The changing landscape for the management of patients with neovascular AMD: brolucizumab in clinical practice

When considering the use of brolucizumab part of the discussion regarding informed consent will need to include the benefit vs risk. The potential benefit of brolucizumab for the treatment of patients with nAMD has been demonstrated in the HAWK and HARRIER, randomised, phase 3 clinical trials [19, 20].

In these trials, brolucizumab demonstrated noninferiority with respect to BCVA change from baseline at Week 48 (least squares [LS] mean, +6.6 [6 mg] letters with brolucizumab vs. +6.8 letters with aflibercept [HAWK]; + 6.9 [brolucizumab 6 mg] vs. +7.6 [aflibercept] letters [HARRIER]; P < 0.001 for each comparison) [20]. The mean change (LS mean ± standard error) in BCVA from baseline to 96 weeks was maintained in HAWK (5.90 ± 0.78 letters for brolucizumab 6 mg, and 5.3 ± 0.78 letters for aflibercept) and in HARRIER (6.1 ± 0.73 letters for brolucizumab 6 mg and 6.6 ± 0.73 letters for aflibercept) [19]. In terms of fluid in the macula, eyes treated with brolucizumab (6 mg) had greater CST reductions throughout the duration of the study and significantly lower IRF and/or SRF compared to aflibercept [19, 20]. In addition, at Week 16, after identical treatment exposure, fewer brolucizumab–treated eyes (6 mg) had disease activity compared to aflibercept in HAWK (24.0% vs. 34.5%; P = 0.001) and HARRIER (22.7% vs. 32.2%; P = 0.002, Fig. 1). This better control of fluid would be expected to lead to a reduced frequency of injections using a personalised regimen such as Treat and Extend and may suggest the possibility of better fluid control in patients already on optimal treatment with an existing anti-VEGF but with persistent fluid.

Fig. 1: Disease activity at week 16 in HAWK and HARRIER.
figure 1

Full analysis set; analysis conducted based on the efficacy/safety approach. *The 95% confidence interval (CI) for treatment difference, –13.2 to 0.3; P = 0.033. 95% CI for treatment difference, –17.1 to –3.5; P = 0.001. 95% CI for treatment difference, –15.8 to –3.1; P = 0.002. One-sided P values versus aflibercept.

Also of note, in both trials, approximately half the enroled eyes receiving brolucizumab (6 mg) were maintained on a 12-weekly (Q12W) dosing interval through to Week 48 immediately following the initial three 4-weekly loading doses [20]. Importantly, eyes treated with brolucizumab that did not require a treatment between the final loading injection and the first Q12W injection were likely to be maintained on a Q12W injection interval for the study, demonstrating a decreased disease activity and durability with brolucizumab [19, 20].

An important reason for establishing a patient profile is to avoid treating those who may be susceptible to the AEs identified during clinical trials of brolucizumab [32]. Even with careful profiling, however, any pharmacological treatment carries a risk of unwanted or unexpected AEs [40]. This is why healthcare bodies such as the Medicines and Healthcare products Regulatory Agency (MHRA) compile post-marketing reports of side effects and adverse drug reactions [40].

Injection site reactions (ISRs) are a local phenomenon and are one of the most commonly occurring AEs following administration of a drug or vaccine via injection [41]. ISRs can include swelling, erythema, pruritus and pain at the injection site [41]. In most cases, ISRs are mild to moderate and resolve after a few days. In addition to the risk of reaction from the injection itself, reactions may also occur from the drug injected. These AEs are extensively studied in clinical trials and are included in the Summary of Product Characteristics (SmPC) and patient information leaflet (PIL) to help clinicians and patients make informed decisions about their care [32, 42].

Adverse events with anti-VEGF treatments in nAMD

The availability of multiple anti-VEGF therapies, each with different molecular configurations, creates unique challenges to mapping treatment responses [43]. This is compounded by individual patient and disease characteristics—such as age, lesion characteristics and lesion duration—in addition to variations in injection frequency observed between clinical centres delivering the same agent [43, 44]. Despite variation in treatment responses to anti-VEGF therapies, potential AEs are similar across the different agents [45].

Each intravitreal injection with an anti-VEGF therapy in patients with nAMD is associated with a risk of post-injection and drug-class-associated AEs (Table 3) [45,46,47].

Table 3 Adverse events associated with intraocular anti-VEGF injections.

Safety profile for brolucizumab

The most common AEs reported in the pivotal Phase 3 trials, HAWK and HARRIER, included cataract, conjunctival haemorrhage, reductions in visual acuity and vitreous floaters (Table 4) [20].

Table 4 Ocular adverse events reported in HAWK and HARRIER [20].

Of the AEs reported, there were three key observations of interest, which included: [48]

Following the occurrence of 70 IOI-related AEs in HAWK and HARRIER, 87.1% (n = 61) were treated [49]. The majority of patients received topical corticosteroids, while a minority received systemic and intraocular corticosteroids [49]. Inflammation resolved completely in 79.6% of eyes (n = 39), resolved with sequelae in 10.2% of eyes (n = 5) and did not resolve in 10.2% of eyes (n = 5) by the end of the study [49].

The 2-year risk of definite (28/50 patients) and probable (22/50 patients) IOI, retinal vasculitis and/or retinal occlusion following treatment with brolucizumab are outlined in the table below, following a review of observations of interest by an independent Safety Review Committee (SRC), supported by Novartis to analyse these investigator-reported cases in the phase 3 HAWK and HARRIER trials (Table 5) [48].

Table 5 Two-year risk of intraocular inflammation, retinal vasculitis and/or retinal occlusion following treatment with brolucizumab [48].

