Review on the Safety and Efficacy of Brolucizumab for Neovascular Age-Related Macular Degeneration From Major Studies and Real-World Data : The Asia-Pacific Journal of Ophthalmology

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Review on the Safety and Efficacy of Brolucizumab for Neovascular Age-Related Macular Degeneration From Major Studies and Real-World Data

Radke, Nishant V. MD*,†; Mohamed, Shaheeda FRCOphth; Brown, Richard B. BS§; Ibrahim, Ilyana MD; Chhablani, Jay MD§; Amin, Hivam V. MD; Tsang, Chi-Wai FRCOphth; Brelen, Marten E. PhD; Raichand, Nikhil S. MD#; Fang, Dong MD**; Zhang, Shaochong MD**; Dai, Hong MD††; Chen, Guy Li Jia PhD; Cheung, Chui Ming Gemmy MD; Hariprasad, Seenu M. MD; Das, Taraprasad MD‡‡; Lam, Dennis S.C. MD*,§§,∥∥

Author Information
Asia-Pacific Journal of Ophthalmology 12(2):p 168-183, March/April 2023. | DOI: 10.1097/APO.0000000000000602
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Abstract

INTRODUCTION AND BRIEF HISTORY OF BROLUCIZUMAB

Age-related macular degeneration (AMD) is a chronic and progressive condition, which leads to loss of visual acuity and is also a leading cause of visual morbidity.1,2 Ever since the advent of intravitreal use of antivascular endothelial growth factor (anti-VEGF) agents in neovascular AMD (nAMD), treatment strategies have been focusing on injectable means to control and stabilize the neovascular process and thus attempt vision preservation. Landmark studies have established the efficacy of anti-VEGF therapy with ranibizumab (Lucentis; Genentech) and aflibercept (Eylea; Regeneron) in the treatment of nAMD.3–5 Prompt treatment with monotherapy using anti-VEGF agents has been shown to limit vision loss in about 95% of people with nAMD.6,7 However, poor adherence to treatment due to the need for frequent injections, delay in initiating treatment, undertreatment, patient dissatisfaction, as well as the burden of treatments may all contribute to suboptimal or even progressively worse visual outcomes.8–12

Brolucizumab (Beovu; Novartis) is a humanized, single-chain variable fragment antibody acting against VEGF-A with a very low molecular mass of ~26 kDa that inhibits all isoforms of VEGF-A and is approved for use in nAMD and diabetic macular edema (DME) by the US Food and Drug Administration (FDA) on October 8, 2019 and June 1, 2022, respectively.13 A single-chain variable fragment is an autonomous binding agent independent of a heavy molecular support structure despite retaining its total binding capacity to the target. As a result, more molecules can be injected in the same volume, and more bioavailability in target tissues is achieved. Because of its small size, it can penetrate ocular tissues well and achieve high concentrations in the retina.14 Based on noninferiority outcomes in phase 1 and 2 ESBA1008 “safety, tolerability and effects in wet age-related macular degeneration patients” study comparing brolucizumab and ranibizumab, the phase 1 and 2 “efficacy and safety study of ESBA1008 versus EYLEA (OSPREY)” study was conducted, which assessed noninferiority of brolucizumab with aflibercept.15,16 The 12-weekly regimen was noninferior and well tolerated. The noninferiority of brolucizumab with aflibercept was studied in terms of change in best-corrected visual acuity (BCVA) as the primary endpoint in 2 phase 3 trials: “efficacy and safety of RTH258 versus aflibercept”—study 1 (HAWK) and “efficacy and safety of RTH258 versus aflibercept”—study 2 (HARRIER).17 The phase 3 HAWK and HARRIER studies revealed that fewer patients receiving 6 mg brolucizumab had disease activity (secondary outcomes: reduced central retinal thickness and fluid) at weeks 16 and 48 compared with those receiving aflibercept.17 The promising structural results and noninferior functional outcomes of brolucizumab in the HAWK and HARRIER trials have also been marred to an extent by the adverse events, such as intraocular inflammation (IOI) reported 4.6% in brolucizumab versus 1.1% with aflibercept.18 The noninvasive blue widefield scanning laser ophthalmoscope in detecting nonperfusion areas in diabetic retinopathy may similarly help screen occlusive retinal vasculitis (RV) in patients who may develop IOI after injection.19 However, its role would need further elucidation in this particular context.

The coronavirus disease 2019 (COVID-19) pandemic containment strategies forced patients to stay away from clinics. A consensus and recommendations from the Asia-Pacific Vitreo-retina Society looked at a practical outlook to study the treat-and-extend (T and E) regime in the management of nAMD and polypoidal choroidal vasculopathy (PCV). They concluded that aflibercept could be extended gradually every 2–4 weeks up to a maximum of 16 weeks, and ranibizumab could be extended gradually every 2 weeks up to 12 weeks.20 It would be interesting to see whether brolucizumab can extend this treatment interval further.

After getting its FDA approval for use in nAMD in October 2019, the results were extensively probed further as IOI cases were reported in follow-up studies and analyses. The drug’s potential was studied in refractory AMD by scheduling monthly injections in the MERLIN (study of safety and efficacy of brolucizumab 6 mg dosed every 4 weeks compared with aflibercept 2 mg dosed every 4 weeks in patients with retinal fluid despite frequent anti-VEGF injections) study.21 However, increased incidences of IOI led to the termination of the MERLIN study as well as the studies on branch retinal vein occlusion (BRVO) (assessing the efficacy and safety of brolucizumab versus aflibercept in patients with visual impairment due to macular edema secondary to BRVO, RAPTOR) and central retinal vein occlusion (CRVO) (assessing the efficacy and safety of brolucizumab versus aflibercept in patients with visual impairment due to macular edema secondary to CRVO, RAVEN).21 The utility of the drug was reestablished after promising outcomes from the KITE (efficacy and safety of brolucizumab versus aflibercept in patients with visual impairment due to DME) and KESTREL (efficacy and safety of brolucizumab versus aflibercept in patients with visual impairment due to DME) studies and obtained FDA approval for use in DME in June 2022.22 As of now the use of brolucizumab in BRVO and CRVO is not FDA-approved.

This article reviews the safety, especially IOI, and efficacy of brolucizumab for treating nAMD based on major trials and real-world data.

METHODOLOGY

We performed an internet-based literature search from PubMed, MEDLINE, Cochrane database, Embase, and Google scholar for English articles using the combination of terms “Brolucizumab, brolucizumab and: real-world data, IOI, safety, and efficacy” individually between January 2016 and October 2022. The last date of the search was October 31, 2022. A list of original studies, review articles, and relevant articles thus identified was manually collated. Titles and abstracts were studied initially. Duplications of articles were identified across the databases and removed. Eleven non-English articles were omitted. Finally, 237 articles were identified and reviewed. Fifty articles based on search terminology relevant to this study were included finally after review and analyzed in detail. Cross-references from these articles were studied wherever relevant. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses strategy for screening and review. As this is a review article and not an interventional study, approval from any ethics committee was not necessary. Data were tabulated from various studies wherever possible to provide a concise outline to the readers.

