What is the mechanism of action and what are the potential adverse effects of brolucizumab (anti-vascular endothelial growth factor A (VEGF-A) agent)?

Brolucizumab: Mechanism of Action and Adverse Effects

Mechanism of Action

Brolucizumab is a humanized single-chain variable fragment (scFv) antibody that binds to all three major isoforms of VEGF-A (VEGF110, VEGF121, and VEGF165), preventing their interaction with VEGFR-1 and VEGFR-2 receptors, thereby suppressing endothelial cell proliferation, neovascularization, and vascular permeability. 1

Key Pharmacologic Features

• Molecular structure: Brolucizumab is a ~26 kDa single-chain antibody fragment, significantly smaller than full-length antibodies, allowing superior retinal penetration to reach the RPE/choroid with minimal systemic exposure 1, 2

• VEGF inhibition mechanism: By blocking VEGF-A binding to its receptors, brolucizumab prevents the phosphorylation of endothelial nitric oxide synthase and subsequent vasodilation signaling pathways that would otherwise promote angiogenesis 3

• Pharmacokinetics: Mean serum Cmax of free brolucizumab is 49 ng/mL at 24 hours post-dose, with concentrations falling below 0.5 ng/mL at approximately 4 weeks; systemic half-life is 4.4 days (±2.0 days) 1

• Clinical efficacy: In Phase 3 trials (HAWK and HARRIER), 55.6% and 51.0% of patients respectively maintained a q12-week dosing interval after loading phase, demonstrating superior durability compared to other anti-VEGF agents 2

Adverse Effects

Ocular Adverse Events

The most critical safety concern with brolucizumab is intraocular inflammation (IOI), including retinal vasculitis and occlusive vasculitis, which occurs at substantially higher rates than with other anti-VEGF agents.

Intraocular Inflammation (IOI)

• Incidence: Overall IOI-related adverse events occur in 10.5% of treated eyes; 7.1% experience IOI without retinal involvement, 3.4% have IOI with retinal involvement (2.0% vasculitis, 1.4% vascular occlusion with or without vasculitis) 4

• Timing: 81.1% of IOI-related events occur during the loading phase, with a median of 25 days from the last injection; most cases occur after a median of 2 brolucizumab injections 4

• Clinical presentation: Most frequently reported symptoms are floaters (52.8%) and blurred or decreased vision (37.8%) 4

• Real-world variation: Incidence of intraocular inflammation ranges from 0% to 19% across real-world studies, with four eyes experiencing IOI in one cohort of 37 treated eyes 5, 6

Management of IOI

• Treatment approach: Of IOI cases, 86.8% require treatment; most are managed with topical corticosteroids (75.5%), 28.3% require systemic corticosteroids, and 26.8% need intraocular corticosteroids 4

• Visual outcomes: Median BCVA change at IOI resolution from baseline is +1 letter (range -74 to +32 letters); 2 patients with occlusive vasculitis experienced BCVA loss ≥15 letters 4

• Treatment discontinuation: All eyes permanently discontinued brolucizumab after the first IOI-related adverse event 4

Other Ocular Complications

• Endophthalmitis: Infectious endophthalmitis rates range from 0.019% to 0.09% in clinical trial settings, consistent with other anti-VEGF agents 3

• Rare complications: Retinal detachment, cataract formation, and sustained elevated intraocular pressure are rare with anti-VEGF therapy including brolucizumab 3

• RPE tears: May occur with or without anti-VEGF treatment and are not a contraindication to continued therapy 3

Systemic Adverse Events

• Thromboembolic risk: All anti-VEGF treatments carry theoretical risks for systemic arterial thromboembolic events, though clinical trial results remain inconclusive 3

• Meta-analysis findings: Some evidence suggests a modest increased risk of death and cerebrovascular events with monthly anti-VEGF therapy over two years, though a 2018 Cochrane review reported "moderate certainty evidence" of safety with no definite increased risk demonstrated 3

• Hypertension: As a class effect of anti-VEGF agents, VEGF inhibition causes endothelial dysfunction through decreased nitric oxide production, increased endothelin-1 levels, and capillary rarefaction, leading to increased blood pressure 3

Special Populations

• Pregnancy and lactation: Risks of intravitreal anti-VEGF agents in pregnant or lactating women have not been studied; VEGF inhibition has been shown to cause malformations, embryo-fetal resorption, and decreased fetal weight in animal studies 3, 1

• Contraception requirement: Females of reproductive potential should use highly effective contraception during treatment and for at least one month after the last dose 1

• Fertility concerns: Based on anti-VEGF mechanism of action, treatment may pose a risk to reproductive capacity by affecting follicular development, corpus luteum function, and fertility 1

• Geriatric use: No dosage adjustment required in patients ≥65 years; no significant differences in efficacy or safety with increasing age in Phase 3 studies 1

Critical Clinical Pitfalls

• Patient education is mandatory: Patients must be educated to report any signs of IOI immediately, particularly floaters or vision changes, as prompt recognition and treatment with corticosteroids is essential 4

• Monitoring during loading phase: Heightened vigilance is required during the first 3 monthly loading injections when 81.1% of IOI events occur 4

• Permanent discontinuation after IOI: Once IOI occurs, brolucizumab should be permanently discontinued and alternative anti-VEGF therapy initiated 4

• Povidone iodine is essential: Topical povidone iodine must be used for all intravitreal injections; its non-use carries unacceptably high endophthalmitis risk 3

• Avoid routine antibiotics: Routine antibiotic eye drops before or after intravitreal injections are not recommended as they do not decrease endophthalmitis risk 3