Summary Basis of Decision for Tremfya

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 Tremfya is located below.

Recent Activity for Tremfya

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

Post-Authorization Activity Table (PAAT) for Tremfya

Updated: 2024-08-13

 

The following table describes post-authorization activity for Tremfya, a product which contains the medicinal ingredient guselkumab. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

 

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

 

Drug Identification Number (DIN):

  • DIN 02469758 – 100 mg/mL, guselkumab, solution for injection, subcutaneous administration (pre-filled syringe)
  • DIN 02487314 – 100 mg/mL, guselkumab, solution for injection, subcutaneous administration (auto-injector)

 

Post-Authorization Activity Table (PAAT)

 

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 282404

2023-12-22

Issued NOC 2024-05-17

Submission filed as a Level II – Supplement (Safety) to update the instructions for use in the PM. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

SNDS # 272204

2023-02-07

Issued NOC 2024-01-17

Submission filed as a Level I – Supplement to update the PM based on previously-provided data from studies PSA3001 and PSA3002. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions section of the PM. An NOC was issued.

NC # 277313

2023-07-17

Issued NOL 2023-08-28

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process. The submission was considered acceptable, and an NOL was issued.

SNDS # 268926

2022-10-21

Issued NOC 2023-04-25

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

SNDS # 259046

2021-11-26

Issued NOC 2022-11-08

Submission filed as a Level II – Supplement (Safety) to update the PM with long-term final safety and efficacy data from studies PSA3001 and PSA3002. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions and Clinical Trials sections of the PM. An NOC was issued.

SNDS # 252507

2021-05-07

Issued NOC 2022-04-13

Submission filed as a Level II – Supplement (Safety) to update the PM with long-term final safety and efficacy data from studies PSO3001 and PSO3002. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions and Clinical Trials sections of the PM. An NOC was issued.

SNDS # 251984

2021-04-23

Issued NOC 2021-09-17

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information based on pooled data from studies PSA3001 and PSA3002, and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions section of the PM. An NOC was issued.

NC # 251334

2021-03-30

Issued NOL 2021-05-21

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

SNDS # 232124

2019-09-30

Issued NOC 2020-09-04

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: Tremfya/Tremfya One-Press (guselkumab injection) is indicated for the treatment of adult patients with active psoriatic arthritis. Tremfya/Tremfya One-Press can be used alone or in combination with a conventional disease-modifying antirheumatic drug (cDMARD) (e.g., methotrexate). The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.

NC # 236122

2020-02-13

Issued NOL 2020-05-12

Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 236382

2020-02-21

Issued NOL 2020-03-27

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in scale of the manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 227793

2019-05-15

Cancellation Letter Received 2020-02-07

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

SNDS # 223170

2018-12-19

Issued NOC

2019-11-27

 

Submission filed as a Level I - Supplement to update the PM to include safety and efficacy results from the open-label extensions of two pivotal Phase III studies, and to update two bioanalytical procedures. Based on the data from these studies, appropriate changes were made to the PM. The data were reviewed and considered acceptable. The benefit/risk profile for Tremfya remains positive when used for its approved indication. The transfer of two bioanalytical procedures was also supported and did not change the safety or efficacy profile. An NOC was issued.

Drug product (DIN 02487314) market notification

Not applicable

Date of first sale: 2019-05-20

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

SNDS # 215920

2018-05-24

Issued NOC

2019-04-18

Submission filed as a Level I - Supplement to support a new injection device (auto-injector) for the treatment of moderate to severe plaque-type psoriasis. Based on the data presented, the benefit-risk profile of Tremfya remains unchanged for the approved indication, supporting the proposed Tremfya One-Press device as an alternative to the currently approved pre-filled syringe for the treatment of patients with psoriasis. An NOC was issued. A new DIN (02487314) was issued for the new presentation.

NC # 222985

2018-12-13

Issued NOL

2019-01-15

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

NC # 219929

2018-09-06

Issued NOL

2018-10-22

Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.