BROLUCIZUMAB: EFFICACY AND ADVANTAGES

The Need

The short-lasting benefit and the need for frequent intravitreal injections place an enormous burden on patients, caretakers, physicians, and the entire health care system.23 The reality is that most patients do not receive as many injections of a given drug compared with clinical trials.24 These lead to poor monitoring of disease activity and, ultimately, the progression of vision loss.25 While pro re nata and T and E protocols attempt to circumvent this problem, there is a need for a better solution.26 Brolucizumab is one of the potential solutions, given that patients require only a Q8 or Q12 week (W) injection frequency and perhaps even longer intervals over time. There are now robust clinical data supporting the use of brolucizumab for the treatment of nAMD, PCV, and DME.17,22,27–30

The Advantage

The advantages of brolucizumab owe to its physical structure, which translates into functional success. Despite its small size, weighing 26 kDa, it retains the full binding capacity of all previous anti-VEGF agents and delivers more molecules at equivalent volumes than other anti-VEGF agents. In comparison, aflibercept weighs between 97 and 115 kDa and is 4 times heavier.14,15,31–33

Major Trials Perspective

SEE phase 1/2 was the first human trial of brolucizumab in people with nAMD. It showed that a single injection of either 4.5 mg or 6 mg of brolucizumab was noninferior to 0.5 mg ranibizumab based on the change in central subfield thickness (CST) measured at 1 month. Furthermore, the number of days for additional treatment was 75 days for the brolucizumab 6 mg group compared with 45 days for the ranibizumab group (P = 0.004).15 OSPREY phase 2 was a randomized, double-masked clinical trial that compared brolucizumab 6 mg to aflibercept 2 mg in people with nAMD. After 3 loading doses of each medication at weeks 0, 4, and 8, both groups were treated with Q8W injections until week 40. Brolucizumab was noninferior to aflibercept in visual acuity improvement. Moreover, it achieved a more sustained reduction in CST, had a lower percentage of patients with subretinal fluid (SRF) and intraretinal fluid (IRF) at week 40, and fewer patients required unscheduled rescue injections. After week 40, the brolucizumab group was extended to Q12W injections, and 50% of patients maintained a stable visual acuity during this phase until the end of the trial at week 56.16 SEE 1/2 and OSPREY 2 trials demonstrated both the durability of brolucizumab and showed that Q12W injections are a viable treatment regimen.

The subsequent HAWK and HARRIER phase 3 trials over a 96-week period confirmed the efficacy and durability of brolucizumab over a longer period. In both trials, brolucizumab 6 mg was noninferior to aflibercept in visual acuity outcomes. In addition, brolucizumab 6 mg achieved a better reduction of CST and resolution of IRF, SRF, and/or subretinal pigment epithelium fluid at 16 weeks after either group had received 3 loading injections and again at 48 weeks. Over 50% of patients in both the HAWK and HARRIER trials maintained Q12W treatment intervals at 48 weeks. Visual acuity gains and anatomic outcomes were maintained at week 96, and over 75% of patients who completed Q12W dosing at week 48 continued to do so until week 96.17

After brolucizumab approval for nAMD, 3 randomized, double-masked phase 3 clinical trials: KITE, KESTREL, and KINGFISHER (efficacy and safety of brolucizumab versus aflibercept in patients with visual impairment due to DME) investigated its role in treating DME.22,30 In KITE and KESTREL, the people in the brolucizumab arm were given 5 loading doses (3 mg and 6 mg in KITE and 6 mg in KESTREL) at Q6W intervals and then treated on a Q12W schedule. They were compared with the aflibercept arm of patients who received 5 loading doses of aflibercept 2 mg, but at a Q4W interval, and then treated on a Q8W schedule. In KITE and KESTREL, visual acuity gains with brolucizumab were noninferior to aflibercept and maintained until week 100. In either study, over 50% of patients could maintain Q12W dosing at 52 weeks. Furthermore, brolucizumab 6 mg had a greater drying effect on the retina, with over 60% of patients with a CST <280 microns at 100 weeks compared with around 50% for the aflibercept group; also, fewer people had persistent SRF or IRF. In addition, in the KITE study at 72 weeks, patients receiving Q12W injections were extended to Q16W injections, and those receiving Q8W injections were extended to Q16W.22,30 KINGFISHER was a 52-week long, head-to-head trial comparing brolucizumab 6 mg to aflibercept 2 mg for DME, with both drugs administered at a fixed Q4W interval. Brolucizumab was equally effective in improving visual acuity while achieving a greater decrease in CST and more patients with absent IRF and SRF at 52 weeks (41% vs 22.2%, P < 0.001).34

Real-World Data

Network meta-analyses have indicated that brolucizumab is noninferior to other anti-VEGF agents in functional and structural outcomes.35–37 Furthermore, real-world data from recent studies on people with nAMD and PCV in several countries have corroborated the efficacy shown in the clinical trials. Important points and outcomes from real-world data are outlined in Table 1.28,29,38–44 The readers are encouraged to access individual studies for details of methodology and results.

TABLE 1 - Efficacy Data of Brolucizumab in PCV and nAMD From Recent Publications
Author, Year [Reference] Study, Country Disease/Design Purpose Efficacy and Advantage of Brolucizumab Complications of Brolucizumab
Polypoid choroidal vasculopathy
1 Ogura et al, 202138 HAWK, Japan Prospective, 89 of 152 people randomized to brolucizumab (3 mg, 6 mg) and aflibercept (2 mg) Compare between brolucizumab and aflibercept over 96 wk Brolucizumab Q12W/Q8W monotherapy resulted in robust and consistent vision gains. It was comparable to Q8W aflibercept dosing. Brolucizumab was superior to aflibercept in anatomic outcome, 76% of brolucizumab participants maintained on Q12W dosing after loading to week 48 Higher incidence of IOI, macular hole, RVO
2 Chakrabortyet al, 202239 India PCV/retrospective, 21 people, 21 eyes, brolucizumab 6 mg Treatment‑resistant and treatment‑naive eyes with PCV Brolucizumab was safe and effective in controlling PCV in treatment‑resistant and treatment‑naive eyes Not reported
3 Fukuda et al, 202140 Japan PCV/retrospective, 52 eyes, brolucizumab 6 mg, aflibercept 2 mg Short-term outcomes between 3-monthly aflibercept and brolucizumab injections for treatment-naive PCV 3-monthly brolucizumab was comparable with aflibercept in vision gain. Complete resolution occurred more often after brolucizumab than aflibercept injection (78.6% vs 42.1%; P = 0.043) IOI 14.3%
nAMD
4 Bilgic et al, 202141 REBA, Germany and India nAMD/retrospective, 78 people, 105 eyes Determine the efficacy and safety of intravitreal brolucizumab in the real-world setting There was a good anatomic and functional response to brolucizumab therapy in the real world, regardless of prior treatment status ORV and macular hole, 1 eye each
5 Bulirsch et al, 202042 SHIFT, Germany nAMD/retrospective, 57 people, 63 eyes Real-world outcomes of switch to brolucizumab therapy in previously anti-VEGF–treated patients Switch to brolucizumab is a treatment option in patients with nAMD poorly responsive to other anti-VEGF agents IOI 7/57 patients
6 Chakravarthy et al, 202143 BRAILLE, India nAMD/retrospective, 94 people, 94 eyes Real-world short-term efficacy and safety study Efficacious and safe in nAMD over short term RPE tear 1/94
7 Bilgic et al, 202141 PROBE, India nAMD/retrospective, 27 people Efficacy and PRN brolucizumab without a loading dose in the real-world setting Initial PRN brolucizumab without a loading dose demonstrated significant visual improvement Not reported
8 Enriquez et al, 202144 US nAMD/retrospective, 152 people, 172 eyes Brolucizumab 6 mg Clinical outcomes after intravitreal injection in switch-over and treatment-naive people Brolucizumab-treated eyes with nAMD remained stable in vision, and with a reduction in CST IOI 8.1% ORV 1 eye
9 Sharma et al, 202045 US nAMD/retrospective, n = 42, brolucizumab 6 mg Clinical outcomes after intravitreal injection in switch-over patients Brolucizumab was safe and effective in stabilizing vision in patients treated with other anti-VEGF agents. It was effective in further reducing SRF and IRF. Approximately half of the cases had a reduced PED None reported
CST indicates central subfield thickness; IOI, intraocular inflammation; IRF, intraretinal fluid; nAMD, neovascular age-related macular degeneration; ORV, occlusive retinal vasculitis; PCV, polypoidal choroidal vasculopathy; PED, pigment epithelial detachment; PRN, pro re nata; RPE, retinal pigment epithelium; RVO, retinal vascular occlusion; SRF, subretinal fluid; VEGF, vascular endothelial growth factor.

