Summary Basis of Decision for Beovu

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 Beovu is located below.

Recent Activity for Beovu

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 Beovu, a product which contains the medicinal ingredient brolucizumab. 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: 2024-04-10

 

Drug Identification Number (DIN):

DIN 02496976 – 6 mg/0.05 mL, brolucizumab, solution (single use pre filled syringe), intravitreal injection

DIN 02496984 – 6 mg/0.05 mL, brolucizumab, solution (single use vial), intravitreal injection

 

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 259754

2021-12-17

Issued NOC 2022-11-30

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: Beovu (brolucizumab injection) is indicated for the treatment of diabetic macular edema (DME). The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.

SNDS # 256915

2021-09-22

Issued NOC 2022-02-23

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM. Corresponding changes were made to Part III: Patient Medication Information and to the package inserts. An NOC was issued.

Health Professional Risk Communication

Not applicable

Posted 2022-02-03

Health Professional Risk Communication posted (Beovu [brolucizumab] – Risk of Intraocular Inflammation, Retinal Vasculitis and/or Retinal Vascular Occlusion), containing new safety information for health professionals.

SNDS # 252316

2021-05-03

Issued NOC 2021-12-14

Submission filed as a Level I – Supplement  for a change to a drug substance manufacturing facility and a change in scale of the manufacturing process. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 254660

2021-07-12

Issued NOC 2021-11-23

Submission filed as a Level II – Supplement (Safety) to update the PM. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Dosage and Administration sections of the PM. Corresponding changes were made to Part III: Patient Medication Information and to the package inserts. An NOC was issued.

SNDS # 252531

2021-06-08

Issued NOC 2021-11-04

Submission filed as a Level II – Supplement (Safety) to update the PM. The changes were in response to an Advisement Letter issued by Health Canada, dated 2021-05-10, to Novartis Pharmaceuticals Canada Inc. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions section of the PM. Corresponding changes were made to the package inserts. An NOC was issued.

SNDS # 254297

2021-06-30

Cancellation Letter Received 2021-10-22

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The changes were not in scope of Level II changes but were considered to be Level I changes. The submission was cancelled by the sponsor.

SNDS # 251156

2021-03-31

Issued NOC 2021-08-18

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 # 239445

2020-05-12

Issued NOC 2020-09-30

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM. Corresponding changes were made to Part III: Patient Medication Information and to the package inserts. An NOC was issued.

Drug product (DIN 02496976) market notification

Not applicable

Date of first sale: 2020-05-15

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

NC # 237630

2020-03-26

Issued NOL 2020-04-06

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

NDS # 226224

2019-03-27

Issued NOC 2020-03-12

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

Date SBD issued: 2020-08-04

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

Brolucizumab

Drug Identification Number (DIN):

  • DIN 02496976 - 6 mg/0.05 mL, solution (single‑use pre&‑filled syringe), intravitreal injection
  • DIN 02496984 - 6 mg/0.05 mL, solution (single‑use vial), intravitreal injection

Novartis Pharmaceuticals Canada Inc.

New Drug Submission Control Number: 226224

 

On March 12, 2020, Health Canada issued a Notice of Compliance to Novartis Pharmaceuticals Canada Inc. for the drug product, Beovu.

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 Beovu is favourable for the treatment of neovascular (wet) age related macular degeneration (AMD).

 

1 What was approved?

 

Beovu, an ophthalmological/anti‑neovascularization agent, was authorized for the treatment of neovascular (wet) age‑related macular degeneration (AMD).

Data regarding the use of Beovu in patients younger than 18 years of age have not been submitted to Health Canada. Therefore, Health Canada has not authorized an indication for pediatric use. No dosage regimen adjustment is required for geriatric use. In the two pivotal clinical studies, approximately 90% of patients were 65 years of age or older and approximately 60% were 75 years of age or older.

Beovu is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation (including any non‑medicinal ingredient), or to any component of the container. Beovu is also contraindicated for patients with active or suspected ocular or periocular infection, or active intraocular inflammation.

