Clinical outcomes of switching to aflibercept using a pro re nata treatment regimen in patients with neovascular age-related macular degeneration who incompletely responded to ranibizumab

Neovascular age-related macular degeneration (nvAMD) is one of the leading causes of visual impairment in the population aged over 50 years of age [1]. The prevalence of sight threatening nvAMD is predicted to increase with time [2].

The mainstay of treatment for nvAMD is with intravitreal administration of drugs targeting vascular endothelial growth factor (VEGF). Ranibizumab (RBZ) [Lucentis, Genentech, San Francisco, California, USA] was first licensed by the Federal Drug Administration (FDA) for the treatment of nvAMD in 2006 and became the most widely used anti-VEGF agent. RBZ is a monoclonal antibody fragment that specifically targets VEGF-A [3]. Large multicentre clinical trials have demonstrated that RBZ intravitreal therapy (IVT) stabilises long-term best-corrected visual acuity (BCVA) in the majority of patients with nvAMD and improves BCVA in a minority of patients [4, 5]. However, maintaining a frequent treatment schedule for patients with nvAMD is difficult for patients and places a heavy burden on health services [6]. As a result a number of variable treatment, follow-up and dosing schedules have been developed including pro re nata (PRN) strategies [7‐9]. Despite RBZ treatment some patients with nvAMD continue to demonstrate persistent macular fluid [10]. Taken together this points to the need to test alternative treatments for nvAMD in patients who are incompletely treated with RBZ IVT.

Aflibercept (AFL) [Eylea, Regeneron, Tarrytown, New Jersey] was FDA-approved as an alternative anti-VEGF treatment for nvAMD in late 2011. AFL is a recombinant fusion protein consisting of VEGF-binding portions from the extracellular domains of human VEGF receptors. These protein domains are fused to the Fc portion of a human immunoglobulin to improve their half-life [11]. AFL mimics VEGF target receptors and acts to trap both VEGF-A, VEGF-B and placental growth factor reducing downstream effects of these chemokines. Multicentre clinical trials have also confirmed the clinical efficacy of AFL in the treatment of nvAMD [12]. Additionally, AFL has also been shown to reduce persistent macular fluid in cases of nvAMD which appear refractory to treatment with RBZ [13, 14]. AFL has been found to have a higher binding affinity for VEGF than RBZ which predicts a lower required concentration and potentially longer clinical effect [15]. AFL administered at an interval of two months after 3 initial monthly loading doses, was found to be non-inferior to RBZ in treatment-naive eyes [12]. The less frequent treatment regime with AFL and reduced cost of AFL compared with RBZ treatment for nvAMD also has potential implications for improved cost-utility when compared with RBZ in a PRN dosing schedule [16].

Increasingly patients who have initially been treated with RBZ are being switched to AFL. However, there is a relative dearth of real world clinical data on the effect of switching patients using a PRN treatment strategy. In this study we describe the effects of switching to AFL PRN therapy in AMD patients who had recurrent nvAMD despite a RBZ PRN schedule at a regional AMD treatment centre in the United Kingdom.

This study compared visual and anatomical outcomes in nvAMD patients who already appeared to have persistent or recurrent nvAMD on RBZ IVT and subsequently transitioned to AFL using a PRN dosing schedule after an initial loading period.

In clinical trials, AFL has been shown to have a similar efficacy and side effect profile to RBZ but with a longer dosing interval [17]. It has been suggested that AFL may be more effective in cases of refractory disease following preclinical studies which have shown that VEGF Trap-Eye binds to VEGF-A with a higher affinity than other anti-VEGF molecules [18]. Additionally, it also acts on other molecules that may result in intra- or sub-retinal fluid such as placental growth factor (PIGF) which are not inhibited by other anti-VEGF drugs [18]. We found that a small number of patients (n = 7) did not require any further treatment after initial AFL loading. However, an equal number were also switched back to RBZ due to worsening of intra- and/or sub-retinal fluid.

