo), an imbalance in suicidal ideation (0.5% Mayzent, 0.2% placebo), and suicidal behaviour (0.3% Mayzent, 0% placebo). An increase in frequency of seizures and elevations in liver transaminases have also been reported during clinical experience with fingolimod.

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

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

7.2 Non-Clinical Basis for Decision

The non-clinical studies of siponimod, the medicinal ingredient in Mayzent, support the use of Mayzent for the specified indication.

Safety pharmacology studies demonstrated that siponimod caused a transient decrease in heart rate, induced second-degree atrioventricular blocks, and reduced blood pressure. There were no respiratory and central nervous system adverse findings at doses equivalent to the human therapeutic dose. High levels of covalent drug-protein adducts were observed in human hepatocytes.

General toxicology studies revealed a consistent reduction in the number of circulating lymphocytes at all doses used, which is an expected, primary pharmacodynamic effect of siponimod.

Siponimod did not exhibit genotoxic potential in in vitro and in vivo genotoxicity studies. Increased incidences of malignant lymphomas, hemangiosarcomas, lung lesions, and ovarian cysts were observed in a carcinogenicity study in mice. A carcinogenicity study in rats revealed findings of polyarteritis, uterine hemangiosarcoma, vascular inflammation and hemorrhages, numerous eye-related adverse effects, considered secondary to the chronic corneal inflammation, brain vascular inflammation and mineralization, testis vascular inflammation and seminiferous tubule degeneration.

Reproductive and developmental toxicity studies revealed drug-related embryonic lethality and teratogenicity in rats and rabbits, at doses below the human therapeutic dose. Based on these results, the risks to the fetus are considered high. Consequently, various risk mitigation strategies have been implemented, such as specifying a contraindication for use of Mayzent in women who are pregnant or women of childbearing potential who are not using effective contraception and including relevant warnings in the Mayzent Product Monograph to limit exposure during pregnancy.

No evidence of siponimod abuse liability was found in the non-clinical abuse liability studies or in the clinical trials.

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

Appropriate warnings and precautionary measures are in place in the Mayzent Product Monograph to address the identified safety concerns.

For more information, refer to the Mayzent 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 Mayzent 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 18 months is acceptable when the drug product is stored at a temperature of 2ºC to 8ºC.

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

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

All non-medicinal ingredients found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The excipient lactose monohydrate is derived from milk obtained from healthy animals under the same conditions as milk collected for human consumption. 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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