Drug product (DIN 02469758) market notification

Not applicable

Date of first sale: 2017-11-27

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

NDS # 200590

2016-11-25

Issued NOC 2017-11-10

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

Date SBD issued: 2018-03-23

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

Guselkumab
100 mg/mL, solution for injection, subcutaneous

Drug Identification Number (DIN):

  • 02469758

Janssen Inc.

New Drug Submission Control Number: 200590

 

On November 10, 2017, Health Canada issued a Notice of Compliance to Janssen Inc. for the drug product Tremfya.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and effectiveness) information submitted. Based on Health Canada's review, the benefit-risk profile of Tremfya is favourable for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

 

1 What was approved?

 

Tremfya (guselkumab) is an immunomodulator, a human immunoglobulin G subclass 1λ (IgG1λ) monoclonal antibody (mAb) which selectively binds to the p19 subunit of interleukin 23 (IL-23) and inhibits its interaction with cell surface IL-23 receptor. Tremfya was authorized for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Tremfya is intended for use under the guidance and supervision of a physician.

Tremfya is contraindicated in patients with known serious hypersensitivity to guselkumab or any of the components.

Of the 1,748 plaque psoriasis patients exposed to Tremfya in Phase II and Phase III clinical trials, a limited number of patients were 65 years or older [number of patients (n) = 93, 5%] or 75 years and older (n = 4, 0.2%). Therefore data in these age groups are limited.

The safety and efficacy of Tremfya in pediatric patients (<18 years of age) have not been evaluated. Therefore, Tremfya is not indicated in this patient population.

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

Tremfya (100 mg/mL, guselkumab, a human IgG1λ mAb) is supplied as a sterile solution for injection in a single-dose prefilled syringe. The Tremfya prefilled syringe contains a 1 mL glass syringe with a fixed 27 gauge ½ inch needle and is manufactured to deliver 100 mg guselkumab. In addition to the medicinal ingredient guselkumab, each prefilled syringe contains the non-medicinal ingredients L-histidine, L-histidine monohydrochloride monohydrate, sucrose, polysorbate 80, and water for injection.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Tremfya Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Tremfya approved?

 

Health Canada considers that the benefit-risk profile of Tremfya is favourable for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Psoriasis is a common immune-mediated, inflammatory skin disease which affects approximately 2% to 4% of the general population. It is a complex disorder, characterized by inflammation, keratinocyte hyperproliferation, and altered epidermal differentiation. Approximately 90% of psoriasis patients have the variant known as plaque psoriasis, characterized by raised, thick, red and scaly patches (psoriatic lesions) that can occur anywhere on the body. Approximately 20% of plaque psoriasis is moderate to severe, with body surface area (BSA) involvement of greater than 5%. Such patients often require chronic treatment. Although this disease is rarely life-threatening, consequences of having plaque psoriasis may include depression and social isolation.

Stepped care is the traditional means of treatment of plaque psoriasis, starting with topicals, followed by phototherapy, and progressing to systemic agents as needed. Modern guidelines often endorse a 2-tiered system which distinguishes mild disease amenable to topical therapy (e.g., steroids, tar, anthralin [dithranol], calcipotriene, and tazarotene) from moderate-to-severe disease requiring photo- and/or systemic therapy, including biologics. Use of topical steroids can often be associated with adverse events such as skin atrophy, striae, suppression of the hypothalamic pituitary adrenal axis, and tachyphylaxis. Phototherapy and PUVA (psoralen and ultraviolet A radiation) are often effective and well-tolerated, but inconvenient and of limited accessibility. Toxicities include sunburn, photo-aging, and an increased risk of skin cancer (particularly with PUVA).

Several pharmaceutical drugs, such as methotrexate, acitretin, and cyclosporine have been authorized in Canada for the treatment of psoriasis. However, these drugs can often be associated with adverse events such as organ damage and teratogenesis. Apremilast, a recently-approved oral phosphodiesterase 4 inhibitor for psoriasis may also be associated with adverse events such as diarrhea, depression, weight loss, and possible drug interactions.

Biologic agents that target various functions of pathogenic T cells and proinflammatory cytokines, such as tumour necrosis factor -alpha and interleukin (IL)-12/23 (ustekinumab), and IL-17A (secukinumab and ixekizumab) are also utilized for the treatment of psoriasis. The safety concerns associated with these agents vary by class and can include infections, malignancies, inflammatory bowel disease, and immunogenicity.

