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Suboptimal responders: Treating anti-VEGF tachyphylaxis

$currentPage/@nodeName Figure 1. OCT scan of an 84-year-old patient with neovascular AMD showing persistent subretinal fluid and pigment epithelial detachment despite eight intravitreal ranibizumab injections. VA is 6/6.


Dr Simon Chen
Retinal specialist and surgeon
Vision Eye Institute Sydney
Conjoint Senior Lecturer 
University of New South Wales


Intravitreal anti-vascular endothelial growth factor (VEGF) drugs have revolutionised the treatment of the neovascular form of age-related macular degeneration (AMD) and are the current standard of care for the condition. These agents work by blocking the actions of VEGF, a substance important in the pathogenesis of neovascular AMD due to its ability to stimulate the growth of abnormal blood vessels underneath the retina.

Anti-VEGF drugs used to treat neovascular AMD

There are three anti-VEGF agents currently available in Australia, all of which have been shown to be safe and effective for the treatment of neovascular AMD in numerous high-quality, large randomised multicentre clinical trials. 

Bevacizumab (Avastin) is a full-length antibody against VEGF and was the first anti-VEGF agent to become available in Australia in 2006. It was designed for intravenous use in the treatment of colon cancer and is not licensed for intraocular use; its use for the treatment of neovascular AMD is off-label. The efficacy and safety of intravitreal bevacizumab has been confirmed in the IVAN and CATT trials.1-2

Ranibizumab (Lucentis) is an anti-VEGF antibody fragment, which was designed for ocular use. It was first listed on the Pharmaceutical Benefits Scheme (PBS) in 2007 for the treatment of subfoveal choroidal neovascularisation (CNV) due to AMD. The efficacy and safety of monthly ranibizumab was demonstrated in the MARINA and ANCHOR trials.3-4

Aflibercept (Eylea) is a decoy receptor produced by fusing DNA sequences from VEGF receptors onto a human antibody backbone, known as the Fc region. This is the most recent addition to our treatment armamentarium against neovascular AMD and was first listed on the PBS in November 2012. The efficacy and safety to aflibercept was proven in the VIEW 1 and VIEW 2 trials.5

The visual results reported for each of the three anti-VEGF agents after one year of treatment are impressive and broadly comparable, with all drugs maintaining visual acuity (VA), defined as losing less than 15 ETDRS letters, in approximately 95 per cent of patients, and leading to a marked improvement in VA, defined as gaining at least 15 ETDRS letters, in 30 per cent to 40 per cent of patients.

There is ongoing debate among experts regarding subtle differences between the agents in relation to duration of efficacy, effectiveness in reducing subretinal fluid, the frequency of injections required, ocular side-effects such as uveitis and progression of geographic atrophy, as well as concerns about systemic cardiovascular risks. It is currently uncertain how much of the observed differences are genuine drug effects or simply due to random chance.

With the increasing numbers of patients with neovascular AMD needing regular anti-VEGF injections in Australia, the issue of frequency of injections is important. More frequent injections impose a psychological, financial and logistic burden on patients and their carers, expose patients to the risks of endophthalmitis and retinal detachment associated with injections, and are expensive for the health-care system.

The VIEW 1 and 2 trials demonstrated that aflibercept injected every eight weeks is clinically equivalent to ranibizumab injected every four weeks for maintaining VA over one year.5 The potential advantage of aflibercept to achieve similar efficacy and safety results with fewer intravitreal injections than required with ranibizumab has led it to become one of the fastest-growing medicines in the history of biotechnology.

Suboptimal responders to anti-VEGF treatment

Despite the excellent results reported in clinical trials and routinely seen in clinical practice, many patients require continued monthly anti-VEGF injections on a long-term basis because of persistent fluid exudation in the macula from leaking CNV. In the CATT trial, persistent fluid was demonstrated on ocular coherence tomography (OCT) at one year in 56 per cent of patients receiving monthly injections of ranibizumab.2 It is possible that resolution of this fluid might result in improved visual outcomes.

Some patients have a good initial response to treatment with resolution of fluid exudation, but then later become resistant to further treatment and develop recurrent exudation with vision loss. The mechanism of this resistance to treatment is not well understood but tachyphylaxis, that is, a diminishing response to repeated doses of a drug, may be an important factor.6

Patients who develop persistent or recurrent macular fluid exudation following anti-VEGF treatment can be termed `suboptimal responders'. Potential strategies employed to treat suboptimal responders include increasing the frequency of treatment, increasing the dose of the anti-VEGF agent used, or using a drug with a higher VEGF-binding affinity.