Overall, fifty patients (4.6%) developed IOI, of which 26 (3.3%) developed retinal vasculitis and 23 (2.1%) developed concomitant retinal vasculitis and retinal occlusion [30, 48]. Over two years, the absolute risk of developing IOI of any form was 4.6%, and the risk of visual loss due to IOI (≥15 letters) was 0.7% [30, 48]. The overall rate of vision loss was similar when comparing the brolucizumab and aflibercept arms of the study population [48].

The majority of inflammatory events (74%, 37/50) occurred in the first 6 months following the first dose of brolucizumab [48]. Additionally, nearly half of these events occurred within the first 3 months (48%, 24/50) [30]. Post-hoc analysis of HAWK and HARRIER reported that, of the 8 cases of vision loss ≥15 ETDRS letters in eyes with IOI, 5 patients experienced their first IOI-related event within 3 months of the first brolucizumab injection [30]. By 6 months, this increased to 7 out of the 8 patients [30].

Of the 73.5% (36/49) eyes that continued receiving brolucizumab following the first IOI-related AE, 24 completed the study and 12 discontinued [49]. Mean BCVA change in these eyes was 7.8 and –7.7 ETDRS letters, respectively, from baseline to the end of the study [49]. 26.5% (13/49) eyes were not treated with brolucizumab following the first IOI-related AE and the mean BCVA change was—10.4 ETDRS letters from baseline to the end of the study [49].

The MERLIN phase 3 study was designed to compare safety and efficacy of brolucizumab 6 mg dosed every 4 weeks to aflibercept 2 mg dosed every 4 weeks in those nAMD patients with retinal fluid despite frequent anti-VEGF injections [50]. In this study, brolucizumab administered every 4 weeks demonstrated a higher incidence of IOI-related AEs with more frequent dosing compared with aflibercept [51]. However, these are the first interpretable results and further analysis of the data is required. Furthermore, MERLIN also adopted a 4-week injection interval following the first three initiation doses. However, the current posology and data from the clinical trials (HAWK/HARRIER) are based on injections every 8 or 12 weeks depending on disease activity after the 3 initiation doses [20, 32]. Given the data from the MERLIN study, it is recommended that patients should have a minimum 8-week interval between injections once the loading phase has been completed.

A recent cohort study of patients from the Intelligent Research in Sight (IRIS) Registry (US eye disease database) and Komodo Healthcare Map (US claims database) has examined real-world evidence of IOI, including retinal vasculitis (RV) and/or retinal vascular occlusion (RO) in patients with nAMD who received brolucizumab treatment between October 8, 2019, and June 5, 2020 [52]. The analysis include over 21,000 treated eyes, with the majority being switched from another anti-VEGF therapy [52]. In this cohort analysis, the overall incidence of IOI and/or RO was 2.4% in each registry. Also of note is that patients with a history of IOI and/or RO in the preceding 12 months had an increased observed risk rate (8.7% [95% CI, 6.0–11.4%] and 10.6% [95% CI, 7.5–13.7%]) for an IOI and/or RO event in the 6 months following the first brolucizumab treatment compared with patients without prior IOI and/or RO (2.0% in both data sets) [52]. However, due to the nature of the design of the studies, there are limitations to using the analysis of the risk factors as predictors of the rates of IOI and/or RO events [32, 52].

Data regarding IOI following brolucizumab administration is constantly evolving and will likely change in the future as experience and evidence increases.

Mitigating and managing adverse events

Several approaches can be used to mitigate possible AEs following administration of brolucizumab [53]. The most conservative approach to monitoring is to have patients return between injections for safety assessments; however, this will reduce the benefit vs. risk ratio due to the increased burden on the service. Another option is to allow patients to self-monitor for symptoms between injection visits. The most pragmatic approach is for patients to be monitored and assessed for IOI at each scheduled visit in conjunction with educating the patient to self-monitor. Clinical management recommendations include; slit-lamp biomicroscopy (for anterior chamber inflammatory activity), dilated fundus examination, colour fundus photography and optical coherence tomography (OCT) scan (for the detection of vitreous cells and evaluation of the retina for signs of inflammation). Also consider (if available) ultra-widefield (UWF) imaging and fluorescein angiography as helpful adjunctive investigational tools [53].

Assessments for side effects, visual acuity and anatomy on OCT scans and appropriate detailed questioning of patients are recommended at each treatment visit to help optimally guide future treatment. Intermediary assessment visits are not required in the intervals between treatment visits unless the patient presents as an emergency with new visual symptoms. Reports indicate that 75% of patients who had inflammatory side effects to brolucizumab did so in the first six months [20, 49]. This offers some reassurance to the patient and clinician that risk is reduced after six months on treatment but in view of the small ongoing risk, checks for inflammation and RO are recommended at each visit.

Educating patients on the importance of reporting symptoms as soon as they arise can be vital in ensuring an early diagnosis [53]. This can include asking the patients specific questions about any changes they observed after injection and ensuring they know what to look out for (change in vision) between injection visits and providing patient materials to support them.

Careful monitoring, prompt diagnosis and timely intervention are key to managing potential AEs associated with brolucizumab [53]. Upon diagnosis of IOI, RV or a RO, treatment with brolucizumab should be discontinued [32, 53]. Intensive treatment of IOI with corticosteroids, followed by regular monitoring, may help in preventing IOI progression [53].

Recent studies have identified several risk factors for IOI, including neutralising antibodies (Nab), female gender and prior history of IOI [54, 55]. In the phase 3 trial HAWK and HARRIER, 86% of patients with IOI and RV had demonstrated Nab prior to, or at the time of, the AE [54]. Nab and their involvement in inflammation following treatment with brolucizumab is being explored to enable us to provide better advice in the future. However, the information available to date does not provide any clinically relevant predictive tests for IOI. Further studies will be needed to develop better understanding of these risk factors and whether they can be used when deciding which patients should receive treatment with brolucizumab.

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