Beovu 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.

Beovu (6 mg/0.05 mL brolucizumab) is presented as a solution in a single‑use pre‑filled syringe or single‑use vial. In addition to the medicinal ingredient, brolucizumab, the solution contains polysorbate 80, sodium citrate, sucrose, 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 Beovu Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Beovu approved?

 

Health Canada considers that the benefit‑risk profile of Beovu is favourable for the treatment of neovascular (wet) age‑related macular degeneration (AMD).

Wet AMD is a chronic eye disease characterized by the growth of abnormal new blood vessels (neovascularization) from the subjacent choroid into the sub‑retinal pigment epithelium space and the sub‑retinal space. It affects approximately 1.0% to 1.3% of individuals over the age of 65 in North America. Without treatment, most affected eyes will be legally blind within 12 months. Intravitreal administration of a vascular endothelial growth factor (VEGF) inhibitor is the current global standard of care in wet AMD. At the time of authorization, two VEGF inhibitors, Lucentis (ranibizumab) and Eylea (aflibercept), were marketed in Canada for the treatment of wet AMD.

Beovu (brolucizumab) is a humanized single‑chain Fv (scFv) antibody fragment which binds to VEGF A isoforms, thereby preventing binding of VEGF A to its receptors: VEGFR 1 and VEGFR 2.

Beovu is authorized for the treatment of wet AMD. The market authorization was based on two randomized, multicentre, double‑masked, active‑controlled non‑inferiority Phase III studies known as RTH258‑C001 (HAWK) and RTH258‑C002 (HARRIER). In these studies, a total of 1,817 patients with wet AMD were randomized to receive either Beovu 3 mg (in HAWK only), Beovu 6 mg or aflibercept 2 mg, an approved drug for wet AMD treatment. Beovu was administered every 8 or 12 weeks based on disease activity assessments after the first 3 monthly doses. Aflibercept was administered every 8 weeks after the first 3 monthly doses. For both studies, the primary efficacy endpoint was the change in Best Corrected Visual Acuity (BCVA) from baseline to Week 48. In both studies, Beovu administered every 8 or 12 weeks demonstrated a non‑inferior efficacy to aflibercept 2 mg administered every 8 weeks for the change in BCVA from baseline to Week 48.

The safety of Beovu was also assessed in the HAWK and HARRIER studies. Similar to other VEGF inhibitors, major safety issues included intraocular inflammation/endophthalmitis, retinal detachment/tear, traumatic cataract, intraocular pressure increase, arterial thromboembolic events, and hypersensitivity. The rate of intraocular inflammation/endophthalmitis was higher in the pooled Beovu 6 mg group (37 patients [5.1%]) than in the pooled aflibercept 2 mg group (7 patients [1.0%]). Other adverse events occurred at rates which were similar to aflibercept. The most common (≥5% of pooled patients) ocular adverse events after treatment with Beovu 6 mg were visual acuity reduced, cataract, conjunctival hemorrhage, intraocular inflammation including endophthalmitis, vitreous floaters, and eye pain. Less common (<1%) serious adverse drug reactions reported in the patients treated with Beovu 6 mg were endophthalmitis, blindness, retinal artery occlusion, and retinal detachment. The most frequently reported adverse drug reactions resulting in permanent discontinuation of Beovu treatment were endophthalmitis, uveitis, and retinal artery occlusion. There were no clinically meaningful differences between Beovu 6 mg and 3 mg doses in the safety profile.

A Risk Management Plan (RMP) for Beovu was submitted by Novartis Pharmaceuticals Canada Inc. to Health Canada. Health Canada recommended that the sponsor update the RMP regarding important potential risks, risk minimization measures, medication/administration errors, systemic absorption and educational materials. 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 Beovu Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A Look‑alike Sound‑alike brand name assessment was performed and the proposed name, Beovu, was accepted.

Overall, the benefits of Beovu outweigh the risks for the indicated treatment of wet AMD. Beovu provides an option for eligible patients at a reduced treatment frequency. Beovu has been shown to have a favourable benefit‑risk profile in the target patient population based on non‑clinical and clinical studies. Warnings and precautions are in place in the Beovu 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 Beovu?

