T&E with anti-VEGF agent optimizes visual outcomes in patients with nAMD

Case 1: Early T&E strategy in a patient with newly diagnosed PCV
History and presentation
A 79-year-old male patient was diagnosed with neovascular age-related macular degeneration (nAMD) of the polypoidal choroidal vasculopathy (PCV) subtype and subretinal fluid (SRF) in the left eye in November 2018 via indocyanine green angiography (IGA), fundus fluorescein angiography (FFA) and optical coherence tomography (OCT). Baseline visual acuity (VA) in the left eye was 0.2. His right eye had been blind for several years, with no light perception due to chronic untreated retinal detachment.

The patient’s left eye also had glaucoma, which was controlled with brinzolamide plus brimonidine and latanoprost plus timolol. It had a cup/disc ratio of 0.7 with stable intraocular pressure of 12 mm Hg and stable OCT/visual field findings.

Treatment
The patient received photodynamic therapy (PDT) to the left eye shortly after PCV diagnosis, followed by three consecutive monthly intravitreal injections of the anti–vascular endothelial growth factor (anti-VEGF) agent, aflibercept, between December 2018 and February 2019, which led to PCV resolution. A pro re nata (PRN) approach with aflibercept was initially followed, but after 6 months, the patient’s PCV recurred. Aflibercept treatment had to be reinitiated, with the first three monthly loading doses administered in August, September and October 2019, followed by an additional dose in November 2019. After these four doses, the patient entered a treat-and-extend (T&E) protocol, where injection intervals were increased by 2- to 4-weekly increments. Subsequent aflibercept injections were administered in January, May, August and December 2020, in March, July and November 2021, in January, April and August 2022, and with two latest doses given in January and April 2023. (Figure 1) Incidentally, the patient also had cataract surgery on his left eye in July 2020, which did not impact aflibercept’s T&E schedule.

Currently, the patient is maintained on Q16W–Q18W intervals for his aflibercept injections, on average receiving three injections per year. He has not experienced any disease recurrence with the T&E protocol based on regular OCT follow-ups, and has not reported any adverse events (AEs).

Case 2: Switching to T&E aflibercept in a patient with recurrent nAMD
History and presentation
A 67-year-old female initially consulted in June 2015 for blurred vision in the right eye. IGA, FFA and OCT led to diagnosis of nAMD of the PCV subtype. Baseline OCT, in particular, showed active disease with haemorrhages, polyps, SRF, and retinal pigment epithelial detachment (PED). (Figure 2A) Baseline VA in the right eye was 0.8

Treatment
The patient initially received three consecutive monthly intravitreal injections of an anti-VEGF agent, ranibizumab (3 July, 30 July and 28 August 2015), followed by PDT (30 September 2015), which was based on the treatment protocol used in the 24-month phase IV EVEREST II study in patients with symptomatic macular PCV.¹ However, OCT findings on 16 October 2015 showed increased SRF and haemorrhages, with VA worsening to 0.6. (Figure 2B)

The patient was switched to another anti-VEGF agent, aflibercept, which was just approved in Hong Kong at that time. She received three consecutive monthly loading intravitreal injections of aflibercept between October and December 2015.² On 22 January 2016, OCT findings showed resolution of the PCV, which was also associated with improvement in VA to 0.7. (Figure 2C) Although a T&E protocol was recommended, the patient opted for a PRN regimen with monthly follow-ups.

Although the patient’s VA remained stable at 0.7–0.8 while on the PRN regimen for several years, she experienced several recurrences or incomplete resolution of the PCV after several months of no treatment based on the OCT findings. This resulted in reloading of aflibercept treatment every time PCV was assessed to be active.

On 10 June 2016, 6 months after the first three loading doses of aflibercept, the patient’s disease recurred, and she received three aflibercept doses (July to September 2016, Q4W) and PDT, which led to PCV resolution. (Figure 2D) After 1 year, PCV recurred and she again received three doses of aflibercept (September to November 2017, Q4W). PCV recurred yet again after 6 months, and the patient received another three doses of aflibercept (May to July 2018, Q4W). At that time, PCV recurred 1 month after the last dose. After this, she received PRN injections of aflibercept in October 2018 and in January, March, May and June 2019. She received PDT in April 2019, followed by focal ablation in August 2019.

Due to the waxing and waning nature of her condition with PRN aflibercept treatment, the patient eventually agreed to follow the T&E protocol. She received aflibercept injections in September, October and November 2019, then in January, February, April, May, July and August 2020. (Figure 3) Currently, the patient receives aflibercept injections Q8W–Q12W, with VA nd OCT of her right eye remaining stable with this approach, which allows easy adjustment of visit frequency. (Figure 2E) The patient has not experienced any treatment-related AEs.