Brolucizumab has a superior drying effect on the retina, an important marker of disease activity. It may be particularly useful in recalcitrant or recurrent retinal edema, given its ability to achieve such high concentrations in the retina.46 Finally, brolucizumab’s Q12W schedule has the potential to significantly decrease the burden of frequent injections associated with treating nAMD. Studies have shown that patients often do not receive the required loading dose of anti-VEGF agents14,47 and that the burden increases with each injection visit over time.2 The new and emerging real-world data can help clinicians identify patients more prone to adverse events.

INTRAOCULAR INFLAMMATION FOLLOWING BROLUCIZUMAB AND OTHER ADVERSE EVENTS: MAJOR TRIALS AND REAL-WORLD SAFETY DATA

Brolucizumab has a relatively higher rate of IOI compared with other anti-VEGF molecules, although the specific mechanism and pathogenesis of these differences have yet to be discovered.48 The high molar concentration of brolucizumab (6 mg) delivered in the same volume (0.05 mL) results in a significantly higher VEGF-binding capacity 11 times greater than aflibercept and 22 times greater than ranibizumab.15 IOI after brolucizumab can present in various forms. Patients may show anterior chamber cells or vitreous cells (which can also be visualized on optical coherence tomography). RV may be central (affecting the optic nerve or the macula), peripheral (including occult RV), or multifocal (affecting both small and large caliber vessels). Retinal arteries tend to be affected more than retinal veins. Usual signs include perivascular focal/multifocal cuffing or sheathing and perivenular hemorrhages.49 Ultrawide-field fluorescein angiography (UWF-FA) may reveal delayed arterial filling, vessel nonperfusion, staining of vessel walls, and late leakage at the optic disc. Retinal occlusion (RO) may present as cotton wool spots, retinal whitening, cherry-red spots, arteriolar attenuation, box-carring of blood column in vessels, and optic disc edema. Other than UWF-FA to assess the extent of nonperfusion, ultrawide-field indocyanine green may be useful to assess inflammatory or ischemic changes in the choriocapillaris and choroidal vasculature.49

All anti-VEGF molecules, despite their humanized structure, are proteins and may be immunogenic. The pathogenesis of IOI is postulated to be due to a type III hypersensitivity reaction after intravitreal brolucizumab, leading to the deposition of immune complexes along the vessel walls and resulting in vascular occlusion.50,51 Barchichat et al52 showed that a type IV hypersensitivity reaction was unlikely as a lymphocyte transformation test performed in a patient with bilateral panuveitis and ischemic vasculitis after brolucizumab was negative and speculated that a type II hypersensitivity reaction or massive VEGF depletion might be the most likely cause of occlusive vasculitis after brolucizumab.

MAJOR TRIALS PERSPECTIVE ON INTRAOCULAR INFLAMMATION RELATED TO BROLUCIZUMAB

In HAWK and HARRIER, IOI was reported to be higher in brolucizumab versus aflibercept at week 48.17 Of the 1088 eyes treated with brolucizumab in HAWK/HARRIER, 50 cases of IOI were considered to have definite/probable drug-related events. Overall, the incidence of IOI was 4.6% (50 eyes), IOI and RV was 3.3% (36 eyes), whereas the simultaneous IOI, RV, and RO was 2.1% (23 eyes). These 50 cases were further analyzed by Khoramnia et al,53 who reported 12 patients with RV or RO. In their study, 6 of 12 identified patients developed IOI before RV or RO. They suggested that IOI symptoms might be useful for the early detection of more serious adverse events.53 Singer et al54 reported 70 IOI-related adverse events in HAWK and HARRIER, and 87.1% of these were treated, the majority with topical corticosteroids and some with systemic and intraocular corticosteroids. After a review by an independent safety review committee, the overall risk of developing IOI, RV, or retinal vein occlusion (RVO) was 4.6% (50/1088). The risk of developing RV with IOI was 3.3% (36/1088), and the risk of developing RVO, IOI, and RV was 2.1% (23/1088). The risk of visual loss due to IOI (15 letters or more) was 0.7%.54 Rates of visual loss were similar when comparing brolucizumab and aflibercept arms. Of IOI, 74% of events occurred in the first 6 months after the first dose of brolucizumab, and 48% of these occurred within the first 3 months.18 IOI-adverse events were defined as mild, where the patient was aware of the adverse events but could easily tolerate them, moderate where the IOI resulted in significant discomfort that interfered with the patient’s usual activities, and severe where the IOI was incapacitating, resulting in the patient’s inability to work or engage in usual activities.54 Thirty-eight eyes (54.3%) were classified as having mild IOI, 28 eyes (40.0%) as moderate, and 4 eyes (5.7%) as severe IOI. Of the 49 eyes, inflammation resolved completely in 39 eyes (79.6%), with sequelae in 5 eyes (10.2%), and did not resolve in 5 eyes (10.2%).18 Of 49 eyes, 22 eyes lost vision by the end of the study, 9 of which had a loss of 15 letters or more, usually due to retinal vascular occlusion.54

The MERLIN phase 3 trial with brolucizumab administered every 4 weeks compared with aflibercept given every 4 weeks resulted in a higher frequency of IOI (9.3% vs 4.5%, of which RV occurs in 0.8% vs 0% and RVO in 2.0% vs 0%) and a higher frequency of visual loss (15 letters or more) (4.8% in brolucizumab arm vs 1.7% in aflibercept arm). This resulted in the early termination of the MERLIN study. Also, there was early termination of RAPTOR and RAVEN studies assessing brolucizumab in RVO where 6 initial monthly injections were given.21 After MERLIN, the sponsoring pharmaceutical company (Novartis AG, NJ) recommended a minimum 8-week interval between injections after the loading of 3 monthly brolucizumab injections.

Since brolucizumab became commercially available, the Intelligent Research in Sight Registry (US eye disease registry) and Komodo Health care Map (US claims database) examined adverse events of IOI, RV, or RVO in a cohort of over 21,000 patients with nAMD from October 8, 2019 to June 5, 2020. The overall incidence of IOI and/or RVO was 2.4% in each registry.55 Postmarketing surveillance has reported the incidence of RV with retinal vascular occlusion to be 4.6 per 10,000 injections, most of whom have switched from other anti-VEGF treatments.56,57

REAL-WORLD DATA PERSPECTIVE ON ADVERSE EVENTS AND INTRAOCULAR INFLAMMATION

Some differences have been reported between the treatment outcomes seen in clinical trials and real-world studies. HAWK and HARRIER, along with their subsequent data analysis, reported outcomes of patients with treatment-naive eyes. As a new drug, patients switching to brolucizumab due to recalcitrant AMD or seeking a longer treatment interval are relatively likely to have previously taken another anti-VEGF medication. By Komodo Health Care Map and the Intelligent Research in Sight Registry in the United States, over 90% of patients had switched from another anti-VEGF treatment;55 thus, it may approximate real-world outcomes in this population. In a meta-analysis involving 6 randomized controlled trials (RCTs), no significant difference was found in BCVA between brolucizumab and aflibercept-treated eyes between 1 and 12 months after the first injection.58 In addition, in 1 case series of 172 previously treated eyes from 152 patients, investigators found no significant difference between baseline and final visual acuity, even when stratifying analyses by the number of injections, IOI, and retinal fluid.44 Conversely, a study evaluating short-term real-world outcomes in 63 eyes reported a significant increase in mean BCVA in patients with recalcitrant fluid accumulations.42 In addition, the multicentric “real-world experience with brolucizumab in wet age-related macular degeneration (REBA)” study evaluated 105 eyes from both treatment-naive and switched-medication patients. They reported a significant gain in BCVA in each subpopulation, even when stratifying switched-medication patients for those experiencing recurrence, recalcitrant cases, and patients desiring a longer treatment interval.29 Interestingly, the baseline mean BCVA was much lower in this study (49.4 letters, treatment-naive; 40.0 letters, switched-treatment) than reported in the HAWK and HARRIER trials (60.6 and 61.2 letters, respectively, both treatment-naive) and the Enriquez study (64.1 letters, switched-treatment eyes).17,29,44 Such differences in baseline visual acuity may account for the improvement seen in the Bilgic et al29 study, where a ceiling effect may have influenced visual acuity gain.

