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AMD after anti-VEGF

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Dr Sharon Bentley
BScOptom MOptom PhD MPH FAAO FACO
School of Medicine (Optometry), Deakin University

Anti-vascular endothelial growth factor (anti-VEGF) pharmaceutical agents have revolutionised the treatment of wet AMD (Figure 1). There is no doubt these therapeutic agents are having a significant impact on controlling disease progression and improving visual acuity to some degree for many patients. Just how effective the treatment is in improving functional vision and quality of life, and for how long, is less apparent. It is important that we understand which patients are eligible for treatment, exactly what level of functional visual acuity they are left with, how many remain vision impaired and how many remain in need of low vision services.

906-Figure -1

Figure 1. Wet (neovascular) age-related macular degeneration: fundus photograph and
optical coherence tomography scan (see feature image).
Images: Roman Serebrianik, Australian College of Optometry

Prevalence of vision impairment caused by wet AMD

It is estimated that more than 180,000 Australians have vision impairment (visual acuity worse than 6/12 in both eyes that cannot be corrected) and that AMD is a leading contributor to the problem.1 AMD is the leading cause of legal blindness (visual acuity worse than 6/60 in both eyes that cannot be corrected or visual field constriction to within 10 degrees of fixation in the better eye) in Australia and other economically developed countries.1,2

Based on data collected prior to the introduction of anti-VEGF therapeutic agents, about 107,000 Australians are estimated to have vision impairment due to AMD.2 Although only about 20 per cent of all cases of AMD are the wet (neovascular) form rather than the dry (atrophic) form, wet AMD is by far the predominant cause of vision impairment.3,4

The estimated total number of Australians with wet AMD affecting at least one eye is about 108,000 and the number with wet AMD who are vision impaired is about 62,000.2 Given the association of wet AMD with age and the ageing of our population, this public health problem is expected to increase dramatically over the coming decades.2,5

New treatments for wet AMD

Currently, the three main anti-VEGF pharmaceutical agents used to treat wet AMD are ranibizumab (Lucentis, Novartis), becavizumab (Avastin, Roche)* and aflibercept (Eylea, Bayer). They are intravitreally injected.

Lucentis is a humanised antibody fragment that binds all VEGF isoforms and is designed specifically for ophthalmic use. It was the first of these agents to be approved by the Therapeutic Goods Administration (TGA) for treating wet AMD and gained reimbursement through the Pharmaceutical Benefits Scheme (PBS) in 2007.

It is a costly treatment, about $2,000 per injection, and seems to require continual monthly dosages, making it highly burdensome to government, patients and practitioners. To combat the cost in patients who are not eligible for Lucentis through the PBS, practitioners have been using Avastin off-label—in other words, without TGA
approval for treating AMD.

Avastin is a full-length antibody approved for treating some systemic cancers and is considerably less expensive than Lucentis, about $50 per injection. More recently in 2012, Eylea, an engineered protein that binds VEGF, was developed for intravitreal injection and approved and PBS listed for treating wet AMD. While Eylea is similar in cost, its main benefit is a longer serum half-life compared with Lucentis, thus potentially requiring fewer dosages every other month.

Who is eligible for ­treatment?

There are about 18,000 new cases of wet AMD per year in Australia.6  There is no consensus on when to commence anti-VEGF treatment but the UK National Institute for Health and Clinical Evidence (NICE) guidelines suggest treatment should start when visual acuity is 6/12 to 6/96, the lesion is less than 12 DD in size, there is no permanent structural foveal damage and there are signs of progression.7

This seems to be generally consistent with what is occurring in Australian practice, although some practitioners are now also treating recent onset subfoveal choroidal neovascularisation (CNV) in eyes with visual acuity better than 6/12. The PBS does not stipulate a particular level of visual acuity. Based on the NICE criteria and the eligibility criteria of research trials, about 68 per cent of new cases of wet AMD may be eligible for treatment with anti-VEGF agents,8 leaving 32 per cent ineligible.

How effective is the ­treatment?

