Summary Basis of Decision for Vabysmo

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 Vabysmo is located below.

Recent Activity for Vabysmo

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.

 

The following table describes post-authorization activity for Vabysmo, a product which contains the medicinal ingredient faricimab. 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.

 

Updated: 2024-08-21

 

Drug Identification Number (DIN):

DIN 02527618 - faricimab 6 mg/0.05 mL, solution, intravitreal injection

 

Post-Authorization Activity Table (PAAT)

 

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 278042

2023-08-08

Issued NOC 2024-07-24

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: Vabysmo (farcimab injection) is indicated for the treatment of macular edema secondary to retinal vein occlusion (RVO). The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.

NC # 283130

2024-01-26

Issued NOL 2024-04-26

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the controls (in‐process tests and/or acceptance criteria) applied during the drug substance and drug product manufacturing process or on intermediates. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 281716

2023-11-30

Issued NOC 2024-04-15

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions section of the PM. An NOC was issued.

SNDS # 268321

2022-10-03

Issued NOC 2023-09-13

Submission filed as a Level I – Supplement to update the PM with 2-year data from the two pivotal studies (TENAYA and LUCERNE) conducted in patients with wet age-related macular degeneration. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Adverse Reactions; Dosage and Administration; Clinical Pharmacology; and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

NC # 268491

2022-10-03

Issued NOL 2022-11-28

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the parameters of an approved holding step or addition of a new holding step. The submission was considered acceptable, and an NOL was issued.

Drug product (DIN 02527618) market notification

Not applicable

Date of first sale: 2022-07-18

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

NDS # 253904

2021-06-18

Issued NOC 2022-05-27

NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Vabysmo

Date SBD issued: 2022-08-31

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

Faricimab

Drug Identification Number (DIN):

  • DIN 02527618 - faricimab 6 mg/0.05 mL, solution, intravitreal injection

Hoffmann-La Roche Ltd.

New Drug Submission Control Number: 253904

 

On May 27, 2022, Health Canada issued a Notice of Compliance to Hoffmann-La Roche Limited for the drug product Vabysmo.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit-risk profile of Vabysmo is favourable for the treatment of neovascular (wet) age-related macular degeneration (AMD) and diabetic macular edema (DME).

 

1 What was approved?

 

Vabysmo, an ophthalmological agent, was authorized for the treatment of neovascular (wet) age-related macular degeneration (AMD) and diabetic macular edema (DME).

Vabysmo is not authorized for use in pediatric patients (<18 years of age), as no clinical safety or efficacy data are available for this population.

No dose adjustment is required in patients >65 years of age.

Vabysmo (faricimab 6 mg/0.05 mL) is presented as a solution. In addition to the medicinal ingredient, the solution contains acetic acid 30%, D-sucrose, L-histidine, L-methionine, polysorbate 20, sodium chloride, and water for injections.

The use of Vabysmo is contraindicated in patients with ocular or periocular infections, patients with active intraocular inflammation, and in patients who are hypersensitive to Vabysmo or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Vabysmo Product Monograph is available through the Drug Product Database.

For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

 

2 Why was Vabysmo approved?

 

Health Canada considers that the benefit-risk profile of Vabysmo is favourable for the treatment of neovascular (wet) age-related macular degeneration (AMD) and diabetic macular edema (DME).

Neovascular (wet) age-related macular degeneration is one of the most common causes of vision loss in people 60 years of age and older. It is characterized by the growth of abnormal new blood vessels (neovascularization) under the retina.

Diabetic macular edema is the main cause of vision loss in patients with diabetes. It is characterized by edema and retinal thickening in the macula subsequent to microvasculopathy of the retina.

The current standard of care for the treatment of wet AMD and DME is intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents.

Faricimab is a first-in-class humanized bispecific immunoglobulin G1 (IgG1) antibody intended for the treatment of wet AMD and DME. It acts by inhibiting both VEGF-A and angiopoietin-2 (Ang-2), two mediators involved in the pathogenesis of wet AMD and DME. The inhibition of VEGF-A suppresses endothelial cell proliferation, neovascularization, and vascular permeability. The inhibition of Ang-2 is thought to increase vascular stability and desensitize blood vessels to the effects of VEGF-A. The combination of these two effects is expected to improve the durability of efficacy in wet AMD and DME when compared to anti-VEGF therapy alone.

