Summary Basis of Decision for Ponvory

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 Ponvory is located below.

Recent Activity for Ponvory

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 Ponvory, a product which contains the medicinal ingredient ponesimod. 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: 2023-07-12

Drug Identification Number (DIN):

DIN 02515474 – 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, and 10 mg ponesimod, tablet, oral administration

DIN 02515482 – 20 mg ponesimod, tablet, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Drug product (DINs 02515474, 02515482) market notification Not applicable Date of first sale: 2021-11-01 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 239537 2020-05-15 Issued NOC 2021-04-28 NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Ponvory

Date SBD issued: 2021-08-05

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

Ponesimod

Drug Identification Number (DIN):

  • DIN 02515474 - 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, and 10 mg ponesimod, tablets, oral administration
  • DIN 02515482 - 20 mg ponesimod, tablet, oral administration

Janssen Inc.

New Drug Submission Control Number: 239537

On April 28, 2021, Health Canada issued a Notice of Compliance to Janssen Inc. for the drug product Ponvory.

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 Ponvory is favourable for the treatment of adult patients with relapsing remitting multiple sclerosis (RRMS).

Ponvory 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 Ponvory and are able to discuss benefits/harms with patients.

1 What was approved?

Ponvory, a sphingosine 1-phosphate receptor modulator, was authorized for the treatment of adult patients with relapsing remitting multiple sclerosis (RRMS).

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

Clinical studies of Ponvory did not include patients aged 65 years and older. Therefore, it is not known whether the safety and efficacy differ in elderly patients compared to younger patients.

Ponvory is contraindicated in:

  • Patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
  • 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 have in the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III or IV heart failure.
  • Patients with presence of Mobitz Type II second degree atrioventricular (AV) block or higher-grade AV block, sick-sinus syndrome, or sinoatrial heart block unless the patient has a functioning pacemaker.
  • Patients with moderate or severe hepatic impairment (Child-Pugh Class B and C).
  • During pregnancy and in women of childbearing potential not using highly effective contraception.

Ponvory 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.

Ponvory (2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, and 20 mg ponesimod) is presented as tablets. The dosage strengths ranging from 2 mg to 10 mg are grouped into an initiation pack designed to be used for titration towards the recommended dose of 20 mg once daily. The 20 mg tablets are available separately as maintenance packs, to be used after the titration period is complete. In addition to the medicinal ingredient (ponesimod), the tablets contain croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone K30, silica colloidal anhydrous and sodium laurilsulfate. Opadry II is used for the tablet coating and includes hydroxypropyl methylcellulose, lactose monohydrate, polyethylene glycol 3350, titanium dioxide, and triacetin. The tablet coating for certain dosage strengths also contains iron oxide red (3 mg, 4 mg, 7 mg, 8 mg, 9 mg and 10 mg doses), iron oxide black (4 mg, 5 mg, 8 mg and 9 mg doses), or iron oxide yellow (3 mg, 5 mg, 7 mg, 9 mg, 10 mg and 20 mg doses).

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

2 Why was Ponvory approved?

Health Canada considers that the benefit-harm-uncertainty profile of Ponvory is favourable for the treatment of adult patients with relapsing remitting multiple sclerosis (RRMS).

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS). The two main clinical features of MS are exacerbations (i.e., relapses) and progressive loss of neurological function (i.e., disability accumulation). Relapses are considered the clinical expression of acute inflammatory and focal lesions of the brain or spinal cord, which may translate to various clinical symptoms and signs. The accumulation of disability (progression) may result from incompletely recovered relapses or may be independent from relapses, and is caused by neurodegeneration due to demyelination, axonal loss, and gliosis.

An estimated 85% of patients with MS initially present with RRMS, which is characterized by acute attacks (relapses) of neurological disability alternating with periods of remission. During remission, symptoms may remain stable with residual effects or may fully resolve. Over time, many patients will transition to secondary progressive MS with relapses superimposed on progression (SPMS with relapses). This stage is characterized by a decreasing frequency of relapses and/or less focal inflammation, with a parallel steady accumulation of disability. Some patients will eventually transition to SPMS, in which there is an absence of relapses with a steady accumulation of disability. Approximately 15% of patients with MS initially present with primary progressive MS (PPMS). The most recent descriptions of relapsing MS and progressive MS now subdivide both into active and inactive forms, based on the presence or absence of acute disease activity.