 

Submission Milestones: Beovu

Submission Milestone Date
Pre-submission meeting: 2018-08-30
Submission filed: 2019-03-27
Screening  
Screening Acceptance Letter issued: 2019-05-17
Review  
Quality Evaluation complete: 2020-02-03
Review of Risk Management Plan complete: 2020-02-13
Clinical/Medical Evaluation complete: 2020-03-09
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2020-03-11
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate: 2020-03-12

 

The Canadian regulatory decision on the review of Beovu was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.

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

 

4 What follow-up measures will the company take?

 

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

 

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

 

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 Beovu 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

Brolucizumab, the medicinal ingredient in Beovu, is a humanized vascular endothelial growth factor (VEGF) inhibitor that binds to VEGF‑A isoforms (e.g. VEGF110, VEGF121, and VEGF165), thereby preventing binding of VEGF‑A to its receptors: VEGFR‑1 and VEGFR‑2.

Neovascular (wet) age‑related macular degeneration (AMD) is characterized by proliferation of abnormal blood vessels in the choroid (choroidal neovascularization). Leakage of blood and fluid from choroidal neovascularization may cause retinal thickening or edema. In clinical studies, reductions in central retinal subfield thickness were observed in wet AMD patients treated with Beovu.

Beovu is administered directly into the vitreous to exert local effects in the eye. After a single intravitreal administration of 6 mg brolucizumab per eye to patients with wet AMD, the geometric mean serum maximum concentration (Cmax) of free brolucizumab was 49.0 ng/mL (range: 8.97 to 548 ng/mL) and was attained in 1 day, post‑dose. The estimated mean systemic half‑life was 4.3 days (standard deviation: ±2.2 days).

Following the proposed intravitreal dose regimen, brolucizumab concentrations were generally near or below the quantitation limit (<0.5 ng/mL) approximately 4 weeks after dosing and no accumulation in serum was observed in most patients.

No drug metabolism and excretion studies were conducted. As a single‑chain antibody fragment, free brolucizumab is expected to undergo elimination through metabolism via proteolysis and target‑mediated disposition and/or passive renal excretion.

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

Clinical Efficacy

The clinical efficacy of Beovu (brolucizumab) was demonstrated in two randomized, multicentre, double‑masked, active‑controlled non‑inferiority Phase III studies: RTH258‑C001 (HAWK) and RTH258‑C002 (HARRIER). A total of 1,817 patients with wet AMD received either Beovu or aflibercept, an approved drug for wet AMD treatment.

Patients in the HAWK study were randomized to receive Beovu 3 mg, Beovu 6 mg, or aflibercept 2 mg in a 1:1:1 ratio. Patients in the HARRIER study were randomized to receive Beovu 6 mg or aflibercept 2 mg in a 1:1 ratio. In both studies, after the first 3 monthly doses (Week 0, 4, and 8), Beovu was administered every 8 or 12 weeks based on visual and anatomical measures of disease activity determined by the treating physicians. Patients who showed disease activity were adjusted to an 8 week dosing interval until the end of the studies. Aflibercept was administered every 8 weeks regardless of disease activity after the first 3 monthly doses (Week 0, 4, and 8). The total duration of the HAWK and HARRIER studies was 96 weeks.

For both studies, the primary efficacy endpoint was the change in Best Corrected Visual Acuity (BCVA) from baseline to Week 48. This was measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score with the primary objective being to demonstrate non‑inferiority of Beovu vs. aflibercept using a non‑inferiority margin of 4 letters.