Vabysmo has been shown to be efficacious in patients with AMD and DME. The clinical efficacy and safety of Vabysmo were assessed in 1,329 patients with wet AMD who were enrolled in two randomized, multicentre, double-masked, active-controlled pivotal studies (TENAYA and LUCERNE). Efficacy was compared following intravitreal injections of Vabysmo or aflibercept (marketed in Canada as Eylea) using the mean change in best corrected visual acuity (BCVA) from baseline, measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score. It measures the ability of the eye to distinguish the details and shapes of objects (the clarity or sharpness of vision) at a given distance. In both studies, Vabysmo demonstrated non-inferiority to aflibercept administered every 8 weeks (Q8W) for the primary endpoint of mean change in BCVA from baseline based on an average at Weeks 40, 44, and 48. The mean change in BCVA from baseline in the study eye was clinically meaningful and generally maintained over 60 weeks. After one year of treatment, patients treated with Vabysmo showed similar improvement in visual acuity as patients treated with aflibercept.

The clinical efficacy and safety of Vabysmo were also assessed in 1,891 patients with DME who were enrolled in two randomized, multicentre, double-masked, active-controlled pivotal studies (YOSEMITE and RHINE). In both studies, non-inferiority of Vabysmo as compared to aflibercept administered Q8W was demonstrated for the primary efficacy endpoint of the mean change in BCVA from baseline based on an average at Weeks 48, 52 and 56. The mean change in BCVA from baseline was clinically meaningful and generally maintained through Week 100. After one year of treatment, patients treated with Vabysmo showed similar visual acuity improvement as patients treated with aflibercept.

In both the wet AMD and DME clinical studies, a substantial number of patients who received Vabysmo could extend their treatment intervals. This additional benefit of Vabysmo could lead to a reduction of the number of intravitreal injections and treatment burden in eligible patients, and a reduction of the potential risks associated with the injection procedure.

Vabysmo demonstrated an acceptable safety profile in both wet AMD and DME patients in the clinical studies. The overall incidence of ocular adverse events and ocular serious adverse events was generally similar between the Vabysmo and aflibercept arms. The adverse events that occurred in both the wet AMD and DME populations included intraocular inflammation (including endophthalmitis), retinal detachment/tear, conjunctival hemorrhage, cataract, vitreous detachment, vitreous hemorrhage, increased intraocular pressure, vitreous floaters, and eye pain. These adverse events have been appropriately addressed in the Vabysmo Product Monograph.

A Risk Management Plan (RMP) for Vabysmo was submitted by Hoffmann-La Roche Limited to Health Canada. 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. Upon review, the RMP was considered to be acceptable.

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

The sponsor submitted a brand name assessment that included testing for look-alike sound-alike attributes. Upon review, the proposed name Vabysmo was accepted.

Overall, the benefits of Vabysmo therapy seen in the pivotal studies are comparable to those of the comparator therapy and are considered to outweigh the potential risks. Vabysmo 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 Vabysmo 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 issued 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 Vabysmo?

 

The New Drug Submission (NDS) for Vabysmo was reviewed as part of the New Active Substance Work-Sharing Initiative, a work-sharing initiative of the national health regulatory agencies of Canada, Australia, Singapore, Switzerland, and the United Kingdom (the Access Consortium). This partnership aims to promote collaboration, optimize the use of resources, reduce duplication, and enhance the ability of each agency to ensure consumers have timely access to safe, effective, and high-quality therapeutic products.

Health Canada reviewed the clinical efficacy and safety components for the neovascular (wet) age-related macular degeneration indication of the NDS for Vabysmo. The primary reviews of the other components were completed as follows:

  • Clinical efficacy and safety components for the diabetic macular edema indication were reviewed by the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA)
  • Pharmacology components were reviewed by Australia’s Therapeutic Goods Administration (non-clinical) and the MHRA (clinical)
  • Quality components were reviewed by Singapore’s Health Sciences Authority (the drug substance data) and the Swiss Agency for Therapeutic Products (Swissmedic) (the drug product data), with Health Canada reviewing Canadian-specific quality elements.

The review of the submission was collaborative, with each regulatory agency sharing the outcome of its review with the others.

As per Method 2 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada, the reviews of the clinical component of the NDS for the diabetic macular edema indication, and of the non-clinical, clinical pharmacology, and quality components were based on a critical assessment of reviews conducted by the regulatory agencies listed above. The data package submitted to Health Canada was referred to as necessary. The Canadian regulatory decision on the Vabysmo NDS was made independently based on the Canadian review.