The accumulation of disability in MS occurs predominantly in the progressive forms of the disease, but may be caused by incomplete recovery from relapses. In order to evaluate the efficacy of treatments, it is important to consider their effect on progression as well as their effect on relapses.

Ponesimod, the medicinal ingredient in Ponvory, is a selective modulator of the sphingosine 1-phosphate subtype 1 (S1P1) receptor. Sphingosine 1-phosphate (S1P) plays a central role in lymphocyte trafficking, and lymphocyte egress from lymphoid organs is dependent on the S1P1 receptor. Modulators of the S1P1 receptor block lymphocyte migration out of lymphoid tissues into the lymphatic and vascular circulation. This reduces the number of lymphocytes in peripheral blood, thereby preventing lymphocyte recruitment to sites of inflammation. Several other drugs are authorized in Canada for the treatment of MS, including other modulators of S1P receptors. Compared to other modulators which interact with multiple S1P receptors, ponesimod is a selective modulator of the S1P1 receptor and induces a rapid, dose-dependent, and reversible reduction in peripheral blood lymphocytes by blocking the egress of lymphocytes from lymphoid organs.

The clinical efficacy and safety of Ponvory were primarily evaluated in the pivotal Phase III superiority study, OPTIMUM, in which teriflunomide served as an active control. A total of 1,133 patients with relapsing MS were enrolled in the study, with 566 patients randomized to the Ponvory treatment group (20 mg once daily) and 567 patients randomized to the teriflunomide treatment group (14 mg once daily). Neurological evaluations were performed every 12 weeks, and at the time of a suspected relapse. Magnetic resonance imaging (MRI) scans of the brain were performed at baseline and at Weeks 60 and 108. The study data was evaluated through a pre-specified hierarchical fallback testing sequence.

The primary efficacy endpoint was the annualized relapse rate (ARR) from baseline until the end of the study. The relative ARR was 0.695 (a reduction of 30.5%; p = 0.0003), indicating that Ponvory is statistically significantly superior to teriflunomide. The results from the first two secondary efficacy endpoints tested also indicated that Ponvory has a superior effect relative to teriflunomide. The first secondary endpoint evaluated the change in fatigue-related symptoms from baseline to Week 108 in the symptoms domain of the Fatigue Symptoms and Impacts Questionnaire - Relapsing Multiple Sclerosis (FSIQ-RMS). The second secondary endpoint assessed the cumulative number of combined unique active lesions (CUALs) on MRI scans of the brain from baseline to Week 108. The findings for the third secondary endpoint were not statistically significant, and due to the hierarchical design, subsequent endpoints were not analyzed.

The most commonly reported treatment-emergent adverse event (TEAE) was increased alanine aminotransferase, which was reported more frequently in the Ponvory group (19.5%) than in the teriflunomide group (9.4%). Increased aspartate aminotransferase was also commonly reported (6.4% and 3.5% in the Ponvory and teriflunomide groups, respectively). In decreasing order, TEAEs of nasopharyngitis, respiratory tract infection, urinary tract infection, dyspnea, bronchitis, and cough were all reported with higher incidences in the Ponvory group of the OPTIMUM study.

A Risk Management Plan (RMP) for Ponvory was submitted by Janssen 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 Ponvory Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

The brand name originally proposed for this drug was Vivmory. During review, the sponsor requested a change to the name Ponvory to align with international approvals. A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name Ponvory was accepted.

Ponvory 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 Ponvory 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 Ponvory?

Submission Milestones: Ponvory

Submission Milestone Date
Pre-submission meeting 2020-04-07
Submission filed 2020-05-15
Screening  
Screening Acceptance Letter issued 2020-07-02
Review  
Quality Evaluation complete 2021-04-26
Labelling Review complete 2021-04-27
Non-Clinical Evaluation complete 2021-04-27
Clinical/Medical Evaluation complete 2021-04-28
Review of Risk Management Plan complete 2021-04-28
Notice of Compliance issued by Director General, Therapeutic Products Directorate 2021-04-28

The Canadian regulatory decision on the review of Ponvory 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 and Applications 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 Ponvory?