Recent data on switching therapy to aflibercept

Anecdotally, retinal specialists commonly find that individual patients respond better to one anti-VEGF agent than to another (Figures 1 and 2). Following the introduction of aflibercept, there has been a plethora of recently published studies from the United States, each reporting a beneficial response from switching treatment to aflibercept in patients who are suboptimal responders to bevacizumab or ranibizumab.

Five of these studies are retrospective case series reports from different research groups spread throughout the USA.7-11 Each report describes the treatment results for a group of between 28 to 94 patients (with a collective total of 296 eyes of 272 patients) who had been classified as suboptimal responders to an average of 17 to 29 bevacizumab or ranibizumab injections. All patients had their anti-VEGF treatment switched to aflibercept and received a minimum of three aflibercept injections with subsequent follow-up ranging from three to six months.

Ph 792 Figure 2

Figure 2. OCT scan of the same patient as in Figure 1 showing complete resolution
of subretinal fluid and pigment epithelial detachment four weeks after a single
intravitreal aflibercept injection. VA had improved to 6/24.

All of the published papers demonstrated a statistically significant anatomical improvement, with a reduction or elimination of macular fluid exudation demonstrable on OCT scanning occurring in 50 per cent to 91 per cent of patients.

A switch study by Kumar and colleagues involving 34 eyes of 33 patients showed no improvement in VA after switching to aflibercept at three months, but did demonstrate a significant improvement in VA at six months after initiating aflibercept treatment.10

The authors suggest that in suboptimal responders to previous anti-VEGF agents, the response to treatment with aflibercept may be different from the treatment to naïve eyes evaluated in clinical trials, such that an improvement in VA requires more time and a greater number of injections to become apparent. The other recently published switch studies demonstrated no change in VA despite the anatomical improvements, although two of the studies had follow up of less than six months.7,9

A study by Yonekawa and colleagues of 102 eyes of 94 patients who were switched to aflibercept after a suboptimal response to multiple bevacizumab or ranibizumab injections reported that switching to aflibercept reduced the injection burden by enabling an increase in the interval between injections from 7.2 weeks prior to switching, to 9.5 weeks after initiating aflibercept treatment.11

Mechanism of action of aflibercept in suboptimal responders

There are various potential mechanisms that may explain the improved anatomic changes seen after switching suboptimal responders to aflibercept.

Aflibercept has a significantly higher binding affinity in vitro to VEGF compared with bevacizumab and ranibizumab.12 The intravitreal half-life of aflibercept is 4.7 days in rabbit eyes, which is longer than ranibizumab (2.9 days) and bevacizumab (4.3 days). The combination of a higher binding affinity and longer half-life has led to a calculated duration of effect of an intravitreal injection of aflibercept of six to 12 weeks in human eyes compared to four weeks for ranibizumab.13

In contrast to bevacizumab and ranibizumab, which bind only to the VEGF-A isoform of VEGF, aflibercept has additional mechanisms of action by also blocking the effects of the VEGF-B isoform as well as a substance related to VEGF called placental growth factor.14 VEGF-B and placental growth factor have been implicated in pathogenesis of neovascular AMD.

Tachyphylaxis may develop following repeated anti-VEGF injections possibly due to the formation of neutralising antibodies to bevacizumab or ranibizumab.15 By switching to a new anti-VEGF such as aflibercept, tachyphylaxis to the previous agents is avoided.


The use of aflibercept by Australian retinal specialists to treat neovascular AMD has increased rapidly since it was listed on the PBS in December 2012. Many patients have been switched from ranibizumab to aflibercept with the goal of extending treatment intervals or achieving better responses for refractory cases.

With increasing clinical experience, published data is rapidly accumulating to indicate that switching to aflibercept is effective in producing anatomical improvements in the macula while maintaining VA in patients who are suboptimal responders to bevacizumab or ranibizumab.

  1. Chakravarthy U, Harding SP, Rogers CA et al. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomised trial. Ophthalmology 2012; 119: 7: 1399-1411.
  2. Martin DF, Maguire MG, Fine SL et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011; 1897-1908.
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  11. Yonekawa Y, Andreoli C, Miller JB et al. Conversion to aflibercept for chronic refractory or recurrent neovascular age-related macular degeneration. Am J Ophthalmol 2013; 156: 29-35.e2.
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  13. Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol 2008; 92: 667-668.
  14. Papadopoulos N, Martin J, Ruan Q et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis 2012; 15: 171–185.
  15. Gasperini JL, Fawzi AA, Khondkaryan A et al. Bevacizumab and ranibizumab tachyphylaxis in the treatment of choroidal neovascularisation. Br J Ophthalmol 2012; 96: 14-20.

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