Tremfya has been shown to be efficacious in the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. The market authorization was based primarily on two ongoing Phase III placebo- and active comparator-controlled trials, VOYAGE 1 and VOYAGE 2, which evaluated the efficacy and safety of Tremfya in adult patients with plaque psoriasis. The two trials enrolled a total of 1,829 patients 18 years of age and older who had a minimum body surface area involvement of 10%, an Investigator's Global Assessment (IGA) ≥3, a Psoriasis Area and Severity Index (PASI) score ≥12, and were candidates for phototherapy or systemic therapy.

In both pivotal trials, patients randomized to Tremfya received 100 mg at week 0 and 4, then every 8 weeks. Patients randomized to active comparator adalimumab received 80 mg at Week 0 followed by 40 mg at Week 1 and then every 2 weeks. Both pivotal trials had the same co-primary endpoints, which were the proportion of patients who achieved an IGA score of cleared (0) or minimal (1) and the proportion of patients who achieved a PASI 90 response at Week 16, comparing the Tremfya group, the adalimumab group, and the placebo group. Results at Week 16 demonstrated that Tremfya was superior to placebo for both co-primary endpoints and statistically superior to adalimumab for IGA 0 or 1, PASI 90 and PASI 75. Improvement in plaque psoriasis symptoms at Week 16 was seen with Tremfya compared to placebo in both studies based on the Symptom Score of the Psoriasis Symptoms and Signs Diary (PSSD).

The safety profile of Tremfya is favourable for the treatment of psoriasis. The most common adverse effects of Tremfya included non-serious upper respiratory infections, headache, injection site reactions, arthralgia, elevated liver enzymes, diarrhea, gastroenteritis, tinea infections, and herpes simplex infections.

A Risk Management Plan (RMP) for Tremfya 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.

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

Overall, the benefits of Tremfya therapy are considered to outweigh the potential risks. Tremfya 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 Tremfya 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 Tremfya?

 

Submission Milestones: Tremfya

Submission Milestone Date
Pre-submission meeting: 2016-08-04
Submission filed: 2016-11-25
Screening  
Screening Acceptance Letter issued: 2017-01-16
Review  
On-Site Evaluation:  
Quality Evaluation complete: 2017-10-06
Clinical Evaluation complete: 2017-11-10
Biostatistics Evaluation complete: 2017-11-10
Review of Risk Management Plan complete: 2017-07-18
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2017-11-08
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2017-11-10

 

The Canadian regulatory decision on the quality, non-clinical and clinical review of Tremfya was based on a critical assessment of the data package submitted to Health Canada.

For additional information about the drug submission process, refer to the Management of 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 Tremfya?

 

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

 

The PAAT for Tremfya is found above.

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

 

6 What other information is available about drugs?

 

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

 

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

 

Clinical Pharmacology

The medicinal ingredient of Tremfya (guselkumab), is a human immunoglobulin G subclass 1λ (IgG1λ) monoclonal antibody (mAb) that binds selectively to the p19 subunit of interleukin 23 (IL-23), a naturally occurring proinflammatory cytokine. Elevated levels of IL-23 have been observed in the skin of patients with plaque psoriasis. Guselkumab inhibits the release of proinflammatory cytokines and chemokines (e.g., IL-17A, IL-17F and IL-22).

The clinical pharmacological data support the use of Tremfya for the recommended indication.

Guselkumab pharmacokinetics were characterized by three early phase pharmacokinetic studies in subjects with psoriasis (PSO1001 [Part 2], PSO1002, and PSO2001) and two studies in healthy subjects (NAP1001 and NAP1002). Sparse pharmacokinetic sampling (for guselkumab trough concentrations) collected from two Phase III studies (PSO3001 and PSO3002) and pharmacokinetic data from the Phase II study (i.e., PSO2001) in psoriasis patients constitutes the database for population pharmacokinetic modeling analysis.