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 Ponvory 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

Ponesimod, the medicinal ingredient in Ponvory, is a sphingosine 1-phosphate (S1P) receptor modulator. Ponesimod activates the S1P subtype 1 (S1P1) receptor with high potency. The binding of ponesimod to S1P1 receptors on lymphocytes prevents lymphocyte egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which ponesimod exerts its therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.

The pharmacokinetics of ponesimod was characterized in healthy subjects and in patients with multiple sclerosis, and results were similar between the two groups. Ponesimod is absorbed extensively, and reaches the maximum plasma concentration (Cmax) 2 to 4 hours post-dose. The absolute oral bioavailability of a 10 mg dose is 84%. Following oral administration, the exposure as measured by the area under the plasma concentration-time curve (AUC) and the Cmax increased in a dose-proportional manner within the range studied (1-75 mg). Steady-state levels were achieved after 3 days of administration of the maintenance dose of ponesimod (20 mg/day). Food was not found to have a clinically relevant effect on the pharmacokinetics of ponesimod.

Ponesimod is extensively metabolized prior to elimination, although unchanged ponesimod is the main circulating component in plasma. Ponesimod is metabolized by a wide variety of enzymes, include cytochrome P450 (CYP450) enzymes, uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes, and other enzymes. Two metabolites, M13 and M12, have been identified in human plasma and account for 20% and 6% of total drug-related exposure, respectively. Based on the results of in vitro potency assays, neither of the two metabolites is expected to contribute meaningfully to activity at the recommended therapeutic dose of ponesimod. However, the co-administration of strong inducers of CYP3A4 and UGT1A1 is expected to decrease the systemic exposure to ponesimod due to the involvement of these enzymes in the metabolism of ponesimod. No other interactions with ponesimod or its metabolites are expected.

The half-life of ponesimod after oral administration is approximately 33 hours. Following a single oral administration, ponesimod, M12, and M13 were recovered mainly in the feces, with a smaller proportion recovered in urine.

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

Clinical Efficacy

Evidence of the clinical efficacy of Ponvory was provided primarily through the results of the Phase III pivotal study, OPTIMUM. This study was a randomized, double-blind, superiority study conducted over 108 weeks to evaluate the efficacy and safety of Ponvory relative to teriflunomide in patients with relapsing remitting multiple sclerosis.

A total of 1,133 patients were enrolled in the study, with 566 patients randomized to receive 20 mg Ponvory once daily, and 567 patients randomized to receive 14 mg teriflunomide once daily. Neurological evaluations were performed every 12 weeks, as well as at the time of a suspected relapse. Magnetic resonance imaging (MRI) scans of the brain were performed at baseline and at Weeks 60 and 108. Of the randomized patients, 86.4% of patients treated with Ponvory and 87.5% of patients treated with teriflunomide completed the study. The study data was evaluated through a pre-specified hierarchical fallback testing sequence.

The primary efficacy endpoint was the annualized relapse rate (ARR) from baseline until the end of the study. The relative ARR was 0.695 (a reduction of 30.5%; p = 0.0003), indicating that Ponvory is statistically significantly superior to teriflunomide.

The first of the secondary efficacy endpoints to be examined was the change in fatigue-related symptoms from baseline to Week 108, in the symptoms domain of the Fatigue Symptoms and Impacts Questionnaire - Relapsing Multiple Sclerosis (FSIQ-RMS). The mean difference in the FSIQ-RMS weekly symptom scores between patients in the Ponvory group and in the teriflunomide group was -3.57 (p = 0.0019), which is statistically significant and indicates that Ponvory had a superior effect relative to teriflunomide.

The second secondary efficacy endpoint examined was the cumulative number of combined unique active lesions (CUALs) on MRI scans of the brain from baseline to Week 108. A reduction of 56% (relative rate 0.444; p<0.0001) was observed between patients in the Ponvory group compared to the teriflunomide group. This difference is statistically significant, and indicates that Ponvory had a superior effect relative to teriflunomide.

