Switching to a new anti-VEGF improves visual outcomes in a patient with recalcitrant nAMD

Dr. Nicholas Fung
Specialist in Ophthalmology, Clinical Assistant Professor
University of Hong Kong and Grantham Hospital
Hong Kong
15 Jun 2022
Switching to a new anti-VEGF improves visual outcomes in a patient with recalcitrant nAMD

History, presentation and treatment
The patient is a 62-year-old male who started to experience blurred vision in his left eye in November 2015. Previously, he was diagnosed with neovascular age-related macular degeneration (nAMD) in the right eye (polypoidal choroidal vasculopathy [PCV] subtype) in January 2012, which is currently maintained with Q4W intravitreal injections of the anti-vascular endothelial growth factor (anti-VEGF) agent, aflibercept. A treat-and-extend (T&E) regimen with aflibercept could not be achieved with the right eye since nAMD recurred every time treatment intervals were increased beyond Q4W. As of May 2022, he has received in excess of 70 intravitreal injections of aflibercept to the right eye, which has a stable but poor visual acuity of 1/60.

The patient has been monitored regularly with optical coherence tomography (OCT) on both eyes since 2012 due to the nAMD in his right eye. Prior to the report of blurred vision in November 2015, his left eye was noted to have pigment epithelial detachment and drusen with a baseline visual acuity of 0.8.

At the time of reporting blurred vision, visual acuity in the left eye had reduced to 0.6. OCT confirmed nAMD and the patient was given three injections of anti-VEGF fragment, ranibizumab, at 4-weekly intervals plus photodynamic therapy (PDT), which appeared to be successful. The left eye did not require any further treatment until July 2016 when a breakthrough vitreous haemorrhage (likely a type of PCV) occurred, necessitating vitrectomy with injection of air.

The quiescent disease in the left eye required no further treatment over the next 3 years. However, regular fundus fluorescein angiography and OCT identified disease recurrence in July 2019, whereupon the patient started to receive aflibercept injections to the left eye. He originally received aflibercept Q4W between July and September 2019, followed by a successful extension to 8-week intervals between October 2019 and February 2020, when the intervals had to be reduced to 6 weeks due to accumulation of subretinal fluid and insufficient control of nAMD in the left eye. Between February and December 2020, the patient continued to receive aflibercept at 4- or 6-week intervals, followed by successful treatment interval extension to 8 weeks between January and July 2021.

However, poor response to aflibercept with resumed accumulation of subretinal fluid was noted in August 2021, and the patient was switched to a newer anti-VEGF, brolucizumab, which had recently become available in Hong Kong.1 Shortly after the first brolucizumab injection, OCT showed decreased subretinal fluid in the left eye as well as a reduction of central macular thickness from 542 μm to 309 μm. (Figure) There was still some thickening under the retinal pigment epithelium, but a marked reduction in retinal fluid was noted. Visual acuity improved to 0.8.

HK-NOV-317md_01

The patient received his second dose of brolucizumab in September, 4 weeks after the first dose, followed by a 6-week interval, with the third dose taking place in November 2021. The dosing intervals were then successfully extended to 10 weeks in January 2022 and subsequently to 12 weeks, with the latest dose administered in April 2022. The next injection of brolucizumab is planned for July 2022.

As of May 2022, the patient has received a total of five brolucizumab injections, with no sign of recurrence or active disease, and experienced no adverse events (AEs).

Discussion
AMD is a leading cause of adult blindness worldwide, especially in those >60 years of age.2 In Hong Kong, a cross-sectional survey conducted between 2016 and 2017 reported an estimated prevalence of early AMD ranging from 0.17 percent among those aged 40–49 years to 7.51 percent among those age ≥70 years.3 Prevalence is expected to increase due to ageing population, precipitating the need for effective and durable treatment options, especially in patients with refractory or recalcitrant disease (ie, those with active disease despite aggressive Q4W treatment or those unable to achieve increased treatment intervals due to recurrence or worsening of disease), like our patient.2–5

Intravitreal anti-VEGF injections are currently the standard of care for nAMD. Since nAMD is a progressive disease, a fixed injection interval of 4 weeks may be needed to achieve optimal disease control. However, such frequent injections pose a heavy burden on both ophthalmologists and patients. Thus, a T&E regimen is usually attempted to achieve a balance between treatment burden and vision improvement.2

Of the anti-VEGF agents available for nAMD in Hong Kong, aflibercept and brolucizumab are considered more durable than ranibizumab and may thus help achieve increased treatment intervals.2,4

In terms of efficacy and safety, a 96-week follow-up of two similarly designed phase III trials, HAWK and HARRIER, compared aflibercept vs brolucizumab in patients with treatment-naïve eyes with nAMD. Results showed that brolucizumab was associated with vision gains (ie, mean best-corrected visual acuity [BCVA]) comparable to aflibercept, and with superior resolution of intraretinal fluid and subretinal fluid vs aflibercept while increasing the probability to extend treatment interval up to Q12W. Both treatments were well tolerated, suggesting that brolucizumab may offer better disease control and reduced treatment burden vs aflibercept in patients with nAMD.6

Switching anti-VEGF treatments may be appropriate for select patients to achieve extended injection intervals, thus reducing treatment burden.4,5 In our patient’s case, this was not considered for the right eye, as little or no improvement was anticipated due to the chronicity of nAMD and the presence of scarring following multiple injections. Meanwhile, his left eye had better baseline anatomical and functional vision status and was thus considered for switching to brolucizumab.

Our patient’s positive outcome with switch therapy for his left eye is consistent with results of REBA, a retrospective observational real-world study on the efficacy and safety of intravitreal brolucizumab therapy in patients with nAMD regardless of prior treatment.7

REBA enrolled 78 consecutive patients (105 eyes), including treatment-naïve and switch-therapy patients (ie, those who presented with either fluid recurrence, fluid recalcitrance, or inability to extend beyond Q4W/Q6W regimens with ranibizumab or aflibercept). After a mean follow-up of 10.4 months, significant mean BCVA gains of +11.9 ±3.9 letters (p=0.011) and +10.4 ± 4.8 letters (p=0.014) vs baseline were achieved in the treatment-naïve and switch-therapy groups, respectively. Central subfield thickness was also significantly decreased in both groups. Two patients in the switch-therapy group experienced AEs (ie, vascular occlusion and macular hole), but they recovered uneventfully.7

Since brolucizumab is a relatively new anti-VEGF, careful patient selection, including prior good tolerance of intravitreal injections, and more frequent monitoring are recommended to optimize results and reduce the risk of AEs (as the risk of intraocular inflammation tends to increase after several injections) while aiming for less frequent injections.8,9 At Grantham Hospital, we employ a T&E protocol with brolucizumab where eligible patients with nAMD are administered 6 mg of intravitreal brolucizumab injections Q4W for the first three doses, followed by reassessment of disease activity 16 weeks (4 months) after treatment initiation. To remain on schedule, patient assessments are performed 1 week before their scheduled injections. Those with no disease activity may receive injections on an as-needed or T&E basis.

Our patient’s positive experience demonstrates that switching treatment from aflibercept to brolucizumab can improve functional and anatomical outcomes in recalcitrant nAMD and may help reduce treatment frequency with a T&E regimen.

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