Discussion
AMD is one of the leading causes of visual impairment worldwide, accounting for 1.8 million cases of blindness in 2020.^3,4 The PCV subtype, in particular, is known to be more prevalent among East Asians compared with Caucasians, with a prevalence rate of approximately 22 percent to over 50 percent vs 8–13 percent.^5-7

Intravitreal anti-VEGF injections are currently the standard of care for nAMD, including PCVs.⁸ For PCVs, PDT may be added to anti-VEGF, but long-term visual prognosis remains controversial.^9,10 Since this is a chronic progressive disease, affected eyes initially require monthly injections, which poses a heavy treatment burden on both the healthcare system and patients. While as-needed injections can be used, the PRN approach has been associated with undertreatment and poorer visual outcomes vs the fixed dosing regimen. With current anti-VEGF agents allowing longer intervals between injections, the T&E strategy has emerged as the preferred approach to achieve optimal visual outcomes while reducing treatment burden.^8,11-13

T&E is a proactive, individualized dosing strategy for patients with nAMD, which allows gradual extension of intervals between intravitreal injections if functional and anatomic stability is maintained. However, in case of deterioration, injection intervals can be shortened, helping pre-empt disease recurrence instead of responding to it. This strategy may also lessen the burden of clinic visits, making it more convenient for patients and helping facilitate better planning of public healthcare service capacity in the long run.^14-16

Currently available anti-VEGF agents approved for nAMD in Hong Kong include ranibizumab, aflibercept, brolucizumab, and faricimab. Compared with ranibizumab and brolucizumab, aflibercept is noted to have the highest binding affinity and potency and the longest estimated intravitreal half-life, affording the longest estimated VEGF suppression time (aflibercept, 71 days; brolucizumab, 51 days; ranibizumab, 36 days).^8,17-21

Aflibercept’s long-term efficacy and safety were demonstrated in ALTAIR, a 96-week, randomized, open-label phase IV study in Japan involving treatment-naïve adult patients ≥50 years of age with nAMD. Results showed that after three monthly doses, aflibercept 2 mg administered according to a T&E dosing protocol was continuously efficacious (ie, improved mean change in best-corrected VA from baseline and reduced mean change in central retinal thickness) and safe throughout the study. Importantly, aflibercept administered using either a 2- or 4-week adjustment T&E regimen resulted in large proportions of patients (ie, 41.5 percent and 42.3 percent, respectively) achieving and maintaining a Q16W dosing interval until study completion, consistent with our patient’s experience in case 1.²² In fact, case 1 patient initiated the T&E regimen immediately after the first episode of recurrence with the PRN regimen. This prompt switch may have stabilized his disease earlier and facilitated achieving up to Q18W dosing intervals with aflibercept.

In Hong Kong, the T&E regimen is recommended and offered to as many eligible patients as possible. Approximately 80 percent of patients initially follow the PRN regimen, with up to 80 percent of these patients experiencing recurrence. Possible reasons for initially following the PRN regimen include patient preferences, which was true for our patient in case 2, inconvenience (ie, frequent clinic visits), treatment costs, and fatigue and psychological unpreparedness for chronic management. Although the Hospital Authority (HA) provides assistance to many eligible patients requiring a T&E regimen, implementation of this strategy is limited by manpower and resource availability.⁸

Our patient’s experience in case 1 highlights the advantages of aiming for a T&E regimen with aflibercept early in the course of the disease, which may result in improved functional and anatomic outcomes, facilitating longer treatment intervals (ie, Q16W to Q18W) due to more stable disease and concomitantly, fewer injections per year (ie, he currently receives approximately three aflibercept intravitreal injections per year). Meanwhile, case 2 demonstrates the challenges associated with a PRN strategy in the long term, namely, multiple recurrences which may have resulted in irreversible functional and anatomical damage, concomitantly affecting our patient’s ability to achieve a longer dosing interval (ie, Q16W). However, despite the late-start T&E regimen, case 2 patient’s functional and anatomic outcomes still improved, demonstrating aflibercept’s efficacy despite previous nAMD recurrences.

Importantly, consistent with the drug label and results of ALTAIR, both patients tolerated their aflibercept treatment well, with no reported AEs associated with intravitreal injections (eg, conjunctival haemorrhage, infection and endophthalmitis) or any systemic AEs associated with aflibercept (eg, nonocular haemorrhages and arterial thromboembolic events).^18,22

In summary, our patients’ positive experience with aflibercept demonstrates the long-term efficacy and safety of a T&E strategy in optimizing visual outcomes, consistent with current recommendations and available clinical data. Early initiation of a T&E regimen is ideal to ensure faster optimization of treatment and stabilization of nAMD, which may allow for longer treatment interval durations.