No pharmacokinetic studies were conducted in special populations (i.e., pediatrics, elderly, and subjects with renal or hepatic impairment). Results from population pharmacokinetic analyses indicate that neither age (≥65 years versus <65 years), nor baseline laboratory measurements (alkaline phosphatase and estimated serum creatinine clearance) had a clinically relevant effect on the clearance of guselkumab. The overall incidence of developing anti-drug antibodies (ADA) to guselkumab following 52 weeks of exposure to guselkumab was 5.5% (number of patients [n] = 96/1,730). Of these, 7 subjects (7.3%) were positive for neutralizing antibodies, based on the Phase II - III studies. The development of anti-drug antibodies did not appear to significantly impact the pharmacokinetics of guselkumab based on observed data comparing trough serum guselkumab concentrations in subjects who had developed anti-drug antibodies to levels in those who had not. However, lower trough serum guselkumab concentrations were observed in some subjects after the formation of anti-drug antibodies.

Note that the total number of patients ≥65 years of age who participated in the Tremfya clinical trials was small (5%). Therefore data are limited in this age group.

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

Clinical Efficacy

The efficacy and safety of Tremfya in adult patients with moderate-to-severe plaque psoriasis was evaluated primarily in two ongoing multicentre, randomized, double-blind Phase III trials, VOYAGE 1 and VOYAGE 2. The trials enrolled a total of 1,829 patients 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%, an Investigator's Global Assessment (IGA) ≥3, and Psoriasis Area and Severity Index (PASI) score ≥12, and who were candidates for phototherapy or systemic therapy.

Each pivotal study evaluated short-term efficacy, up to 16 weeks, of Tremfya compared to placebo. In addition to placebo, the VOYAGE 1 and VOYAGE 2 trials also included adalimumab as an active comparator treatment.

In the VOYAGE 1 trial, subjects who satisfied all inclusion and exclusion criteria were randomized in a 2:1:2 ratio to 1 of 3 treatment groups: Tremfya (guselkumab), placebo or adalimumab. Patients randomized to Tremfya received 100 mg at Weeks 0 and 4, then every 8 weeks thereafter through Week 44. Patients randomized to placebo received a placebo at Weeks 0, 4, and 12 followed by a cross over to 100 mg guselkumab at Weeks 16, 20 and q8w thereafter through Week 44. Patients randomized to the active comparator adalimumab received adalimumab 80 mg at Week 0 followed by adalimumab 40 mg at Week 1 and every 2 weeks thereafter.

In the VOYAGE 2 trial, subjects who satisfied all inclusion and exclusion criteria were randomized in a 2:1:1 ratio to 1 of 3 treatment groups: Tremfya (guselkumab), placebo or adalimumab. Patients randomized to Tremfya received guselkumab 100 mg at Weeks 0, 4, 12, and 20. Patients randomized to placebo received a placebo at Weeks 0, 4 and 12 followed by a cross over to 100 mg guselkumab at Weeks 16 and 20. Patients randomized to the active comparator adalimumab received adalimumab 80 mg at Week 0 followed by adalimumab 40 mg at Week 1 and every 2 weeks thereafter through Week 23.

In both pivotal studies, the co-primary endpoints were the proportions of patients who achieved at least a 90% reduction in the Psoriasis Area and Severity Index (PASI 90) score from baseline to Week 16 and the proportion of patients with an Investigator's Global Assessment (IGA) score of cleared (0) or minimal (1). The IGA is a 5-category scale (0 = cleared, 1 = minimal, 2 = mild, 3 = moderate, 4 = severe) that indicates the physician's overall assessment of psoriasis, focusing on plaque thickness/induration, erythema and scaling.

Other endpoints included in both the VOYAGE 1 and VOYAGE 2 studies were the proportions of patients who achieved an IGA score of cleared (0), a PASI 100, PASI 75 response and regional disease as measured by scalp-specific IGA (ss-IGA). Patient-reported outcomes were assessed based on the Psoriasis Symptoms and Signs Diary (PSSD) and Dermatology Life Quality Index (DLQI).