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

 

Submission Milestones: Vabysmo

Submission Milestone Date
New Drug Submission filed 2021-06-18
Screening  
Screening Acceptance Letter issued 2021-08-03
Review  
Review of Risk Management Plan completed 2022-04-29
Quality evaluation completed 2022-05-13
Non-clinical evaluation completed 2022-05-13
Biostatistics evaluation completed 2022-05-17
Clinical/medical evaluation completed 2022-05-18
Labelling review completed 2022-05-24
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate 2022-05-27

 

4 What follow-up measures will the company take?

 

In addition to requirements outlined in the Food and Drugs Act and Regulations, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market, including (but not limited to) the submission of the final clinical study reports for Studies GR42691 (AVONELLE-X) and GR41987 (RHONE-X).

 

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

 

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 Vabysmo 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

 

As described above, the New Drug Submission (NDS) for Vabysmo was reviewed as part of the New Active Substance Work Sharing Initiative. Health Canada reviewed the clinical efficacy and safety components for the wet age-related macular degeneration (AMD) indication of the NDS for Vabysmo. The primary reviews of the clinical efficacy and safety components for the diabetic macular edema (DME) indication, as well as the clinical pharmacology component were conducted by the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA). Although the agencies collaborated on the review of the submission, each agency made its regulatory decision independently.

As described above, the review of the clinical component for the DME indication, and of the clinical pharmacology component of the NDS for Vabysmo was conducted as per Method 2 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Clinical Pharmacology

Faricimab, the medicinal ingredient in Vabysmo, is a humanized bispecific immunoglobulin G1 (IgG1) antibody. It acts by inhibiting both angiopoietin-2 (Ang-2) and vascular endothelial growth factor A (VEGF-A), two mediators involved in the pathogenesis of neovascular (wet) age-related macular degeneration (AMD) and diabetic macular edema (DME). The inhibition of VEGF-A suppresses endothelial cell proliferation, neovascularization, and vascular permeability. Secondly, the inhibition of Ang-2 is thought to increase vascular stability and desensitize blood vessels to the effects of VEGF-A. Levels of Ang-2 are increased in some patients with wet AMD and DME.

The clinical pharmacology included reports of human pharmacodynamic and pharmacokinetic studies. Nine clinical studies, four of which were Phase III, provided data that described the pharmacokinetic and pharmacodynamic characterization of faricimab following intravitreal (IVT) administration in patients with wet AMD or DME.

Following IVT administration of 6 mg faricimab every 4 weeks for the first four doses, and subsequent administration of the same dose every 8 weeks, maximum concentrations (Cmax) in the vitreous body were reached immediately with an estimated median Cmax of 1,340 µg/mL in both wet AMD and DME patients. The elimination of faricimab from the vitreous body was slow, with an estimated half-life (t1/2) of 7.5 days.

In the plasma, the Cmax of faricimab was reached approximately 2 to 3 days after IVT dosing with a median Cmax of 0.22 µg/mL in patients with wet AMD and 0.21 µg/mL in patients with DME. The apparent volume of distribution in the plasma compartment (Vc/F) was 1.48 L, consistent with a limited distribution.

No accumulation of faricimab was observed in the vitreous body or in the plasma following the proposed IVT dose regimens, with steady state reached by the end of the 4-week dosing interval. Based on population pharmacokinetic analysis, the estimated plasma apparent systemic clearance (CL/F) was 2.33 L/day, corresponding to a short plasma t1/2 of approximately 0.44 days.

A decrease from baseline in the level of ocular free Ang-2 and VEGF-A was observed at Day 7 with no apparent suppression of Ang-2 or VEGF-A in plasma.

The clinical pharmacology data support the use of Vabysmo for the recommended indication. For further details, please refer to the Vabysmo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

Neovascular (Wet) Age-Related Macular Degeneration

The clinical efficacy of Vabysmo was assessed in two randomized, multicentere, double-masked, active comparator-controlled pivotal studies (TENAYA and LUCERNE) in patients with neovascular (wet) age-related macular degeneration (AMD). The two studies were identical in design and each assessed the non-inferiority of Vabysmo to aflibercept (marketed in Canada as Eylea).

