Before the era of anti-VEGF, treatment options for nAMD and DMO were limited, primarily involving photodynamic therapy (PDT) for nAMD and laser photocoagulation for DMO. These treatments were suboptimal as they failed to provide visual improvement for many patients and were often associated with significant side effects.1,2

Anti-VEGF therapy changed the treatment landscape by targeting the underlying pathophysiology of these diseases – namely, the overexpression of VEGF, a key protein that promotes abnormal blood vessel growth and increased vascular permeability in the retina. The early clinical trials investigating the efficacy of anti-VEGF agents, including the MARINA and ANCHOR trials for nAMD and the RISE and RIDE trials for DMO, demonstrated significant improvements in visual acuity (VA) and retinal anatomy, firmly establishing anti-VEGF therapy as the gold standard in treating these conditions.3,4

In the past decade, bevacizumab, ranibizumab, and aflibercept 2 mg are the three earliest anti-VEGF agents to demonstrate efficacy in high quality clinical trials that have been available in Australia on the pharmaceutical benefits scheme (PBS) for use in the treatment of nAMD and DMO.

However, despite these advancements, the frequent injections required by standard anti-VEGF regimens have imposed a substantial burden on patients, clinicians, and healthcare systems, prompting the development of newer agents with improved durability and efficacy.

THE UNMET NEED OF CURRENT ANTI-VEGF THERAPY

Despite the clear benefits of anti-VEGF therapy, there remains a significant unmet need in the treatment of DMO and nAMD. One of the main challenges is the limited durability of existing anti-VEGF agents, necessitating frequent intravitreal injections and regular clinic visits, sometimes
as frequently as monthly, to maintain therapeutic effects. This high treatment burden poses a substantial challenge not only for patients, who may struggle with the inconvenience and discomfort of frequent injections, but also for healthcare systems and providers, who must manage the logistical and financial demands of such intensive treatment regimens.

Moreover, while anti-VEGF therapy has been shown to improve visual acuity in many patients, its efficacy is not universal. For example, data from Protocol I reveals that despite six-monthly injections of anti-VEGF for treatment of DMO, about a third of patients still have unresolved DMO with reduced visual acuity.5 Similarly, in nAMD, studies have shown that approximately a third of patients still have evidence of active exudation after one year of regular anti-VEGF therapy.6

In real-world clinical practice, these limitations are further exacerbated. The rigorous treatment schedules used in clinical trials are often difficult to replicate in everyday settings, leading to issues with patient adherence and compliance. As a result, the visual acuity gains observed in clinical trials are not always mirrored in real-world outcomes. This discrepancy highlights the limitations of current anti-VEGF agents and underscores the pressing need for therapies that can provide longer-lasting effects with fewer injections, thereby improving patient adherence and overall outcomes.

A NEW GENERATION OF ANTI-VEGF AGENTS

In response to the challenges posed by current anti-VEGF therapies, several new agents have been developed in recent years that aim to improve both the efficacy and durability of treatment.

Brolucizumab, a single-chain monoclonal antibody fragment blocking VEGF-A, was designed to offer greater tissue penetration and thus better fluid control and a longer duration of action compared to earlier anti-VEGF agents. The HAWK and HARRIER Phase 3 clinical trials demonstrated that at week 48, brolucizumab 3 mg or 6 mg was non-inferior to aflibercept 2 mg in improving visual acuity in patients with neovascular AMD, and more than 50% of patients treated with brolucizumab 6 mg were maintained on 12-weekly dosing interval.7 Similarly, the KESTREL and KITE clinical trials revealed that brolucizumab 6 mg was non-inferior
to aflibercept 2 mg in mean change in best corrected visual acuity (BCVA) from baseline, with more than 50% maintained on more than 12-weekly dosing at 52 weeks. However, despite these promising visual and durability outcomes, the adoption of brolucizumab has been limited by safety concerns, particularly the risk of intraocular inflammation and retinal vascular inflammation and occlusion, which can lead to severe visual loss.7,8,9

Faricimab, a bispecific antibody targeting both VEGF-A and Angiopoietin-2 (Ang-2), was designed to have a synergistic dual-pathway inhibition mechanism on both the VEGF pathway and the Tie-2 receptor pathway, which has been shown to play a role in vascular stability. The TENAYA and LUCERNE Phase 3 clinical trials for nAMD over 48-weeks revealed that faricimab was non-inferior to aflibercept 2 mg in terms of BCVA change from baseline, with around 80% of patients achieving 12-weekly dosing or longer by the end of year two.10 The YOSEMITE and RHINE Phase 3 clinical trials for DMO reported that faricimab was non-inferior to aflibercept 2 mg in terms of BCVA from baseline at two years, and around 80% of patients achieved 12-weekly dosing or longer by the end of year two.11 The safety profile of faricimab in these trials was also comparable to that of aflibercept 2 mg.10,11

AFLIBERCEPT 8 MG: THE LATEST ADVANCEMENT

Aflibercept 8 mg represents the newest advancement in the anti-VEGF therapy landscape in Australia, offering a four-fold increase in molar dose compared to the original aflibercept 2 mg formulation. This higher concentration is expected to improve both the efficacy and durability of treatment through decreased ocular clearance of the drug and prolonged VEGF suppression.

