New Anti-VEGF Agents Extend Dosing Intervals in Wet AMD

The advent of second-generation anti-VEGF drugs is transforming the treatment of exudative age-related macular degeneration (AMD) due to their prolonged efficacy, which allows for fewer injections but at the cost of a higher risk for inflammation. A presentation at the 131st Congress of the French Society of Ophthalmology, held in Paris, France, reviewed the impact of these new approaches.

The therapeutic management of AMD has undergone significant changes in recent years, the most important of which is undoubtedly the introduction of second-generation anti-VEGF agents (brolucizumab, faricimab, and aflibercept 8 mg), with administration schedules that allow up to 5 months between injections.

While these new developments will redefine therapeutic management in AMD, for now, “it remains difficult to arrive at a simple algorithm,” as management has become so complex, stressed Sarah Mrejen, MD, from the Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, Paris, during her presentation.

Tolerance Concerns

Adjustments are particularly expected with the use of new anti-VEGFs, following the emergence of a signal of poorer tolerance in real life with these drugs, particularly brolucizumab. This observation raises questions about the best strategy to follow, particularly after the appearance of intraocular inflammation under second-generation anti-VEGF treatment.

AMD is characterized by progressive degeneration of the macula, the central part of the retina. It is the leading cause of vision loss in older adults. In the exudative form of AMD (approximately 10% of cases), abnormal blood vessels develop in the macula, leading to rapid central vision loss.

AMD treatment involves intravitreal injections of an anti-VEGF drug under local anesthesia. Ranibizumab and aflibercept 2 mg were the first approved treatments for AMD, with a regimen that includes three consecutive monthly induction injections followed by maintenance doses based on disease activity.

These anti-VEGF drugs have allowed better disease control, but 20%-25% of patients still require injections at least every 2 months. To improve the duration of action and avoid patient noncompliance, other anti-VEGF drugs have been developed.

Greater ‘Drying’

Brolucizumab is the first second-generation anti-VEGF to have obtained marketing authorization for AMD in 2020. It is an antibody fragment that targets all isoforms of VEGF-A. The HAWK and HARRIER phase 3 trials demonstrated noninferiority to aflibercept 2 mg.

Brolucizumab was administered with monthly injections for the first 3 months of induction. It was then administered every 2-3 months depending on disease activity, while aflibercept was administered every 2 months during the maintenance phase.

Results showed that brolucizumab was noninferior in terms of visual acuity after 1 year, and this benefit was maintained up to 2 years. Anatomically, brolucizumab showed superior efficacy, with significantly greater drying of the macula. More than 75% of patients on brolucizumab maintained a 3-month interval between injections.

Faricimab is a bispecific antibody targeting both VEGF-A and angiopoietin-2. Its noninferiority to aflibercept 2 mg was demonstrated in the TENAYA and LUCERNE trials. After monthly induction, it was then injected every 2-4 months, depending on disease activity.

In both the TENAYA and LUCERNE trials, faricimab maintained visual acuity at 2 years. At that time, 71% of patients in the TENAYA trial and 81% in the LUCERNE trial had an injection interval of 3-4 months compared with the bi-monthly regimen of aflibercept.

Finally, aflibercept 8 mg was compared with aflibercept 2 mg in the PULSAR trial. After an induction phase of three monthly injections, patients receiving aflibercept 8 mg were able to switch to injections every 2-4 months depending on disease activity.

Again, noninferiority was shown for aflibercept 8 mg. After 2 years, 88% of patients on aflibercept 8 mg maintained an injection interval of at least 3 months.

First-Generation Anti-VEGF Drugs

These three second-generation drugs are now indicated, alongside first-generation anti-VEGFs, for first-line treatment of exudative AMD, but with different administration regimens. For faricimab, the injection interval cannot exceed 4 months during maintenance compared with 5 months for brolucizumab and aflibercept 8 mg.

However, studies have reported differing safety profiles, with brolucizumab being associated with more frequent and severe intraocular inflammation, including retinal vascular occlusions, Mrejen noted. “These occur later, after 6-8 months of treatment.”

In contrast, intraocular inflammations are rare and reversible with both faricimab and aflibercept 8 mg. These typically occur early in treatment, after 2-4 injections. This observation remains to be confirmed in real-world practice with aflibercept 8 mg, “for which we have less experience.”

These findings suggest that first-generation anti-VEGFs still remain a good first-line treatment choice. Ranibizumab and aflibercept 2 mg “have excellent safety profiles and very good efficacy,” said Mrejen.

Cost-Effective Alternatives

The advent of biosimilars for first-generation anti-VEGFs, which are more affordable but still underutilized, also supports the preference for these drugs as first-line options. Ranibizumab biosimilars became available in 2023, while aflibercept biosimilars are expected to launch in 2026.

However, after the induction phase with first-generation agents, “if macular fluid control is not optimal, or it is difficult to extend the injection interval beyond 2 months, it is better to switch to second-generation molecules with more potent efficacy,” said Mrejen.

Among second-generation anti-VEGFs, brolucizumab occupies a unique place due to its less favorable safety profile. “It should be reserved for second-line treatment, especially in more severe forms of AMD,” said Mrejen. Faricimab and aflibercept 8 mg, which are better tolerated than brolucizumab, are not recommended as first-line agents “in the case of prior inflammation.”

Ultimately, the use of these new anti-VEGF drugs requires personalized care, with an emphasis on evaluating prior inflammation history before prescribing. Mrejen stressed the importance of having clear communication with patients to explain the early warning signs of intraocular inflammation, such as pain, redness, or blurred vision. In the event of inflammation, patients should be referred for urgent consultation.

Precautionary Approach

In the case of inflammation under second-generation anti-VEGFs, opinions remain divided on the best course of action to prevent further deterioration into retinal vasculitis. This was revealed during a discussion following the presentation of the session on exudative AMD.

Mrejen recommended that once intraocular inflammation resolves, patients should switch to a first-generation molecule. Paris-based ophthalmologist Maté Streho, MD, argued that the therapeutic switch should depend on the severity of the inflammation, especially given patients’ reluctance to have more frequent injections.

The session moderator, Stéphanie Baillif, MD, PhD, head of the Department of Ophthalmology at the Nice University Hospital, Nice, France, reminded the audience that inflammation under second-generation anti-VEGFs primarily occurs during the induction phase, “after the first two or three monthly injections.” According to her, patients typically accept switching to a first-generation molecule at this point.

The risk also depends on the type of anti-VEGF used. In the case of inflammation under brolucizumab, switching to another second-generation anti-VEGF (faricimab or aflibercept 8 mg) may be considered. However, this is not the case for the reverse scenario. Until more data are available to guide strategies, the precautionary principle should be applied by opting for the better-tolerated molecules, said Baillif.

This story was translated from Medscape’s French edition.