A total of 1,329 wet AMD patients were randomized in a 1:1 ratio to one of two treatment arms:

  1. Aflibercept 2 mg (number of patients [n] = 664) administered every 8 weeks (Q8W) after three initial monthly doses.
  2. Vabysmo (faricimab) 6 mg (n = 665) administered every 16 weeks (Q16W), every 12 weeks (Q12W), or every 8 weeks (Q8W), after four initial monthly doses. Doses were assigned based on assessments of pre-specified visual and anatomic criteria at Weeks 20 and 24 as well as on clinical assessments. Each patient remained on these dosing intervals, without supplemental therapy, until Week 60.

The TENAYA Study enrolled 40.1% male and 59.9% female patients with a mean age of 76.3 years (range: 50 to 99 years). Similarly, the LUCERNE Study enrolled 40.6% male and 59.4% female patients with a mean age of 75.5 years (range: 50 to 99 years).

The primary efficacy endpoint for both studies was the mean change in best corrected visual acuity (BCVA) from baseline based on an average at Weeks 40, 44, and 48, measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score. Both studies demonstrated that Vabysmo was non-inferior for the primary efficacy endpoint as compared to aflibercept administered Q8W. The adjusted mean difference between the Vabysmo and aflibercept arms was 0.7 (95% confidence interval [CI]: -1.1, 2.5) in the TENAYA study and 0.0 (95% CI: -1.7, 1.8) in LUCERNE study. The lower bound of the 95% CI was greater than the pre-specified non-inferiority margin of -4 letters. The mean change in BCVA from baseline at Weeks 40, 44, and 48 was clinically meaningful and was maintained over 60 weeks.

The primary endpoint results were supported by the results for the secondary endpoints, including the proportions of patients who gained at least 15 letters and those who avoided losing at least 15 letters in BCVA from baseline based on an average at Weeks 40, 44, and 48.

At Week 60, 33% and 45% of patients were able to extend the treatment interval of Vabysmo to Q12W and Q16W, respectively.

Diabetic Macular Edema

The clinical efficacy of Vabysmo was assessed in two randomized, multicentre, double-masked, active comparator-controlled, two-year pivotal studies (YOSEMITE and RHINE) in patients with diabetic macular edema (DME). The two studies were identical in design, and each assessed the non-inferiority of Vabysmo to aflibercept.

A total of 1,891 patients were randomized in a 1:1:1 ratio to one of the three treatment regimens:

  1. Vabysmo (faricimab) 6 mg (n = 632) administered Q8W after six initial monthly doses.
  2. Vabysmo 6 mg variable dosing (n = 632): patients received faricimab 6 mg Q4W for at least four doses and until resolution of edema was achieved. Thereafter, at dosing visits, the dosing interval could be modified between Q4W to Q16W based on assessments of visual and anatomic outcomes.
  3. Aflibercept 2 mg (n = 627) administered Q8W after five initial monthly doses.

The YOSEMITE Study enrolled 59.8% male and 40.2% female patients with a mean age of 62.2 years (range: 24 to 91 years). Similarly, the RHINE Study enrolled 60.9% male and 39.1% female patients with a mean age of 62.2 years (range: 24 to 91 years).

The primary efficacy endpoint for both studies was the mean change in BCVA from baseline based on an average at Weeks 48, 52 and 56, measured by the ETDRS letter score. In both studies, the pre-specified non-inferiority margin for the primary efficacy endpoint was met, thereby demonstrating non-inferiority of both Vabysmo Q8W and Vabysmo variable dosing as compared to aflibercept Q8W dosing. The results for the YOSEMITE study demonstrated an adjusted mean difference between the Vabysmo Q8W and aflibercept Q8W of -0.2 (97.5% CI: -2.0, 1.6), while that for Vabysmo variable dosing and aflibercept Q8W was 0.7 (97.5% CI: -1.1, 2.5). The results for the RHINE study for the same comparisons were: 1.5 (-0.1, 3.2) and 0.5 (-1.1, 2.1), respectively. The lower bounds of the 97.5% CI were greater than the pre-specified non-inferiority margin of -4 letters. The mean change in BCVA from baseline at Weeks 48, 52, and 56 was clinically meaningful and was maintained through Week 100.

The primary endpoint results were supported by the results for the secondary endpoints including the proportions of patients who gained at least 15 letters and those who avoided losing at least 15 letters in BCVA from baseline based on an average at Weeks 48, 52 and 56.

At Week 52, in the Vabysmo variable dosing arm, Vabysmo was administered Q16W in 52% of patients. Among these patients, 76% maintained Q16W dosing without an interval reduction through Week 96.