Haug et al59 first reported that bilateral intravitreal brolucizumab administered to an 88-year-old woman with nAMD led to bilateral painless mild vision loss, anterior chamber reaction, bilateral occlusive RV, and optic nerve inflammation confirmed by fundus fluorescein angiography (FFA) 1 month after the injection. Intravitreal dexamethasone implanted in 1 eye reduced the inflammation. Jain and colleagues reported severe vision loss to count fingers, mild vitritis, retinal whitening, intra-arteriolar greyish material, arteriolar occlusion, and focal choroidal infarcts detected on FFA in a 92-year-old woman 3 weeks after the third brolucizumab for nAMD. She was given topical corticosteroids, and vision remained at counting fingers.45 Similarly, Kondapalli60 reported RV in a 77-year-old woman after the second intravitreal brolucizumab, which resulted in severe vision loss. Baumal et al49 reported eyes with IOI and RV after intravitreal brolucizumab invariably 30 days after the most recent injection. Witkin et al61 reported that patients with IOI and RV presented primarily 25 days after intravitreal brolucizumab and developed vision loss, floaters, pain, and redness. Retinal arteries, veins, and choroidal vessels were involved, and optic nerve leakage and choroidal ischemia were noted on FFA. Most of the patients received topical corticosteroids, nearly 50% received systemic corticosteroids, 25% received intravitreal corticosteroids, and 15% underwent pars plana vitrectomy.

Data from clinical trials and real-world outcomes are more congruent regarding retinal thickness changes. Chuan and colleagues also aggregated data from 3 RCTs evaluating changes in CST. They found that brolucizumab-treated eyes exhibited a greater reduction in thickness at 1, 3, 6, 9, and 12 months postinjection compared with aflibercept.58 These findings are consistent with several case series, which also reported significant decreases in CST.42,44 Enriquez et al44 reported 50 eyes that experienced complete fluid resolution after a single injection. Bilgic et al29 reported that 33.7% and 47.5% of eyes in the switch-therapy group did not have disease activity after the first and second injection, respectively. Treatment-naive eyes demonstrated similar improvement, with 75% of eyes showing complete resolution of exudation after the initial 3-dose loading phase.29 Given that brolucizumab effectively decreased retinal fluid, this anatomic change may have also improved the visual acuity. Table 2 summarizes the adverse events and real-world safety data.

TABLE 2 - Adverse Events and Real-World Safety Data on Brolucizumab
# Study, Year [Reference] No. Patients Prior Treatments AE Incidence Time to Event From Last Injection VA at Baseline VA at Presentation VA Final VA Change Treatments
1 HAWK/HARRIER, 202017 1088 Naive Uveitis = 2.2% (vs 0.3% aflibercept) Iritis = 2.2% (vs 0% aflibercept) IOI: 25.5 days (range = 1–91 days; mean = 22.9) RV or RO: 29.5 days (range = 6–594) *data from Khoramnia et al, 202262 60.6 letters (HAWK) and 61.2 letters (HARRIER) +6.6 (6 mg) and +6.1 (3 mg) letters with brolucizumab vs + 6.8 letters with aflibercept (HAWK); + 6.9 (brolucizumab 6 mg) vs + 7.6 (aflibercept) letters (HARRIER)
2 Jain et al, 202045 1 Ranibizumab, bevacizumab, and aflibercept Developed RAO and RV 16 days after third injection 20/150 CF CF 20/150—>CF
3 Baumal et al, 202049 15 eyes, 12 patients Switched ~30 d 20/53 (mean) 20/191 (mean) 20/13 (mean) 20/53—>20/136
4 Haug et al, 202059 1 Ranibizumab 20/30 OD 20/25 OS 20/40 OD 20/50 OS 20/40 OU Drops + Intravitreal dexamethasone
5 Nguyen et al, 202163 77 IOI: 2.6% 5 d–20 wk Case 1: 20/80—>CF Case 2: 20/150—>CF (RV)—>Oral Pred.—20/200 Case 3: 20/40 unchanged throughout Case 4: 20/40—>20/70—>20/40
6 Bulirsch et al, 202142 63 eyes, 57 patients Switch IOI: 7 eyes in 7 patients (11.1%) RV: 1 case 19 d +/− 6.5 d 0.03 ± 0.14 logMAR
7 Enriquez et al, 202144 172 eyes, 152 patients 96.5% switch IOI: 14 eyes (8.1%) RVO: 1 20/50 20/63 20/50—>20/63
8 Mukai et al, 202164 93 eyes, 93 patients 14 eyes Mean: 20.5 d Individual cases: https://doi.org/10.1371/journal.pone.0259879.t002
9 Khanani et al, 202255 10,654 (IRIS) 11,161 (Komodo) 90+% prior ℞ IOI and/or RO: 2.4% Median time to IOI/RO from first injection = 39 d (IRIS) and 56 d (Komodo) median time from most recent injection = 28 d (both)
10 Bilgic et al, 202141 105 eyes, 78 patients Naive=25 Switch=80 1 patient had RO Naive: 49.4 ± 5.4 letters; Switch: 40 ± 3.2 letters naïve = +11.9 ± 3.8 letters; Switch = + 10.4 ± 4.8 letters (P = 0.014)
11 Witkin et al, 202061 26 eyes, 25 patients Switched Case series of RVO IOI mean: 25 d 20/52 (mean) 20/151 (mean) 20/242 (mean) Various
AE indicates adverse events; CF, counting fingers; IOI, intraocular inflammation; IRIS, intelligent research in sight; OD, right eye; OS, left eye; OU, both eyes; Pred: Prednisolone; RAO, retinal artery occlusion; RV, retinal vasculitis; ℞, treatment; RO: retinal occlusion; RVO, retinal vein occlusion; VA, visual acuity.

SUMMARY OF LANDMARK STUDIES ON ANTI-VEGF AGENTS: BEVACIZUMAB, RANIBIZUMAB, AFLIBERCEPT, CONBERCET, BROLUCIZUMAB, AND FARICIMAB IN nAMD

The VEGF inhibition study in ocular neovascularization (VISION) trial was the first large RCT to evaluate the safety and efficacy of intravitreal anti-VEGF. The effect of pegaptanib in the treatment of nAMD was evaluated in this prospective double-blind RCT.65 Patients were randomly assigned to receive either intravitreal pegaptanib injections (0.3 mg, 1.0 mg, or 3.0 mg) or sham injections, every 6 weeks over 48 weeks. The primary endpoint was measured as the proportion of patients losing fewer than 15 letters at week 54. This may seem conservative by today’s standards. The study found that pegaptanib was significantly more effective compared with sham, and there was no difference in response among all 3 doses of pegaptanib. Of patients, 70% treated with pegaptanib 0.3 mg lost fewer than 15 letters of visual acuity at week 54, compared with 55% of patients in the control group (P < 0.001). The risk of severe visual loss was also significantly lower in patients who received pegaptanib 0.3 mg compared with sham (10% vs 22%, P < 0.001). Reduced risk of visual acuity loss was observed with all doses as early as 6 weeks after treatment and showed increasing benefit over time. The study concluded that pegaptanib seemed to be an effective therapy for nAMD. This also marks the first time we have learned about the safety profile of this class of drug and this delivery method.