Aflibercept 8 mg has been engineered within a new formulation contained in a 0.07 mL volume, compared to the 2 mg dose in 0.05 mL volume.14 Despite the new formulation, aflibercept 8 mg retains the same molecular structure as aflibercept 2 mg, which has been extensively studied and used in clinical practice for over a decade. This continuity in molecular design is expected to translate into a safety profile similar to that of the 2 mg dose, while potentially offering improved clinical outcomes, especially in reducing the treatment burden associated with frequent injections.

THE PULSAR TRIAL

The PULSAR trial is the randomised, double-masked, Phase-3 non-inferiority clinical trial designed to evaluate the efficacy and safety of aflibercept 8 mg in patients with nAMD.12

The main inclusion criteria for the study were treatment-naïve patients aged 50 years or older with active subfoveal choroidal neovascularisation secondary to AMD, and baseline Snellen BCVA of 6/9.5 to 6/95. Study participants were randomised 1:1:1 to aflibercept 8 mg given 12-weekly, aflibercept 8 mg given 16-weekly, or aflibercept 2 mg given eight-weekly, following three initial monthly loading doses.

From week 16, patients in the aflibercept 8 mg groups had their dosing interval reduced if they met pre-specified dose regimen modification criteria (BCVA loss of more than five letters, and either a more than 25 μm increase in central retinal thickness (CRT) or a new foveal haemorrhage or neovascularisation).

The primary endpoint was the mean change in BCVA from baseline to week 48. The key secondary efficacy endpoint was the proportion of patients with no fluid at week 16. Baseline characteristics of the participants were well-matched across the groups, with an average age of around 75 years, a slightly higher proportion of female participants (approximately 55%), and predominantly white racial background (about 76%).

The results revealed that at week 48, the aflibercept 8 mg groups (both 12-weekly and 16-weekly intervals) demonstrated non-inferior BCVA gains compared to the aflibercept 2 mg at eight-weekly interval group, with mean improvements of +6.7 letters (8 mg 12-weekly), +6.2 letters (8 mg 16-weekly) and +7.6 letters (2 mg eight-weekly). Furthermore, approximately 80% of patients in the aflibercept 8 mg groups maintained their assigned dosing of 12 or 16-weekly up to week 48.

In terms of anatomical outcomes, the aflibercept 8 mg groups showed statistically significant superiority compared to aflibercept 2 mg in terms of proportion of patients with no retinal fluid in the centre subfield at week 16 (63% vs 52%).

These results suggest that aflibercept 8 mg for the treatment of nAMD may have the potential for longer dosing intervals and more durable drying effects compared to the current 2 mg formulation, without compromising on visual gains.

THE PHOTON STUDY

The PHOTON study is the randomised, double-masked, Phase-2/3 non-inferiority clinical trial designed to evaluate the efficacy and safety of aflibercept 8 mg in patients with DMO.13

The main inclusion criteria were adults aged 18 years or older with type 1 or type 2 diabetes, and treatment-naïve or previously treated DMO with central involvement, and a baseline Snellen BCVA of 6/9.5 to 6/95.

Study participants were randomised 1:2:1 into either aflibercept 2 mg every eight weeks, aflibercept 8 mg every 12 weeks, or aflibercept 8 mg every 16 weeks, following initial monthly dosing (five loading doses in the aflibercept 2 mg arm and three loading doses in the aflibercept 8 mg arms).

Similar to the PULSAR trial, from week 16, dosing intervals for the aflibercept 8 mg groups were reduced if patients met pre-specified dose regimen modification criteria (decrease in BCVA of more than 10 letters and an increase in central retinal thickness of at least 50 μm).

The primary endpoint was change from baseline in BCVA at week 48. The secondary endpoints included at least a two-step improvement from baseline in Diabetic Retinopathy Severity Scale (DRSS) score at week 48, and the change in central retinal thickness from baseline at week 48.

Baseline demographic and ocular characteristics were similar between treatment groups, with an average age of approximately 62 years, a slightly higher proportion of male patients (61%), and a predominantly white population (72%).