Indication

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

  • Vabysmo (faricimab injection) is a bispecific angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) inhibitor indicated for:
    • Neovascular (wet) age-related macular degeneration (nAMD)
    • Diabetic macular edema (DME)

Health Canada approved the following indication:

  • Vabysmo (faricimab injection) is indicated for the treatment of:
    • Neovascular (wet) age-related macular degeneration (AMD)
    • Diabetic macular edema (DME)

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

Clinical Safety

Neovascular (Wet) Age-Related Macular Degeneration

The clinical safety of Vabysmo for the treatment of neovascular (wet) age-related macular degeneration (AMD) was evaluated in the pivotal TENAYA and LUCERNE studies described in the Clinical Efficacy section.

Through Week 60, the overall incidence of ocular adverse events (AEs) and ocular serious adverse events (SAEs) was generally similar between treatment groups with ocular AEs occurring in 42% of Vabysmo patients versus (vs.) 40% of aflibercept patients and ocular SAEs occurring in 2.1% of Vabysmo patients vs. 2.6% of aflibercept patients. The most common ocular AEs that occurred in at least 3% of patients treated with Vabysmo were cataract, conjunctival hemorrhage, vitreous detachment, vitreous floaters, retinal pigment epithelium (RPE) tear, increased intraocular pressure, and eye pain. The most common ocular SAEs that occurred in at least 0.2% of patients treated with Vabysmo were RPE tear, vitritis, uveitis, reduced visual acuity, and cataract.

Diabetic Macular Edema

The clinical safety of Vabysmo was evaluated in the pivotal YOSEMITE and RHINE studies described in the Clinical Efficacy section.

Through Week 100, the overall incidence of ocular AEs was generally similar across the treatment arms (50% for Vabysmo Q8W vs. 50% for Vabysmo variable dosing vs. 46% for aflibercept Q8W). The most common ocular AEs that occurred in at least 3% of patients treated with Vabysmo were cataract, conjunctival hemorrhage, vitreous detachment, vitreous floaters, increased intraocular pressure, dry eye, and eye pain. The incidence of ocular SAEs was numerically higher in the Vabysmo arms as compared to the aflibercept arm (4.1% for Vabysmo Q8W vs. 5.4% for Vabysmo variable dosing vs. 3.2% for aflibercept Q8W). No clusters of specific events were seen. The most common ocular SAEs that occurred in at least 0.2% of patients treated with Vabysmo were cataract, endophthalmitis, uveitis, retinal tear, vitreous hemorrhage, diabetic retinopathy, and diabetic retinal oedema.

Immunogenicity

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity (the development of anti-drug antibodies [ADAs], which have the potential to neutralize the biological activity of the drug). After dosing with Vabysmo for up to 48 weeks (wet AMD) and 100 weeks (DME), treatment emergent anti-faricimab antibodies were detected in approximately 10.4% of wet AMD patients and 9.6% of DME patients. Intraocular inflammation adverse reactions were observed in 5 out of 75 (wet AMD) and 15 out of 128 (DME) ADA-positive patients and in 7 out of 582 (wet AMD) and 5 out of 1,124 (DME) ADA-negative patients.

The long-term safety of Vabysmo will continue to be monitored via pharmacovigilance activities. Appropriate warnings and precautions are in place in the approved Vabysmo Product Monograph to address the identified safety concerns.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

As described above, the New Drug Submission (NDS) for Vabysmo was reviewed as part of the New Active Substance Work Sharing Initiative. Australia’s Therapeutic Goods Administration completed the primary review of the non-clinical component of the NDS for Vabysmo. Although the agencies collaborated on the review of the submission, each agency made its regulatory decision independently.

As described above, the review of the non-clinical component of the NDS for Vabysmo was conducted as per Method 2 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Primary pharmacology studies demonstrated the affinity of faricimab for vascular endothelial growth factor A (VEGF-A) and angiopoietin-2 (Ang-2) and demonstrated the efficacy of faricimab in a cynomolgus monkey model of neovascular (wet) age-related macular degeneration (AMD). Faricimab is not expected to induce complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity. The pharmacokinetics of faricimab was generally consistent with the nature of the biologic drug (i.e., long half-lives and limited distribution).