The third secondary efficacy endpoint to be examined was the difference in time to the first confirmed disability accumulation (CDA) at 12 weeks between the two treatment groups. The difference between patients in the Ponvory group and patients in the teriflunomide group was not statistically significant.

The following secondary efficacy endpoint, the time to 24-week CDA from baseline to the end of the study, was not evaluated due to the hierarchical nature of the analysis and the finding that the previous endpoint was not statistically significant. Other MRI-based exploratory efficacy endpoints, including percent change in brain volume, were analyzed without correction for multiplicity or hierarchical testing.

Indication

Sponsor's proposed indication Health Canada-approved indication
Vivmory (ponesimod) is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (RMS). Ponvory (ponesimod) is indicated for:
The treatment of adult patients with relapsing remitting multiple sclerosis (RRMS).

The initial brand name, Vivmory, was changed to Ponvory during the review of the New Drug Submission to align with international approvals. Additionally, the indication was revised slightly to more closely reflect the patient population in the pivotal trial.

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

Clinical Safety

The safety profile of Ponvory was well characterized in the OPTIMUM study (described in the Clinical Efficacy section). A total of 82% of Ponvory-treated patients completed two years of study treatment, and 12% stayed in the study beyond safety follow-up. The median treatment duration was 108 weeks (25 months) with Ponvory and teriflunomide.

The most commonly reported treatment-emergent adverse event (TEAE) was increased alanine aminotransferase, which was reported more frequently in the Ponvory group (19.5%) than in the teriflunomide group (9.4%). Increased aspartate aminotransferase was also among the most commonly reported TEAEs (6.4% and 3.5% in the Ponvory and teriflunomide groups, respectively). In decreasing order, TEAEs of nasopharyngitis, respiratory tract infection, urinary tract infection, dyspnea, bronchitis, and cough were all reported with higher incidences in the Ponvory group of the OPTIMUM study, with frequencies ranging from 19.3% to 3.5%.

Other important TEAEs noted in the OPTIMUM study include bradyarrhythmia and increased blood pressure.

At treatment initiation, sinus bradycardia (heart rate [HR] <50 bpm) was observed via electrocardiogram (ECG) in 5.8% of patients in the Ponvory group, versus 1.6% of patients in the teriflunomide group. First-degree atrioventricular block was observed in 3.4% and 1.2% of patients in the Ponvory and teriflunomide groups, respectively. In the subset of Ponvory-treated patients at risk for symptomatic bradyarrhythmia at baseline, the proportion of patients with a new ECG finding of sinus bradycardia on Day 1 of the study was 20.0%, compared to 3.0% (all asymptomatic) in the subset of patients not at risk for symptomatic bradyarrhythmia.

Three patients in the Ponvory group who were at risk for symptomatic bradyarrhythmia (with HR <55 bpm prior to Ponvory treatment initiation) experienced asymptomatic post-first-dose HR ≤40 bpm. This was not detected in the subset of patients not at risk for symptomatic bradyarrhythmia.

Chronic treatment with Ponvory is also associated with an increase in blood pressure. Patients treated with Ponvory had an average increase of 2.9 mmHg in systolic blood pressure and 2.8 mmHg in diastolic blood pressure. In patients treated with teriflunomide, the average increases in systolic and diastolic blood pressure were 2.8 mmHg and 3.1 mmHg, respectively. An increase in blood pressure was first detected in patients treated with Ponvory approximately one month after treatment initiation and persisted with continued treatment. Treatment-emergent increases in systolic blood pressure of ≥20 mmHg from baseline were reported for 24.6% of patients in the Ponvory group and 29.2% of patients in the teriflunomide group. Treatment-emergent increases in diastolic blood pressure of ≥15 mmHg from baseline were reported for 26.2% of patients in the Ponvory group and 27.9% of patients in the teriflunomide group.

A list of potential drug-drug interactions with the use of Ponvory has been provided in the Ponvory Product Monograph. Of note, concomitant use of Ponvory with oral hormonal contraceptives is not expected to decrease the efficacy of the hormonal contraceptive.