The outcomes in this study show that initial visual gains made by RBZ therapy on treatment-naive eyes are gradually lost over time using a PRN schedule of treatment. In our study, BCVA and CRT showed significant correlation in stage 1 but not in stages 2, 3 or 4. This suggests that at early stages BCVA may mainly be affected by intra- or sub-retinal fluid which is reflected by CRT. However, at later stages the CRT reflects remaining neuroretinal thickness rather than intra- or sub-retinal fluid. Consequently, higher CRT should lead to better vision. This is supported by findings in stage 4 of our study which found that higher CRT post AFL loading predicted better final BCVA. We did not measure neuroretinal thickness separately in this study. Similar results of a disparity in CRT and BCVA have been found in long term studies with one anti-VEGF agent alone using PRN dosing [10, 19‐21] and following transitioning between anti-VEGF agents [22].

A recent systematic review on patients with treatment-resistant nvAMD on bevacizumab or RBZ subsequently switched to AFL concluded that switching led to significant improvement in CRT but only static BCVA [23]. In contrast, we found that there was gradual deterioration in CRT and BCVA with AFL PRN therapy following an initial improvement with AFL loading. This difference in outcomes might be explained by the longer mean follow-up period (24 months) after AFL switch in our study compared to that of the studies (6–12 months) included by Spooner et al. [23] in their review. A likely interpretation is that a follow-up period of 12 months might not be long enough to capture the full long-term effects of switching to AFL.

There has already been some evidence that outcomes in routine clinical practice for new medications do not match the outcomes found in clinical trials where there are stringent inclusion and exclusion criteria and strict follow-up schedules [24, 25]. A potential cause of the deterioration of vision in stage 2 and the subsequent non-significant improvement of vision and significant improvement in CRT after AFL loading could be under treatment. In this study, patients were treated using a PRN protocol. However, this study compares well with recently published PRN treatment clinical trials when comparing numbers of injections per eye per year. The PrONTO study applied 9.9 injections per eye over two years using OCT guided increase in fluid as a guide to retreatment [7]. This approximates to 0.41 RBZ injections per eye per month. A comparable 0.37 RBZ injections were performed per eye per month in this study. Additionally, we did not find that the number of injections predicted better outcomes in the analysis of this study which suggests that the patients were not significantly undertreated.

There is increasing evidence that tachyphylaxis with anti-VEGF agents may play a part in reduction of clinical efficacy with time [26, 27]. In our study, some of the effect may also be a result of tachyphylaxis to RBZ and the subsequent benefit of switching anti-VEGF agents. It is unclear whether a change to another anti-VEGF agent such as bevacizumab would also have resulted in similar short term improvements as has been reported elsewhere [28]. Tachyphylaxis to AFL treatment may also explain the progressive worsening of visual acuity and CRT following longer term treatment with AFL in stage 4 [29]. In our study only seven patients were reverted back to RBZ due to clinical failure of AFL. It would be interesting to see the effects on CRT and BCVA of switching back more patients to RBZ in a future study in order to estimate the effect of tachyphylaxis on clinical response.

A limitation of our study may be the retrospective review of notes to obtain data. The retrospective data relies on the quality of record keeping to ensure accuracy of the data and may particularly affect history, examination findings and BCVA. Nonetheless, measurements were taken at each visit and as a result an objective measure of CRT was obtained for each time point.

Long-term data comparing RBZ and AFL injection frequency has suggested a reduced required injection frequency with AFL using a treat and extend protocol [30]. However, we found that the number of injections required for treatment increased with an AFL PRN treatment regime. 0.47 AFL injections per eye per month were performed compared to 0.37 RBZ injections per eye per month. Our study is unable to provide direct comparison of injection rates as no control group was used and AFL treatment was performed on those previously treated with RBZ and not on treatment naïve patients. Despite the increased injection rate with AFL we continued to notice a decline in visual acuity again confirming that a degenerative process may have already started prior to switch which could not be halted by AFL therapy. A future study plans to examine a cost-benefit analysis of transitioning patients to AFL on a PRN basis as we found that there was an increase in the number of injections required with AFL which may negate the possible cost savings reported [22].

In summary, this study finds that in patients with nvAMD who are treated with PRN RBZ therapy, macular anatomy is significantly improved following AFL loading. However, this real world clinical data shows that, in the longer term, AFL does not halt the slow deterioration in BCVA and CRT which occurs in patients switched from RBZ despite a higher injection rate using PRN AFL dosing.