The results showed that the aflibercept 8 mg 12-weekly and 16-weekly groups met the primary efficacy endpoint, demonstrating non-inferior BCVA gains at 48 weeks compared with the aflibercept 2 mg eight-weekly group. The mean change from baseline in BCVA at week 48 was +8.8, +7.9, and +9.2 ETDRS letters in the aflibercept 8 mg 12-weekly, 16-weekly and 2 mg eight-weekly groups respectively. Around 90% of patients in each aflibercept 8 mg treatment group (12-weekly or 16-weekly) maintained dosing intervals at week 48.

In terms of secondary endpoints, the proportion of patients that achieved at least a two-step improvement from baseline in DRSS score at 48 weeks was non-inferior between aflibercept 8 mg 12-weekly (29%) when compared to the aflibercept 2 mg eight-weekly group (26.6%). However, non-inferiority between aflibercept 8 mg 16-weekly (19.6%) and aflibercept 2 mg eight-weekly (26.6%) could not be demonstrated based on the prespecified non-inferiority margin. At week 48, the mean change from baseline in CRT was similar in the three groups – approximately -172 μm in the aflibercept 8 mg 12-weekly group, -148 μm in the aflibercept 8 mg 16-weekly group, and -165 μm in the aflibercept 2 mg eight-weekly group.

Collectively, these results show that aflibercept 8 mg was associated with similar treatment outcomes to those of aflibercept 2 mg, even with extended treatment intervals in the patients with DMO. This highlights the potential of aflibercept 8 mg to perhaps reduce the frequency of injections while maintaining or improving visual and anatomical outcomes in patients with DMO.

SAFETY PROFILE OF AFLIBERCEPT 8 MG

The safety profile of aflibercept 8 mg was assessed in both the PULSAR and PHOTON trials.12,13 The overall safety outcomes were comparable to those observed with the 2 mg dose, with no new safety signals detected. The most common ocular adverse events included conjunctival haemorrhage, vitreous floaters, vitreous detachment in the PHOTON study, and reduced visual acuity, cataract and retinal haemorrhage in the PULSAR study. All of these events were mild-to-moderate in severity and consistent with the known safety profile of anti-VEGF agents.

In terms of serious ocular adverse events, the incidence was low across all treatment arms. These events included retinal detachment, retinal haemorrhage, vitreous haemorrhage, and increased intraocular pressure. The number of patients with intraocular inflammation was low across all treatment groups, and they were all of mild or moderate severity. There were no cases of endophthalmitis or retinal vasculitis reported.

In addition, although aflibercept 8 mg was administered in a larger injection volume than aflibercept 2 mg, there were no clinically significant changes in intraocular pressure reported between the treatment groups.

Furthermore, the proportion of patients with non-ocular adverse events was also similar between treatment groups. Despite the higher molar dose of aflibercept 8 mg and potential concerns of systemic VEGF inhibition, these early trials demonstrated that there were no clinically meaningful differences in the observed incidences of hypertension events, arteriothrombotic events or deaths between aflibercept 8 mg and 2 mg.

THE FUTURE OF ANTI-VEGF THERAPY

The future of anti-VEGF therapy holds great promise as we continue to address
the limitations of current treatments and explore new avenues for patient care. The introduction of new generation anti-VEGF agents marks an exciting advancement in this treatment era, offering the potential for extended treatment intervals and improved disease control without compromising safety or efficacy. As real-world data accumulate, it will be critical to observe how these newer anti-VEGF agents truly impact our clinical practice, particularly in terms of visual outcomes, durability, and safety.

Looking ahead, further research is likely to focus on optimising dosing strategies, understanding the long-term safety profile of newer agents, and exploring other new therapies that could enhance outcomes. These innovations aim to achieve more consistent disease control and better visual outcomes, particularly in patients with challenging disease phenotypes or poor response to current therapies.

Moreover, the evolving understanding of the molecular pathways involved in nAMD and DMO could lead to the development of novel therapeutic targets, potentially offering more personalised treatment approaches. As we integrate these emerging therapies into clinical practice, the overarching goal will remain to preserve vision and quality of life for our patients, while minimising the impact of treatment on their daily lives.

CONCLUSION

In conclusion, while current anti-VEGF agents have transformed the management of nAMD and DMO in the last decade, they still present notable challenges, particularly in terms of treatment durability and patient adherence. The frequent injections and clinical visits required with current regimens underscore an unmet need for longer-lasting therapies that can sustain visual and anatomical outcomes over extended intervals. The emergence of newer anti-VEGF agents, such as aflibercept 8 mg, holds significant promise in addressing these limitations, offering improved durability with similar visual outcomes, thus potentially reducing the burden on both patients and healthcare systems. Early trial results are encouraging, but the true impact of these therapies will be better understood as real-world data becomes available. Ongoing research and innovation are essential to further refine treatment strategies, improve patient outcomes, and explore future therapies that may offer even greater efficacy and convenience for patients with retinal diseases.

This article was sponsored by Bayer. MA-AFL_ 8mg-AU-0060-1.

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