The minimally classic/occult trial of the anti-VEGF antibody ranibizumab in the treatment of nAMD (MARINA) and anti-VEGF antibody for the treatment of predominantly classic choroidal neovascularization (CNV) in age-related macular degeneration (ANCHOR) trials were multicenter, double-masked studies, which evaluated the safety and efficacy of intravitreal ranibizumab. MARINA recruited 716 patients with minimally classic or occult neovascularization who were assigned to either receive monthly intravitreal ranibizumab (0.3 mg or 0.5 mg) or sham injections over 24 months.3 The proportion of patients losing fewer than 15 letters at 12 months was significantly higher in the treatment group: 94.5% in patients given ranibizumab 0.3 mg and 94.6% in patients given ranibizumab 0.5 mg, compared with 62.2% patients in the control group (P < 0.001). A higher proportion of patients in the treatment group achieved visual acuity improvement by 15 or more letters: 24.8% in the 0.3 mg group and 33.8% in the 0.5 mg group, compared with 5.0% in the control group (P < 0.001 for both comparisons). Ranibizumab treatment was associated with arrested growth and leakage from CNV and had low rates of adverse events. This study showed that the administration of intravitreal ranibizumab for 2 years prevented vision loss and improved mean visual acuity in patients with minimally classic or occult nAMD.

ANCHOR recruited 423 patients with predominantly classic neovascularization and compared the effects of ranibizumab with photodynamic therapy using verteporfin.4 Patients were randomly assigned to receive either ranibizumab (0.3 mg or 0.5 mg) plus sham verteporfin therapy or sham injections plus active verteporfin therapy. 94.3% of patients given ranibizumab 0. 3 mg and 96.4% of patients given ranibizumab 0.5 mg lost fewer than 15 letters, compared with 64.3% of patients in the verteporfin group (P < 0.001). Patients in both groups of ranibizumab treatment had better mean visual acuity improvement overall compared with the verteporfin group. 40% of patients given ranibizumab 0.5 mg gained 15 letters or more at 12 months, followed by 36% of patients given ranibizumab 0.3 mg, compared with only 6% of patients in the verteporfin group (P < 0.0001). Ranibizumab-treated groups had a smaller increase in CNV area (0.20–0.22 disc area increase) compared with the verteporfin-treated group (1.63 disc area increase). Ranibizumab was superior to verteporfin as the treatment of predominantly classic nAMD and had low rates of adverse events.

Results from the MARINA and ANCHOR trials established the safety and efficacy of intravitreal ranibizumab in nAMD. These 2 landmark trials were game changers, which led to a paradigm shift and the subsequent widespread use of ranibizumab. The first 3 studies described utilized fundus fluorescein angiogram to monitor lesion size, which often showed growth, despite the improvement in visual acuity.

The VEGF trap-eye: investigation of efficacy and safety in wet AMD (View 1, View 2) trials were the first to compare 2 anti-VEGF agents and assess different dosing regimens.5 This was also the first time spectral-domain optical coherence tomography (SDOCT) findings were taken into consideration. These double-masked, multicenter, parallel-group RCTs assigned patients to receive either intravitreal aflibercept (0.5 mg monthly, 2 mg monthly, 2 mg every 2 mo after 3 initial monthly doses) or ranibizumab 0.5 mg monthly. All people in the aflibercept groups showed noninferiority to the monthly ranibizumab group in the proportion of maintaining vision at week 52: 95.1%–96.3% in the aflibercept arms compared with 94.4% in the ranibizumab arms. The reduction in central retinal thickness was comparable between all aflibercept and ranibizumab groups, which was also maintained up to week 52. These studies concluded that aflibercept is an effective treatment for nAMD, with monthly or 2 monthly dosing after 3 initial monthly doses showing similar efficacy and safety outcomes as monthly ranibizumab.

The subsequent trials from this point onward compared one anti-VEGF agent to another, evaluating its increasing durability. The primary endpoint became less reserved, evolving from determining the proportion of patients losing 15 letters to evaluating mean change in visual acuity. This reflects the expectation of visual acuity gain as we get more experienced with anti-VEGF therapy. There is also an evolution in better initial BCVA and incorporation of SDOCT as a secondary endpoint over the years.

HAWK and HARRIER were 2 double-masked, multicenter, active-controlled randomized trials, which compared the efficacy of brolucizumab with aflibercept.17 The dose and frequency have been described earlier. The study outcomes have also been elaborated on earlier. Although these 2 trials concluded that the safety profile for brolucizumab was acceptable, RV events were only identified in the postmarketing survey.49 This demonstrates that the sample size in typical RCTs was not powered to detect such rare events.

Faricimab (F. Hoffmann-La Roche Ltd.) is the newest intravitreal therapy for nAMD, with a bispecific mechanism of action through VEGF and angiopoietin-2 (ANG2) inhibition. Its efficacy compared with aflibercept was evaluated in 2 randomized, double-masked noninferiority trials: TENAYA and LUCERNE (a study to evaluate the efficacy and safety of faricimab in participants with nAMD).66 Patients were randomized to receive either faricimab 6.0 mg up to every 16 weeks, based on disease-activity assessments at weeks 20 and 24, or aflibercept 2.0 mg every 8 weeks. Across the 2 trials, mean BCVA gain from baseline with faricimab averaged over weeks 40, 44, and 48 and was noninferior to aflibercept (5.8 letters with faricimab and 5.1 letters with aflibercept in TENAYA, 6.6 letters with both faricimab and aflibercept in LUCERNE). Anatomic outcomes using SDOCT in both TENAYA and LUCERNE supported functional outcomes. Patients given faricimab every 16 weeks achieved CST reductions from baseline at all time points up to week 48, comparable with aflibercept given every 8 weeks. The rate of ocular adverse events was comparable between both drugs. These results indicate that faricimab can potentially prolong the treatment interval in nAMD patients with sustained efficacy.

In addition to the above agents, which FDA has approved for treating nAMD, 2 other agents have been used in clinics. Bevacizumab has been widely used off-label to treat nAMD at a lower cost compared with most FDA-approved agents. The comparison of age-related macular degeneration treatment trials was a multicenter, single-blind, noninferiority trial comparing the effects of ranibizumab with bevacizumab, either monthly or as needed with monthly evaluation.67 Ranibizumab and bevacizumab had equivalent effects on visual acuity at all time points throughout the first year of follow-up when comparing the same dosing regimen. At 2 years as well, no statistically significant difference in visual acuity outcomes between ranibizumab and bevacizumab was noted when comparing either monthly or pro re nata groups.68 The trial also demonstrated that as-needed dosing with monthly monitoring was noninferior to monthly dosing for either drug. Although no difference was noted in the rates of death, myocardial infarction, and stroke between the 2 anti-VEGF agents, the rates of serious systemic adverse events were higher in the bevacizumab group. This was not identified as an area of concern as it was not proven to be associated with anti-VEGF therapy.