Of all patients who were included in the VOYAGE 1 and VOYAGE 2 studies, 32% and 29% were naïve to conventional systemic and biologic systemic therapy; 54% and 57% had received prior phototherapy, and 62% and 64% had received prior conventional systemic therapy, respectively. In both studies, 21% had received prior biologic systemic therapy, including 11% who had received at least one anti-tumour necrosis factor alpha (TNFα) agent, and approximately 10% who had received an anti-IL-12/IL-23 agent.

Among patients who received Tremfya 100 mg during the 16-week period (short-term efficacy assessment), the proportions of patients with an IGA score of cleared (0) or minimal (1) were:

  • 85% versus (vs.) 7% in placebo-treated patients (difference 78%; 95% confidence interval [CI] [73%, 83%] and 66% in adalimumab-treated patients (difference 19%; 95% CI [13%, 25%] in the VOYAGE 1 trial;
  • 84% vs. 8% in placebo-treated patients (difference 76%; 95% CI [71%, 80%] and 68% in adalimumab-treated patients (difference 16%; 95% CI [11%, 22%] in the VOYAGE 2 trial.

Similarly, the other co-primary endpoint, PASI 90 was achieved by the following proportions of Tremfya patients (during the 16-week period):

  • 73% compared to 3% in placebo-treated patients (difference 70%; 95% CI [65% 76%] and 50% in adalimumab-treated patients (difference 24%; 95% CI [17%, 31%] in the VOYAGE 1 trial;
  • 70% compared to 2% in placebo-treated patients (difference 68%; 95% CI [64%, 72%] and 47% in adalimumab-treated patients (difference 23%; 95% CI [17%, 30%] in the VOYAGE 2 trial.

Based on the results presented above, Tremfya demonstrated superiority to placebo for the co-primary endpoints of IGA cleared (0) or minimal (1), and PASI 90 at Week 16. In addition, Tremfya demonstrated statistical superiority to adalimumab for IGA cleared (0) or minimal (1) and PASI 90 at Week 16.

In each of the pivotal trials, Tremfya-treated patients also met the key secondary endpoint of PASI 75 when compared to adalimumab-treated patients at Week 16. The proportions of PASI 75 responders were:

  • 91% compared to 73% in adalimumab-treated patients (difference 18%; 95% CI [13%, 23%] in the VOYAGE 1 trial;
  • 86% compared to 69% in adalimumab-treated patients (difference 18%; 95% CI [12%, 24%] in the VOYAGE 2 trial.

At Week 24, study results from VOYAGE 1 and VOYAGE 2 demonstrated that Tremfya showed statistical superiority to adalimumab for IGA cleared (0), IGA cleared or minimal (0 or 1) and PASI 90. In VOYAGE 1, with continued treatment over 48 weeks, IGA cleared (0), IGA cleared or minimal (0 or 1) and PASI 90 responses in Tremfya-treated patients were maintained and remained significantly greater than those achieved with adalimumab (IGA cleared (0), 50% vs. 26%, IGA cleared or minimal (0 or 1), 81% vs. 55%, PASI 90, 76% vs. 48%).

In the VOYAGE 1 study, at week 16, 37% of patients receiving Tremfya achieved PASI 100 compared to 17% of adalimumab-treated patients, and 1% of placebo-treated patients. In VOYAGE 2, at Week 16, 34% of patients receiving Tremfya achieved PASI 100 compared to 21% of adalimumab-treated patients, and 1% of placebo-treated patients.

In Tremfya treated-patients, improvement was seen in psoriasis involving the scalp (as measured by the Scalp-specific Investigator Global Assessment [ss-IGA]). Specifically, in the subset of patients with a baseline ss-IGA score ≥ 2, 83.4% and 80.6% in the Tremfya group in VOYAGE 1 and VOYAGE 2, respectively, achieved an ss-IGA score of 0 or 1 and at least a 2-grade improvement from baseline compared to 14.5% and 10.9% in the placebo group, respectively at week 16.

Supportive Study

A Supportive Phase III study NAVIGATE evaluated the efficacy of 24 weeks of treatment with Tremfya in patients [number of patients (n) = 268)] who had an inadequate response (defined as IGA ≥2) at Week 16 after initial treatment with ustekinumab (dosed at Weeks 0 and 4). These patients were then randomized to either continue ustekinumab treatment every 12 weeks or to switch to Tremfya 100 mg given at Weeks 16, 20, and every 8 weeks thereafter.