Beovu administered every 8 or 12 weeks demonstrated non‑inferior efficacy to aflibercept 2 mg administered every 8 weeks for the change in BCVA from baseline to Week 48. In the HAWK study, the mean change in BCVA from baseline to week 48 was 6.6 letters and 6.8 letters for Beovu 6 mg and aflibercept 2 mg, respectively. The LS (least squares) mean difference between the Beovu and aflibercept arms was ‑0.2 letters (lower limit of the 95% Confidence Interval [CI] = ‑2.1 letters, p<0.0001 for non‑inferiority testing). In the HARRIER study, the mean change in BCVA from baseline to Week 48 was 6.9 letters and 7.6 letters for Beovu 6 mg and aflibercept 2 mg, respectively. The LS mean difference between the Beovu and aflibercept arms was ‑0.7 letters (lower limit of the 95% CI = ‑2.4 letters, p<0.0001 for non‑inferiority testing).

At Week 96, the mean change from baseline in BCVA in the HAWK and HARRIER studies was 5.9 letters and 6.1 letters for Beovu 6 mg and 5.3 letters and 6.6 letters for aflibercept 2 mg, respectively.

Among patients randomized to receive Beovu 6 mg in the HAWK and HARRIER studies, the proportion that remained on the 12 week dosing interval through Week 48 was 56% and 51%, respectively, and 45% and 39% through Week 96, respectively. Among patients identified as eligible for the first 12 week dosing interval, 85% of HAWK patients and 82% of HARRIER patients remained on the 12 week dosing interval up to Week 48.

The differences between Beovu 6 mg and 3 mg doses for the change in BCVA from baseline to Week 48 was limited (6.6 letters vs. 6.1 letters). A slightly higher proportion (56% vs. 49%) of patients remained on the 12 week dosing interval in the Beovu 6 mg group than in the Beovu 3 mg group at Week 48.

Overall, the results of the clinical trials demonstrate that patients treated with Beovu showed similar visual acuity improvement as patients treated with aflibercept. Beovu provides an option for eligible patients at a reduced treatment frequency. The recommended dose is 6 mg (0.05 mL) every month for the first 3 months. After that, dosing is continued at 8 or 12 week dosing intervals per the physician's judgment, based on disease activity assessment.

Indication

The New Drug Submission for Beovu was filed by the sponsor with the following indication, which Health Canada subsequently approved:

  • Beovu (brolucizumab) is indicated for the treatment of neovascular (wet) age related macular degeneration (AMD).

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

Clinical Safety

The safety of Beovu was evaluated in two Phase III studies (HAWK and HARRIER) previously described in the Clinical Efficacy section. Similar to other VEGF inhibitors, therapeutic proteins, and intravitreal injections, there are identified and potential risks of intraocular inflammation/endophthalmitis, retinal detachment/tear, traumatic cataract, intraocular pressure increase, arterial thromboembolic events, and hypersensitivity.

The rate of intraocular inflammation and endophthalmitis was higher in the Beovu 6 mg group (5%) than in the aflibercept 2 mg group (1%). The most frequently reported adverse drug reactions in ≥5% of pooled patients treated with Beovu 6 mg, compared to aflibercept 2 mg, were visual acuity reduced (7% vs. 8%), cataract (7% vs. 11%), conjunctival hemorrhage (6% vs. 7%), vitreous floaters (5% vs. 3%), and eye pain (5% vs. 6%). Less common serious adverse drug reactions reported in <1% of the patients treated with Beovu 6 mg were endophthalmitis, blindness, retinal artery occlusion, and retinal detachment. The most frequently reported adverse drug reactions resulting in permanent discontinuation of Beovu treatment were endophthalmitis, uveitis, and retinal artery occlusion.

There were no clinically meaningful differences between Beovu 6 mg and Beovu 3 mg doses in the safety profile.

The rate of arterial thromboembolic events in both studies was 4.5% in the pooled Beovu arms compared with 4.7% in the pooled aflibercept arms.

Anti‑brolucizumab antibodies were detected in the pre‑treatment sample of 36% to 52% of treatment‑naive patients. After dosing with Beovu, anti‑brolucizumab antibodies were detected in at least one serum sample in 53% to 67% of patients. Intraocular inflammation events were observed in 6% of patients with anti‑brolucizumab antibodies detected compared with 1% in patients with no anti‑brolucizumab antibodies detected during Beovu treatment. The clinical significance of anti‑brolucizumab antibodies on clinical effectiveness and safety is unclear at this time.