Conbercept is an anti-VEGF agent used mainly in China and is not available commercially outside China. The effect of conbercept in CNV secondary to AMD compared with sham injections was evaluated in the PHOENIX (A phase 3 clinical trial of intravitreal injections of human recombinant VEGF receptor-Fc fusion protein in patients with CNV secondary to age-related macular degeneration) study.69 In this prospective, double-masked, multicenter study, patients were randomized to either the conbercept group (0.5 mg once monthly for the first 3 mo followed by once quarterly until month 12) or the sham group (sham injections up to month 3, and then by 3 monthly conbercept 0.5 mg followed by quarterly administrations until month 12). The primary endpoint measured at month 3 was the mean change of BCVA from baseline. The conbercept group gained more than 9.2 letters from baseline compared with more than 2.0 letters in the sham group. At 12 months, the conbercept group achieved a mean BCVA improvement of 10 letters from baseline compared with 8.8 letters in the sham group. The study concluded that 3 initial monthly administrations of conbercept followed by quarterly treatment are effective for the treatment of nAMD. However, some limitations of this study include its premature primary endpoint at only month 3 and the low baseline BCVA of 20/100 in both groups.

Table 3 outlines the major trials of important anti-VEGF agents used in the treatment of nAMD and lists their outcomes.

TABLE 3 - Landmark Trials of Anti-VEGF Agents in Treating nAMD
US FDA Approved
Drug Study (y), N Active Agent (A) Comparator (C) Baseline BCVA Key Findings
1 Pegaptanib VISION (2004)65 N = 1186 A: Pegaptanib 0.3 mg B: Pegaptanib 1.0 mg Pegaptanib 3.0 mg C: Sham injections BCVA: 50.7–52.8 Primary endpoint Proportion of patients losing <15 letters at week 54: 70% in pegaptanib 0.3 mg vs 55% in sham group (P < 0.001) Fewer pegaptanib-treated patients suffered severe loss of visual acuity (≥30 letters): 10% pegaptanib 0.3 mg vs 22% sham group Reduced risk of visual acuity loss was observed with all doses as early as 6 wk after treatment, and showed increasing benefit over time No significant difference in response between different doses of pegaptanib Adverse events: endophthalmitis (1.3%), traumatic lens injury (0.7%), retinal detachment (0.6%), severe visual loss (0.1%) Conclusion: pegaptanib seemed to be an effective therapy for nAMD
2 Ranibizumab MARINA (2006)3 N = 716 A: Ranibizumab 0.3 mg B: Ranibizumab 0.5 mg C: Sham injections BCVA: 53.1–53.7 Primary endpoint Proportion of patients losing <15 letters from baseline at 12 mo: 95% in ranibizumab treatment groups vs 62% in sham group (P<0.001) Patients gaining <15 letters at 12 mo: 25% and 34% treated groups (0.3 mg and 0.5 mg respectively) vs 5% controls Average change in visual acuity: 7 letters gained in the treated groups vs 10 letters lost in the controls Ranibizumab treatment was associated with arrested growth of and leakage from CNV Adverse events: endophthalmitis (<1%), uveitis (<1%) No long-term effect on IOP was noted. IOP increased post injection by 1.9–3.5 mm Hg in the ranibizumab group vs 0.8–1.5 mm Hg in the controls. Postinjection IOP >30 mm Hg occurred in 13%–17.6% in the ranibizumab-treated groups compared with 3.4% in controls Serious nonocular events were not significantly different in treated groups vs control Conclusion: administration of intravitreal ranibizumab for 2 y prevented vision loss and improved mean visual acuity in patients with minimally classic or occult nAMD
3 Ranibizumab ANCHOR (2006)4 N = 423 A: Monthly Ranibizumab 0.3 mg + sham PDT B: Monthly Ranibizumab 0.5 mg + sham PDT C: Standard protocol PDT + monthly sham injections BCVA: 45.5–47.1 Primary endpoint Proportion of patients losing <15 letters from baseline at 12 mo: 96% in ranibizumab 0.5 mg, 94% in ranibizumab 0.3 mg, 64% in PDT (P < 0.001) Patients gaining ≥15 letters at 12 mo: 40% ranibizumab 0.5 mg, 36% ranibizumab 0.3 mg, 6% PDT (P < 0.0001) Average change in visual acuity: 11 letters gained ranibizumab 0.5 mg, 9 letters gained ranibizumab 0.3 mg, 10 letters lost PDT (P < 0.001) Smaller increase in CNV area noted in ranibizumab-treated groups (0.20–0.22 disc area increase) compared with PDT-treated group (1.63 disc area increase) Adverse events: Endophthalmitis in 1.4% of patients treated with ranibizumab 0.5 mg Serious uveitis in 0.7% of patients treated with ranibizumab 0.5 mg Conclusion: ranibizumab is superior to verteporfin as treatment of predominantly classic nAMD
4a Aflibercept VIEW 1 (2012)5 N = 1217 A: Aflibercept 0.5 mg monthly B: Aflibercept 2 mg monthly Aflibercept 2 mg every 2 mo (after 3 initial monthly loading doses) C: Ranibizumab 0.5 mg monthly BCVA: 54.0–55.7 (VIEW 1) BCVA: 51.6–53.8 (VIEW 2) Primary endpoint All aflibercept groups were noninferior to monthly ranibizumab group in the proportion of patients maintaining vision at week 52 (losing <15 letters) (95.1%–96.3% in aflibercept arms vs 94.4% in ranibizumab arms) Mean change in BCVA: only aflibercept 2 mg monthly group was statistically superior to ranibizumab, and only in VIEW 1 (gain of +10.9 vs +8.1 letters) All groups had improvements in mean visual acuity after first injection, and maintained through week 52 Reduction in central retinal thickness All aflibercept groups in both studies had reductions in central retinal thickness similar to those for monthly ranibizumab, which was maintained up to week 52 Adverse events per 1000 injections: 1.1 in ranibizumab 0.8 in aflibercept 2 mg monthly 0.1 in aflibercept 0.5 mg monthly 0.2 in aflibercept 2 mg every 2 mo Conclusion: intravitreal aflibercept is an effective treatment for AMD. Monthly dosing or every 2 monthly after 3 initial monthly doses produced similar efficacy and safety outcomes as monthly ranibizumab
4b Aflibercept VIEW 1 (2012)5 N = 1240
5a Brolucizumab HAWK (2019)17 N = 1078 A: Brolucizumab 3 mg Brolucizumab 6 mg B: 3 initial monthly loading doses followed by every 12-weekly or every 8-weekly C: Aflibercept 2 mg every 2 mo (after 3 initial monthly loading doses) BCVA: 60.6 Primary endpoint Each brolucizumab arm demonstrated noninferiority to aflibercept in BCVA change from baseline to week 48. (+6.1 to +6.9 letters in brolucizumab arms vs +6.8 to +7.6 letters in aflibercept arms) HAWK: 56% of brolucizumab 6 mg-treated eyes maintained 12-weekly dosing through week 48 Disease activity at week 16: 24% brolucizumab 6 mg 34.5% aflibercept 2 mg CST reduction from baseline to week 48: −172.8 μm in brolucizumab 6 mg −143.7 μm in aflibercept 2 mg HARRIER: 51% of brolucizumab 6 mg-treated eyes maintained 12-weekly dosing through week 48 Disease activity at week 16: 22.7% brolucizumab 6 mg 32.2% aflibercept 2 mg CST reduction from baseline to week 48: −193.8 μm in brolucizumab 6 mg −143.9 μm in aflibercept 2 mg Conclusion: brolucizumab was noninferior to aflibercept with respect to visual acuity at 48 wk
5b Brolucizumab HARRIER (2019)17 N = 739 A: Brolucizumab 6 mg B: 3 initial monthly loading doses followed by every 12-weekly or every 8-weekly C: Aflibercept 2 mg every 2 mo (after 3 initial monthly loading doses) BCVA: 61.2
6a Faricimab TENAYA (2022)66 N = 671 A: Faricimab 6.0 mg B: 4 initial monthly loading doses followed by retreatment up to every 16 weekly C: Aflibercept 2 mg every 2 mo (after 3 initial monthly loading doses) BCVA: 61.3–61.5 Primary endpoint Mean change in BCVA from baseline averaged over weeks 40, 44, and 48 in faricimab-treated arms (+5.8 to +6.6) were noninferior to aflibercept-treated arms (+5.1 to 6.6 letters) TENAYA: mean BCVA gain from baseline 5.8 letters in faricimab 6 mg 5.1 letters in aflibercept 2 mg Mean CST change from baseline −136.8 μm in faricimab 6 mg −129.4 μm in aflibercept 2 mg Adverse events leading to treatment discontinuation 0.9% in both groups LUCERNE: mean BCVA gain from baseline 6.6 letters in faricimab 6 mg 6.6 letters in aflibercept 2 mg Mean CST change from baseline −137.1 μm in faricimab 6 mg −130.8 μm in aflibercept 2 mg Adverse events leading to treatment discontinuation 2.4% faricimab 6 mg 0.3% aflibercept 2 mg Conclusion: intravitreal faricimab administered at up to 16 wk intervals demonstrated vision benefits and anatomic outcomes comparable with aflibercept given at 8 wk intervals
6b Faricimab LUCERNE (2022)66 N = 658 A: Faricimab 6.0 mg B: 4 initial monthly loading doses followed by retreatment up to every 16 weekly C: Aflibercept 2 mg every 2 mo (after 3 initial monthly loading doses) BCVA: 58.7–58.9
Non-US FDA Approved
1 Bevacizumab CATT Year 1 (2011)67 N = 1208 A: Bevacizumab 1.25 mg Q28 days B: Bevacizumab 1.25 mg as needed C: Ranibizumab 0.5 mg Q28 days Ranibizumab 0.5 mg as needed BCVA: 60.1–61.5 Primary endpoint Mean change in VA between baseline and 1 y: 8.0 letters in bevacizumab monthly vs 8.5 letters in ranibizumab monthly 5.9 letters in bevacizumab PRN vs 6.8 letters in ranibizumab PRN Ranibizumab vs bevacizumab: Both had equivalent effects on visual acuity at all time points throughout the first year of follow-up, when comparing the same dosing regimens. Monthly vs PRN: ranibizumab given as needed was equivalent to ranibizumab administered monthly, in terms of effect on vision The effect of bevacizumab given as needed compared with bevacizumab administered monthly was inconclusive Adverse events: rates of death, myocardial infarction and stroke were similar for patients receiving ranibizumab or bevacizumab The rate of serious systemic adverse events was higher in patients treated with bevacizumab compared with ranibizumab, not identified as areas of concern
2 Bevacizumab CATT Year 2 (2012)68 N = 1107 A: Bevacizumab 1.25 mg Q28 days B: Bevacizumab 1.25 mg as needed At 1 y, patients initially assigned to monthly treatment were reassigned randomly to monthly or as-needed, without changing the drug assignment C: ranibizumab 0.5 mg Q28 days Ranibizumab 0.5 mg as needed BCVA: 59.9–61.6 Ranibizumab vs bevacizumab: at 2 y, no statistically significant difference in visual acuity outcomes between ranibizumab and bevacizumab when comparing either monthly or PRN groups Monthly vs PRN: Patients treated monthly for 2 y performed 1.7 letters better than patients treated PRN for 2 y, but this was not statistically significant Switching from monthly to as-needed treatment resulted in greater mean decrease in vision (−2.2 letters) and a lower proportion without fluid (−19.0%) Adverse events: no difference in rates of death, myocardial infarction, and stroke Higher rates of serious systemic side effects noted at year 1 continued through year 2
3 Conbercept PHOENIX69 N = 114 A: Conbercept 0.5 mg B: 3 initial monthly doses followed by quarterly till month 12 C: Sham up to month 3. Starting from month 3: 3 monthly injections of conbercept 0.5 mg followed by quarterly administration till month 12 BCVA: 48–49 Primary outcome Mean change from baseline in BCVA at month 3 were +9.2 letters in the conbercept group and +2.0 letters in the sham group Mean BCVA improvement from baseline at 3 months: +9.2 letters in conbercept 0.5 mg, +2.0 letters in sham Mean BCVA improvement from baseline at 12 mo: 10.0 letters in conbercept 8.8 letters in sham Conclusion: conbercept (3 initial monthly followed by quarterly treatments) is effective for treatment of AMD
AMD indicates age-related macular degeneration; BCVA, best-corrected visual acuity; CATT: comparison of age-related macular degeneration treatments trial; CNV, choroidal neovascularization; CST, central subfield thickness; IOP, intraocular pressure; nAMD, neovascular age-related macular degeneration; PDT, photodynamic therapy; PRN, pro re nata; VA, visual acuity; VEGF, vascular endothelial growth factor; VISION, VEGF inhibition study in ocular neovascularization.
HARRIER: efficacy and safety of RTH258 versus aflibercept—study 2; HAWK: efficacy and safety of RTH258 versus aflibercept—study 1.
LUCERNE: a study to evaluate the efficacy and safety of faricimab in participants with neovascular age-related macular degeneration.
PHOENIX: a phase 3 clinical trial of intravitreal injections of human recombinant vascular endothelial growth factor receptor-Fc fusion protein in patients with choroidal neovascularization secondary to age-related macular degeneration.
TENAYA: active comparator-controlled study to evaluate the efficacy and safety of faricimab in patients with neovascular age-related macular degeneration.