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

7.2 Non-Clinical Basis for Decision

The mechanism of action of ponesimod, the medicinal ingredient in Ponvory, is believed to be related to the down-modulation and functional antagonism of sphingosine 1-phosphate subtype 1 (S1P1), which leads to the retention of lymphocytes in the lymphoid tissues. Results from secondary pharmacology studies showed that 10 μM ponesimod was associated with significant inhibition of monoamine oxidase B, endothelin receptor A, and the calcium/calmodulin-dependent protein kinase II. However, no signs of off-target toxicity were observed during the non-clinical and clinical safety evaluations.

Two metabolites of ponesimod, M12 and M13, are present in humans and represent 6% and 20% of total drug-related exposure, respectively. Ponesimod is metabolized by several cytochrome P450 (CYP) enzymes, uridine 5’-diphospho-glucuronosyltransferase (UGT) enzymes, and other enzymes. Due to the roles of CYP3A4 and UGT1A1 in the metabolism of ponesimod, the co-administration of strong inducers of these enzymes is expected to decrease the systemic exposure to ponesimod. No other interactions with ponesimod or its metabolites are expected.

Adverse respiratory effects such as pulmonary histiocytosis and lung weight increase were observed in mice, rats, and dogs after treatment with ponesimod. These findings are considered secondary to increased vascular permeability caused by S1P1 receptor modulation. The no-observed-adverse-effect levels (NOAELs) for lung findings were calculated based on 4-week repeat-dose toxicity studies in rats and dogs, along with exposure levels as measured by the area under the plasma concentration-time curve from time 0 to 24 hours (AUC0-24) and maximum plasma concentration (Cmax). These values were associated with exposure levels similar or inferior to human total and peak systemic exposures following the recommended human dose of 20 mg/day.

Cardiodynamic events are well-known adverse events for sphingosine 1-phosphate (S1P) receptor modulators. Adverse cardiodynamic effects were observed in guinea pigs treated with ponesimod at doses of 0.3, 1, 3, 10, and 30 mg/kg, but not at 0.1 mg/kg (0.07-fold the recommended human dose). In dogs, arterial lesions were detected in the posterior papillary muscles of the left ventricle after 13, 26, and 52 weeks of treatment at doses of ≥5 mg/kg/day. This observation is considered secondary to hemodynamic changes, and the dog is known to be sensitive to ponesimod-related hemodynamic changes in the heart. When compared with human systemic exposures at the recommended dose of 20 mg/day, the NOAEL in dogs was 4.3 and 6.2 times the human systemic exposures based on the AUC0-24 and Cmax, respectively.

Reproductive toxicology studies were conducted in rats and rabbits. Signs of embryo-fetal toxicity, including skeletal and visceral abnormalities, were observed in rats and rabbits at exposure levels below the clinical exposure. The NOAEL for embryo-fetal developmental toxicity was established at 1 mg/kg/day for both rats and rabbits. The AUC0-24 values in rats and rabbits at the NOAEL are lower than the human systemic exposures at the recommended dose of 20 mg/day.

In a developmental study in rats, decreased pup survival and body weight gain were observed in offspring at the highest dose tested (20 mg/kg/day), along with reduced fertility in females only. All ponesimod-treated F1 pups had delayed sexual maturation. The NOAEL was established at 10 mg/kg/day. The AUC0-24 at this dose is approximately 1.2 to 1.5 times the AUC0-24 in humans at the recommended dose of 20 mg/day.

Fertility studies in rats indicated that mating and fertility were unaffected at doses up to 100 mg/kg/day. No effects were observed on early pregnancy or on sperm parameters. In repeat-dose toxicology studies, no effects were observed on male reproductive organs for up to 26 weeks in rats and up to 52 weeks in dogs.

Carcinogenicity studies were conducted in mice and rats for up to 2 years in each species, which showed that ponesimod did not induce neoplastic lesions. The incidence of combined hemangiosarcoma and hemangioma was increased in males at all treated dose levels and in females at the highest dose level tested (300 mg/kg/day). Ponesimod was not found to be genotoxic, as the results from various in vitro and in vivo assays were negative.

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

For more information, refer to the Ponvory 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 Ponvory 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 (15 ºC to 30 ºC).

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

All 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.

The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.

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