Beovu is injected by a healthcare professional directly into the eyeball. The recommended dose is 6 mg (0.05 mL) every month for the first three doses. Thereafter, the physician may individualize treatment intervals based on disease activity as assessed by visual acuity and/or anatomical parameters. A disease activity assessment is suggested 16 weeks after treatment start and assessed regularly after that. In patients without disease activity, treatment up to every 12 weeks could be considered. In patients with disease activity, treatment every 8 weeks could be considered.

Beovu has not been studied in pediatric patients (<18 years of age), therefore, Health Canada has not authorized an indication for pediatric use. Based on anti‑VEGF mechanism of action, Beovu must be regarded as potentially teratogenic and embryo‑/fetotoxic. Beovu is not recommended during pregnancy unless the potential benefits outweigh the potential risks to the fetus. It is unknown if Beovu is transferred to human milk and there is no data on the effects of Beovu on a breastfed child or on milk production. Due to the potential for adverse drug reactions in the breastfed child, breastfeeding is not recommended during treatment with Beovu for at least 1 month after the last dose. No dosage regimen adjustment is required for geriatric use.

Overall, the benefits of Beovu 6 mg/0.05 mL outweigh the risks for the treatment of wet AMD. The benefit/risk profile of Beovu is favourable in the target population.

Warnings and precautions are in place in the approved Beovu Product Monograph to address the identified safety concerns.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

Brolucizumab, the medicinal ingredient in Beovu, was shown in non‑clinical studies to bind to human VEGF‑A and to inhibit VEGF‑A interaction with VEGF receptors, VEGFR1 and VEGFR2, as well as VEGF‑A‑induced functional activity in cell‑based assays. In rodent in vivo pharmacodynamic models, brolucizumab administration reduced pre‑retinal and choroidal neovascularization and retinal vascular permeability, but only when administered as a pre‑treatment or prior to disease development.

The pivotal toxicology study consisted of a 6‑month repeat‑dose toxicity study conducted in cynomolgus monkeys (3 animals/sex/group) in which brolucizumab was administered to one eye by intravitreal injection at a dose of 0, 1, 3, or 6 mg/eye (50 µl) once every 4 weeks for 26 weeks. Evaluations included daily observations for morbidity and mortality, clinical observations (including abnormal respiration and behavior), body weight determinations, biomicroscopic and indirect ophthalmoscopic examinations, intraocular pressure measurements, electroretinograms, clinical pathology, toxicokinetic and anti‑drug antibody analysis of the serum and vitreous, and macroscopic and microscopic examinations.

Minimal transient intraocular inflammation was observed in all groups, including the control group, which were attributed to the injection procedure. However, an increase in the severity of intraocular inflammation was observed in a few animals administered brolucizumab (one animal at the 3 mg dose and two animals at the 6 mg dose), but no ocular or systemic toxicity was observed. Systemic exposure was observed following intravitreal administration. The ocular and systemic no‑observed‑adverse‑effect level (NOAEL) with brolucizumab 6 mg/eye every 4 weeks provides a 2‑fold margin of ocular safety, based on comparative ocular volume, for the recommended human dose.

Carcinogenicity, genotoxicity or reproductive and developmental toxicity studies were not conducted with brolucizumab. Based on its anti‑VEGF mechanism of action, brolucizumab is regarded as potentially teratogenic and embryo‑/fetotoxic.

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

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

 

 

7.3 Quality Basis for Decision

 

Characterization of the Drug Substance

Beovu (brolucizumab) is a humanized single‑chain antibody fragment (scFv). It targets vascular endothelial growth factor A (VEGF‑A), preventing binding of VEGF‑A to its receptors, VEGFR1 and VEGFR2, on the surface of endothelial cells. The antibody fragment is a fusion protein comprised of light chain and heavy chain variable domains connected by a flexible glycine/serine linker of 21 amino acids. It does not contain post‑translational modifications.