DISCUSSION

Adverse Events/Intraocular Inflammation

Given that the pathogenesis of IOI-associated conditions is not known, it is possible that variations in genetics, environmental factors, and differences in health care delivery/prescribing practices may make these data less generalizable to persons in other geographic regions.

Throughout the literature, both the presenting symptomatology and timing of presentation are highly variable between patients. Some cases of IOI occurred between 5 days and 20 weeks after injection, whereas RV has been described between 7 and 56 days afterward.48,61,63 In both databases, more than 80% of total events occurred after either the first or second injection.55 These findings are also congruent with case reports by Jain and colleagues and Nguyen and colleagues and previous data describing treatment-naive eyes, with ~50% of cases occurring within 3 months of the first injection and ~75% occurring within 6 months of the first injection.18,45,53,63 Although the risk of inflammation is higher in recently treated patients, episodes may still develop more than 1 year later.18,53

Data on effective treatments are limited, and a variety of modalities have been utilized, including topical steroids, subtenon, and intravitreal injections, oral steroids, and surgical interventions (vitrectomy). In some cases, mild IOI has resolved with observation alone; however, observation may be associated with a higher potential for permanent vision loss compared with treatment with topical steroids.44,48 Kataoka et al70 described treating IOI and RV with oral prednisolone, subtenon triamcinolone acetonide (TA), and topical 0.1% betamethasone drops, with visual acuity restored to baseline in 6 weeks. Bulirsch et al42 reported 3 cases of severe IOI, and 1 patient with RV was successfully treated with weight-dosed systemic steroids. Overall, outcomes for each treatment method have had varying degrees of success. Baumal et al49 also reported 1 case of IOI that progressed to occlusive RV despite steroid treatment, while oral and/or intravitreous corticosteroids successfully resolved 2 cases of occlusive RV. In cases of occlusion, visual acuity outcomes may be more related to the position of occlusion in relation to the macula rather than the treatment modality.49 Pars plana vitrectomy has been performed to remove the remaining drug but has not shown superior outcomes than those treated with nonsurgical methods.44,48,49,61

Many clinicians recommend a complete eye examination, including optical coherence tomography imaging, before every injection and delaying administration if any sign of active IOI is noted.49,53,61 Patient education about potential symptoms associated with IOI (vision changes, floaters, pain, or redness), along with instructions to return to care if any of these develop, may also aid in the early detection of IOI and other potential adverse effects. If signs of IOI are found on clinical examination, imaging can be obtained to assess for concomitant RV or RO. Authors recommend UWF-FA to evaluate leakage, filling defects, or hyperfluorescence, along with optical coherence tomography angiography to characterize microvascular changes and perfusion defects.53,61 For patients with only signs of IOI, Cox et al48 recommend close follow-up and serial FA to assess for RV development.