In patients with an inadequate response to ustekinumab, a greater proportion of patients who switched to Tremfya achieved an IGA score of 0 or 1 and had a ≥2-grade improvement at Week 28 compared to those who continued ustekinumab treatment (31% versus 14%, respectively).

Overall Analysis of Efficacy

Based on the efficacy data from the two pivotal trials, VOYAGE 1 and VOYAGE 2, in addition to the supportive trial NAVIGATE, the efficacy data provided in this submission support the approval of Tremfya for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

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

Clinical Safety

The safety profile of Tremfya in patients with moderate-to-severe plaque psoriasis was based primarily on pooled data from the pivotal Phase III studies, VOYAGE 1 and VOYAGE 2 (previously described in the Clinical Efficacy section). In addition, safety data from supportive clinical trials, Phase II (PSO2001) and Phase III (NAVIGATE) were also included. Of the 1,748 Tremfya-treated patients, 1,393 patients were exposed for at least 6 months (24 weeks) and 728 patients were exposed for at least 1 year (i.e., treated through Week 48). Most patients (n = 1,583) received a dosage regimen of 100 mg Tremfya as subcutaneous injection every 8 weeks.

Through the 16-week placebo-controlled period, adverse events reported at rates ≥1% in Tremfya-treated patients and at higher rates than were reported in placebo-treated patients were: upper respiratory infections (14.3%), headache (4.6%), injection site reactions (4.5%), arthralgia (2.7%), elevated liver enzymes (2.6%), diarrhea (1.6%), gastroenteritis (1.3%), tinea infections (1.1%), and herpes simplex infections (1.1%).

The proportion of Tremfya-treated patients who discontinued treatment due to adverse events was 1.3% compared to 0.9% in placebo-treated patients. Serious adverse events were reported in 1.9% of Tremfya-treated patients and 1.4% of placebo-treated patients through 16 weeks.

Because Tremfya is a selective immunomodulatory agent, it has the potential to increase the risk of infection. In the two pivotal clinical trials, infections were reported in 23% of Tremfya-treated patients compared to 21% of placebo-treated patients through 16 weeks of treatment. The most common type of infection reported was upper respiratory infection. The rates of serious infections for both Tremfya-treated patients and placebo-treated patients during this period were ≤0.2%.

Serious adverse events other than infections reported in the Tremfya clinical program included malignancy, suicide attempt, major adverse cardiovascular events (MACE), and negative pregnancy outcomes (e.g., miscarriage, ectopic pregnancy). Based on the available evidence, Tremfya exposure through one year is not associated with an increased incidence of these or other serious adverse events in the target patient population.

As with all therapeutic proteins, there is the potential for immunogenicity with Tremfya. Anti-guselkumab antibodies were not generally associated with reductions in clinical response, or the development of injection site reactions. In addition, none of the Tremfya-treated patients reported serious allergic or hypersensitivity reactions.

The safety and efficacy of Tremfya in combination with immunosuppressant drugs, including biologics, or with phototherapy, have not been evaluated.

The formation of cytochrome P450 (CYP) enzymes can be altered by increased levels of certain cytokines (e.g., interleukin [IL]-β, IL-6, tumor necrosis factor, and interferon) during chronic inflammation. Although an in vitro study using human hepatocytes showed that IL-23 did not alter the expression of activity of multiple CYP450 enzymes (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4), the potential for interaction cannot be ruled out.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical pharmacology and toxicology studies support the use of Tremfya for the treatment of moderate-to-severe plaque psoriasis.

Cynomolgus monkeys and guinea pigs were determined to be pharmacologically relevant species for use in the non-clinical studies on guselkumab. No significant adverse effects, including respiratory, cardiovascular, central nervous system, or immune function (e.g., immunotoxicity) were observed in cynomolgus monkeys when administered guselkumab by either intravenous or subcutaneous injection. The no-observed-adverse-effect level (NOAEL) for the general toxicity of guselkumab in cynomolgus monkeys is that of 50 mg/kg body weight once weekly; the highest dose tested for both routes of administration.