The toxicology program of faricimab included 2-, 9-, and 26-week repeat-dose intravitreal (IVT) toxicity studies in cynomolgus monkeys. Unilateral IVT administration of faricimab at doses ranging from 0.5 mg/eye to 3.0 mg/eye once every 4 weeks for up to 26 weeks (6 months) resulted in dose-dependent ocular inflammation. At the no-observed-adverse-effect level of 0.5 mg/eye in cynomolgus monkeys, the systemic exposure (area under the concentration-time curve [AUC]) was 1.5 times higher than the exposure observed in humans after the recommended IVT dose of 6 mg/eye. The observed ocular inflammation was consistent with immune complex formation and deposition in non-human species exposed to a humanized antibody. This response is unlikely to be relevant to humans. Assessments after the 13-week recovery period indicated recovery from faricimab-induced ocular inflammation.

No genotoxicity or carcinogenicity studies were conducted. There was no evidence of proliferative lesions in the repeat-dose toxicity study.

Due to its mechanism of action as an inhibitor of VEGF and Ang-2, faricimab must be considered as potentially teratogenic.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Vabysmo Product Monograph. In view of the intended use of Vabysmo, 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 Vabysmo Product Monograph to address the identified safety concerns.

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

 

 

7.3 Quality Basis for Decision

 

As described above, the New Drug Submission (NDS) for Vabysmo was reviewed as part of the New Active Substance Work Sharing Initiative. The quality components of the NDS were reviewed by Singapore’s Health Sciences Authority (the drug substance data) and the Swiss Agency for Therapeutic Products (Swissmedic) (the drug product data), with Health Canada reviewing Canadian-specific quality elements. Although the agencies collaborated on the review of the submission, each agency made its regulatory decision independently.

As described above, the review of the quality components of the NDS for Vabysmo was conducted as per Method 2 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Characterization of the Drug Substance

Faricimab, the medicinal ingredient in Vabysmo, is a humanized recombinant bispecific immunoglobulin (IgG1) antibody that binds to vascular endothelial growth factor A (VEGF-A) and angiopoietin-2 (Ang-2).

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

The drug substance manufacturing process has been optimized and scaled up during development. The process changes introduced at each generation of the process were adequately described and comparatively addressed. Lot release, stability, and characterization data have also been used to support the comparability assessment.

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 of the Drug Substance and Drug Product and Process Controls

Faricimab is produced in engineered Chinese Hamster Ovary (CHO-K1) cells. The manufacture is based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with International Council for Hamonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. Results from genetic characterization studies also demonstrated stability of these cell banks.

The drug substance manufacturing process begins with the thawing of a single vial of the working cell bank derived from the master cell bank, followed by a series of stages including cell culture, harvest, purification, viral inactivation, and filtration. The resulting filtrate is concentrated and filtered further prior to the addition of polysorbate 20 to form the complete drug substance formulation. The purified drug substance is then filtered further and dispensed into bioprocess bags to be stored frozen.

Vabysmo drug product is manufactured from the formulated drug substance by sterile filtration and aseptic filling processes using conventional pharmaceutical equipment and facilities. Vabysmo is supplied as a 120 mg/mL sterile solution for injection, in single-dose vials (faricimab 6 mg/0.05 mL). In addition to faricimab, each vial of product contains the following excipients: acetic acid 30%, D-sucrose, L-histidine, L-methionine, polysorbate 20, sodium chloride, and water for injections. Following filling and stoppering, the capped and crimped vials are 100% visually inspected by manual or automatic inspection and stored at 2 °C to 8 °C.

The materials used in the manufacture of the drug substance and drug product (including biological materials) are considered suitable and/or meet standards appropriate for their intended use.

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of the faricimab 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. Analytical procedures are validated and in compliance with ICH guidelines.

Vabysmo is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs. Through Health Canada's consistency lot testing and evaluation program, manufactured final product lots were tested using a subset of release methods. The testing process confirmed that the methods used in-house are acceptable for their intended use and positively supported the quality review recommendation.

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 shelf life of 30 months for Vabysmo, when stored at 2 to 8 °C protected from light, is considered acceptable.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

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

Based on a risk assessment score determined by Health Canada, on-site evaluations of the drug substance and drug product manufacturing facilities were not deemed necessary.

Both sites involved in production are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The faricimab 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) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.

Raw materials of animal and recombinant deoxyribonucleic acid (DNA) origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. The excipients used in the drug product formulation are not of animal or human origin. The biologic raw materials originate from sources with no risk of transmissible spongiform encephalopathy agents or other human pathogens.

 

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