Several randomised controlled trials have been conducted and systematically reviewed, which demonstrate the effectiveness of Lucentis,9,10 including the landmark `Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularisation in AMD' (ANCHOR)11 and `Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of AMD' (MARINA) studies.12 After 24 months, monthly Lucentis (0.5 mg) appears to stabilise or improve visual acuity in 90 per cent of patients (loss of less than three logMAR lines or 15 letters), as well as reduce retinal thickness and promote resorption of fluid.12

The average improvement in visual acuity with Lucentis is one to two logMAR lines (6.6 letters) in treated eyes compared with a worsening of three lines (14.9 letters) in untreated eyes (Figure 2).12 Just 15 per cent (compared to 48 per cent treated with sham injection) remain legally blind after two years, but about 10 per cent will get worse and 58 per cent will still have mild to moderate vision impairment (visual acuity worse than 6/12, in other words: below the driving standard).12 It should also be noted that outcomes in clinical practice are typically not as favourable as outcomes in controlled clinical trials, where participants are selected according to specific criteria, and usually have a narrower range of disease severity.

906-Figure-2

Figure 2. Monthly treatment with Lucentis compared with sham—change in visual acuity for findings
from the MARINA study. From Cruess et al 2012,9 adapted from Rosenfeld et al 200612

Comparative effectiveness trials, in particular the `Comparison of AMD Treatment Trials' (CATT) and `alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularisation' (IVAN) studies, have demonstrated that the less expensive Avastin (1.25 mg monthly) is as effective as Lucentis (0.5 mg monthly) with regard to improvement in visual function.10,13,14

There are still some concerns that there may be a higher incidence of serious ocular and systemic adverse events with Avastin than with Lucentis, albeit low with both agents.14-16 The results of ongoing trials are expected to determine whether this is actually the case. Likewise, early trials, in particular the `VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD' (VIEW 1 and VIEW 2) studies, suggest that Eylea (2 mg dosed every two months after three initial monthly doses) produces similar efficacy outcomes as Lucentis (0.5 mg monthly).17 As yet, there are no concerns that Eylea causes more adverse events than Lucentis.

Regardless, the outcomes and risks associated with each of these agents are unknown beyond a few years. It is possible that vision outcomes might become sub-optimal after a period of time due to the natural progression of the disease, effects of anti-VEGF undertreatment, or drug tachyphylaxis or tolerance.18

How are new treatments influencing the prevalence of visual impairment?

While we await population-based studies to understand the true impact of anti-VEGF agents, some researchers have estimated that Lucentis treatment decreases the incidence of legal blindness by 72 per cent and the incidence of vision impairment by 37 per cent over two years.8 In addition, a study of blindness registration in Denmark showed a significant reduction of 50 per cent in the incidence of legal blindness attributable to AMD between 2000 and 2010.19 Although the underlying reasons might be more complex, the bulk of the reduction occurred after the introduction of anti-VEGF therapeutic agents in 2006.19 Regardless, the anticipated ageing of our population is likely to outweigh the benefits of anti-VEGF treatments in reducing the risk and prevalence of vision impairment from AMD.20

Study findings taken together are very encouraging and suggest positive outcomes for wet AMD treated with Lucentis, Avastin or Eylea, at least over two years. There is still much room for improvement. While we may see less severe vision impairment, the prevalence of mild to moderate impairment will remain increasingly high. Many patients with wet AMD will remain in need of low vision support. Many can be assisted in primary care, in your practice.

I urge you to follow up your patients undergoing intravitreal anti-VEGF treatment they need you. Provide advice on the treatment, the importance of compliance, counselling on driving where applicable, basic low vision support and refer to a colleague with low vision expertise or a low vision agency when required.

- Dr Sharon Bentley

* Editor's note
Avastin is not indicated for the treatment of wet AMD; its use in this treatment is considered `off label'. The product information for Avastin explicitly states that treatment of various ocular disorders is `unapproved'. There are officially only two registered treatments for wet AMD, Lucentis and Eylea.

References are available from j.megahan@optometrists.asn.au, subject: AMD after anti-VEGF, Low Vision Primer.




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