In a dedicated cardiovascular safety pharmacology study, no adverse events were observed in cynomolgus monkeys following single intravenous doses of up to 50 mg/kg body weight.

In a combined embryo-fetal and pre- and postnatal developmental toxicity study, no guselkumab-related maternal toxicity was observed. Increased incidence rates for fetal and neo-natal infant losses attributable to maternal neglect, trauma, and early or late delivery were observed at both doses tested but for which a drug-related effect could also not be ruled out. No adverse effects on functional or immunological development were observed in surviving infants. A NOAEL for developmental toxicity in cynomolgus monkeys could therefore not be identified.

No guselkumab-related adverse events were observed in a female fertility and early embryonic development study following administration of guselkumab to female guinea pigs at subcutaneous doses up to 100 mg/kg twice weekly (NOAEL) prior to mating, through mating, and during early gestation to implantation.

In a male fertility and early embryonic development toxicity study conducted in guinea pigs, the incidence of total litter loss was increased (5 of 22 untreated females in the treated group versus 0 out of 22 in the control group) following subcutaneous administration of guselkumab to males at a subcutaneous dose of 100 mg/kg twice weekly prior to mating and through mating for a total of 21 doses. In a second male fertility and early embryonic development toxicity study, there were no total litter losses in untreated females mated with treated males (100 mg/kg twice weekly). No effects on male fertility or early embryonic development were observed at a dose of 25 mg/kg. The lower dose of 25 mg/kg body weight is considered to be the overall NOAEL.

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

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

 

 

7.3 Quality Basis for Decision

 

Guselkumab, the medicinal ingredient of Tremfya, is a human immunoglobulin G subclass 1 (IgG1λ) monoclonal antibody designed and engineered to bind selectively to the p19 subunit of interleukin 23 (IL-23) and inhibit its interaction with cell surface IL-23 receptor. Interleukin 23 (IL-23) is a naturally-occurring cytokine which is involved in normal inflammatory and immune responses. Levels of IL-23 are elevated in the skin of patients with plaque psoriasis. Guselkumab inhibits the release of pro-inflammatory cytokines and chemokines (e.g., IL-17A, IL-17F and IL-22).

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that guselkumab consistently exhibits the desired characteristic structure and biological activity.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.

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

Drug Substance

The manufacturing process of the drug substance, guselkumab, consists of cell culture and primary recovery (upstream) and purification (downstream) components with a total of eleven stage operations. The production bioreactor contents are harvested by centrifugation and depth filtration. The clarified broth is purified and treated with a combination of chromatograph and filtration steps and viral inactivation steps and subsequently frozen. It has been demonstrated that the drug substance quality has remained comparable throughout the development stages.

Drug Product

The drug substance is thawed, formulated, filtered and filled into pre-sterilized syringes. It has been demonstrated that the drug product quality has remained comparable throughout the development stages.

Tremfya (100 mg/syringe) is supplied as a sterile solution in a single-use, pre-filled syringe. Each pre-prefilled syringe contains one 100 mg dose of guselkumab. In addition to the medicinal ingredient, guselkumab, each pre-filled syringe also contains the non-active ingredients L-histidine, L-histidine monohydrochloride monohydrate, sucrose, polysorbate 80, and water for injection.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of the guselkumab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications and analytical procedures are validated and in compliance with International Council for Harmonisation (ICH) guidelines.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated, and found to meet the specifications of the drug product and demonstrated consistency in manufacturing.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 24-month shelf life at 2ºC to 8ºC for Tremfya is considered acceptable when the product is protected from light and freezing.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

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

An On-Site Evaluation (OSE) of the facilities involved in the manufacture and testing of the drug substance guselkumab was not warranted since the facility was recently evaluated and obtained a satisfactory rating.

An OSE of the facility involved in the manufacture and testing of Tremfya drug product was waived as a successful OSE had been recently performed for another product whose manufacturing process is similar.

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

Adventitious Agents Safety Evaluation

The guselkumab manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses). Purification process steps designed to remove and inactivate viruses are adequately validated.

 

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