Some studies have reported a higher incidence in females, suggesting that biological sex could be a risk factor for IOI development.44,55,64 Mukai et al64 reported that IOI tended to occur more frequently in people with diabetes. Another observation was that patients with a history of IOI or RO in the 12 months prior had the highest observed risk rate of IOI or RO after the first treatment (8.7% and 10.6%, respectively) compared with 2% for those without this history.55 Enriquez et al44 found that bilateral, same-day injections demonstrated a relative risk of 1.72 (95% CI: 0.61–4.85) for developing IOI. Future research may clarify the pathogenesis of these complications and susceptible patients.61

Patients with a possible risk of IOI after the administration of brolucizumab, particularly within the first 6 months, should receive careful monitoring, prompt diagnosis, and timely intervention. Risk factors for IOI have been identified. These include neutralizing antibodies, female sex, prior history of IOI, and a history of autoimmune disorders. In HAWK and HARRIER phase 3 trial, 86% of patients with IOI and RV had neutralizing antibodies before or at the time of the adverse event.71 Patients with a history of IOI and/or RVO in the preceding 12 months had an increased risk for an IOI event (8.7%) and an RVO event (10.6%) in the first 6 months after the first brolucizumab injection compared with those patients without prior IOI and/or RVO (2.0%).18 Witkin et al62 reported 5 patients with bilateral brolucizumab injections developed bilateral IOI; hence, bilateral brolucizumab injections should be avoided if possible. When an adverse event of IOI, RV, or RVO has been diagnosed, brolucizumab should be discontinued, and the patient monitored intensively or treated with intensive topical, intraocular, or oral corticosteroids.71 Patients should be educated on self-monitoring after every injection, and at scheduled visits after injection, the ophthalmologist should monitor with visual acuity, slit-lamp biomicroscopy for anterior chamber inflammation, dilated fundus examination, color fundus photography, optical coherence tomography, and utilize UWF imaging or UWF-FA/indocyanine green as ancillary investigations.72 In view of postmarketing case reports of IOI as an initial presentation with subsequent development of RV/RVO, Baumal et al71 suggested that early intensive treatment should be initiated regardless of the severity of IOI-adverse events to minimize the risk of progression. Topical corticosteroids, intravitreal, subtenon, and systemic corticosteroids have all been reported in the literature to treat IOI-adverse events. In some cases, vitrectomy or pan-retinal photocoagulation to the ischemic retina was performed.61 Furthermore, Hikichi73 reported on preventing brolucizumab-associated IOI with 20 mg of subtenon triamcinolone combined with intravitreal brolucizumab. Four of the 14 eyes (28.6%) with nAMD receiving brolucizumab alone developed IOI, and brolucizumab was discontinued. None of the 30 eyes, which received a combination of brolucizumab and subtenon triamcinolone developed IOI. Of these eyes,10% showed a transient rise in intraocular pressure, and none developed cataracts.73 Given a lack of data to inform clear treatment guidelines, some authors have a low threshold for corticosteroid use in IOI after the exclusion of infectious agents, whereas others discuss a low threshold for treating cases as infectious, given the overlapping features of endophthalmitis and IOI.44,48 As complete safety data about brolucizumab is still emerging, clinical judgment and close follow-up are useful in guiding ongoing treatment.

Regarding modification of dosing or administration frequency to improve safety outcomes, a recent meta-analysis evaluating 6 RCTs and 3574 patients revealed that there is no significant difference between brolucizumab 6 mg and 3 mg dosing regarding serious adverse events and serious ocular adverse events. Brolucizumab was more likely to lead to severe ocular adverse events compared with aflibercept and ranibizumab (odds ratio: 2.15, 95% CI: 1.11–4.16; P = 0.02).58 Notably, the study did not delineate between types of serious ocular events, so specific conclusions about IOI, RV, and RVO cannot be drawn. In addition, the MERLIN trial, which dictated a rigid 4-week dosing interval, demonstrated a 9.3% incidence of IOI, 2% RVO, and 0.8% RV. The higher incidence of serious ocular adverse events and vision loss in this trial led to early termination.21 Accordingly, it is unlikely that a reduced dose at a higher dosing frequency would improve safety outcomes besides defeating the intended benefit of reduced frequency.21

FUTURE: FARICIMAB AND ABICIPAR

Faricimab is a novel humanized bispecific immunoglobulin G monoclonal antibody, which independently binds to and neutralizes VEGF-A and ANG2. Besides VEGF, the ANG/tyrosine kinase pathway also plays an important role in maintaining vascular stability. TENAYA and LUCERNE are phase 3 randomized, double-masked, multicenter studies, which have evaluated the efficacy and safety of faricimab in comparison to aflibercept in the treatment of nAMD. The rates of adverse events were low for both faricimab and aflibercept, and faricimab was noninferior to aflibercept in the treatment of nAMD.74

Abicipar pegol is a new class of custom-built design ankyrin repeat protein (DARPin) therapeutics that binds all isoforms of VEGF-A with a higher affinity and specificity compared with ranibizumab. Pooled analysis of 2 global phase 3 trials: safety and efficacy of abicipar pegol in participants with nAMD (SEQUOIA and CEDAR) revealed stabilized vision, less frequent injections, as well as noninferiority as compared with ranibizumab. However, a 15.4% of inflammation rate has raised potential concerns.75

Goodman and Gilman’s76 “Pharmacological Basis of Therapeutics” points out that an ideal drug to treat any disease such as nAMD should be administered once, should be devoid of any side effects and should be able to cure the disorder in the first treatment. The pipeline has many more agents, from sustained drug delivery systems and newer molecular targets to gene therapy. However, the scope for covering them all is too vast to be included in this update on brolucizumab.

CONCLUSIONS

Although brolucizumab was approved by US FDA for the treatment of AMD on October 8, 2019, this is a relatively new molecule, and data are now available to support its use as a noninferior agent in managing people with nAMD. In this review, we have tried to highlight the major trials and their outcomes as well as focus on the real-world data and the adverse event profile of brolucizumab as studied in subsequent years. Although major trials reported a higher incidence of adverse events and IOI, real-world data and further meta-analysis have found that the incidence is less. Though this reduction in the incidence of IOI from real-world examples is encouraging, it is still higher than that occurs with other anti-VEGF agents; hence, caution is necessary, and a careful examination is warranted in patients at risk of developing IOI or occlusive RV, which may result in severe vision loss. Although the publications on IOI after injection of brolucizumab seem to have reduced, the actual incidence of adverse events would only be possible if strict reporting to national registries and access to such information becomes available/reported in the future or if the trend of nondecline in IOI versus decline due to factors such as practices of combining subtenon TA are studied. Some questions still remain unanswered, for example, does the duration of occurrence of IOI shorten if injections are repeated? Does the risk of IOI increase with each injection? Is there any difference between incidences of IOI after the first injection versus the second or subsequent injections? Such questions would need continued and further studies. Until then, proper preinjection documentation of history and findings coupled with diligent screening in the postinjection period is mandatory for early identification and prompt management of any adverse events, thus minimizing severe vision loss. Lastly, among the many new developments in understanding, preventing, and managing nAMD,77–86 the importance of developing safe and long-acting anti-VEGF agents such as brolucizumab can never be overemphasized.

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Keywords:

brolucizumab; intraocular inflammation; real-world data; safety and efficacy

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