Characterization studies were performed using a variety of analytical methods that established the structural, biological, and physicochemical properties of Beovu.

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

Drug Substance

The Beovu drug substance is expressed in Escherichia coli cells. The manufacturing process of the drug substance consists of a series of stages. Each batch is initiated through thawing of a vial of the working cell bank. Following expansion of the culture from a working cell bank to the production bioreactor, the antibody fragment is expressed and forms inclusion bodies in the cell cytoplasm that are then isolated, solubilized, and refolded. The protein is then purified through a series of chromatography and ultrafiltration/diafiltration steps, filtered and filled into one‑liter polyethylene terephthalate copolyester, glycol modified (PETG) bottles for storage at ≤‑60°C. The materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use.

During development, multiple changes were made to the drug substance manufacturing process including changes in the facility, scale, and formulation. Comparability was adequately demonstrated between batches manufactured by all processes used throughout development.

Process validation studies were performed to support process consistency through demonstrating all process parameters remained within the proven acceptable ranges, and that in‑process control limits and release specifications were met. These validation studies showed adequate removal of process‑related and product‑related impurities, and established hold times, resin, and membrane lifetimes. Shipping and cleaning validation were also confirmed.

Drug Product

The Beovu drug product is a single‑use, preservative‑free solution for injection at a concentration of 120 mg/mL (6 mg/0.05 mL) and available in either a glass vial or a pre‑filled syringe (PFS). The drug product is manufactured using common methodologies for the production of aseptic protein products including sterilization by filtration of the bulk solution and aseptic filling into sterile glass vials or glass syringes.

The vial drug product is filled into 2 mL Type I glass vials sealed with a rubber stopper and flip off cap, and co‑packaged in a cardboard box with a filter needle.

The PFS drug product is filled in a 0.5 mL Type I glass barrel with siliconized inner surface, a pre‑siliconized bromobutyl rubber plunger stopper, and a tamper‑evident closure system pre‑assembled as a single part with a siliconized rubber tip cap, a Luer lock, and a tamper evident seal.

The vial and the PFS drug products are manufactured at two facilities. The manufacturing processes are generally similar between the presentations, with the main differences arising in later steps with respect to vial or syringe filling. Comparability has been demonstrated between them.

Controls for critical steps of the drug product manufacturing process were appropriately defined throughout development based on a risk assessment and current process understanding. For each manufacturing step, defined operational process parameters were tested and validated, and required performance parameters were defined. Process validation was conducted and all process parameters, release testing results, and stability results met pre‑defined criteria, acceptance limits and specifications, demonstrating that the vial and pre‑filled syringe drug products can be manufactured consistently.

Changes made to the facility, formulation, protein concentration, and manufacturing scale during development of the drug product are considered acceptable upon review.

All excipients found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of the brolucizumab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

All analytical methods were qualified or validated at the appropriate testing facilities. Each lot of Beovu drug product is tested for appearance, content, identity, potency, purity, and impurities. Established test specifications and validated analytical test methods are considered acceptable.

Beovu is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

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 Beovu drug substance is filled into one‑liter PETG bottles, frozen, and stored. The proposed 24‑month shelf life at ≤‑60°C protected from light is considered acceptable. The proposed shelf life for the Beovu drug product of 24 months when stored at 2 to 8°C protected from light in vials and 18 months when stored at 2 to 8°C protected from light in pre‑filled syringes is considered acceptable.

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 facility involved in the manufacture and testing of the Beovu drug substance and drug product was not warranted since the facilities were recently evaluated and obtained satisfactory ratings.

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

Adventitious Agents Safety Evaluation

The manufacture of the Beovu drug substance does not include the use of any human or animal‑derived raw materials. Given that the process uses Escherichia coli cells, there is minimal risk of mammalian viruses or TSE agent transmission. The master cell bank and working cell bank were tested for identity, purity and contaminating phage. Test reports were provided to Health Canada. No contaminating organisms were found in either the master cell bank or working cell bank.

 

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