International Journal of Ophthalmic PathologyISSN: 2324-8599

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Research Article, Int J Ophthalmic Pathol Vol: 4 Issue: 4

Progress and Outcome of Therapeutic Switch to Aflibercept in Patients with Age-Related Macular Degeneration (AMD) Resistant to Bevacizumab

Arturo Alberto Alezzandrini, Paula Cecilia Serraino Barberis*, María Agustina Tammaro and María Belen García
Oftalmos Institute Oftalmologico, University of Buenos Aires - School of Medicine, Buenos Aires, Argentina
Corresponding author : Paula Cecilia Serraino Barberis
Oftalmos Institute Oftalmologico, University of Buenos Aires - School of Medicine, Buenos Aires, Argentina
Tel: 51(11)48169100
E-mail: [email protected]
Received: September 11, 2015 Accepted: October 21, 2015 Published: October 26, 2015
Citation: Alezzandrini AA, Barberis PCS, Tammaro MA, García MB (2015) Progress And Outcome of Therapeutic Switch to Aflibercept in Patients with Age-Related Macular Degeneration (AMD) Resistant to Bevacizumab. J Ophthalmic Pathol 4:4. doi:10.4172/2324-8599.1000170

Abstract

Objective: The purpose of the study is to evaluate the effect of Aflibercept in patients with age-related macular degeneration who had received prior treatment with Bevacizumab.

Material & Methods: An observational retrospective study was conducted in “Oftalmos, Centro Oftalmológico de Alta Complejidad”. We reviewed the clinical records of 41 eyes that had received at least three (3) intravitreal injections of Bevacizumab (1.25 mg) with a period no longer than 4 weeks between each application, prior switch to Aflibercept (2 mg). Of the selected patients, 27 had a diagnosis of choroidal neovascular membrane (CNVM), 5 had CNVM associated with neuroepithelium detachment and the remaining 9 eyes only had retinal pigment epithelium detachment (RPED). Rotation of anti-VEGF was due to the persistence or increase in central macular thickness observed in spectral domain optical coherence tomography (OCT). All patients received a loading dose of three intravitreal 2 mg Aflibercept injections at 4-week intervals. Evaluation included central macular thickness and maximum pigment epithelium (PED) height measured by spectral domain OCT and best-corrected visual acuity (BCVA) prior to the switch of therapy and 4 weeks after the last Aflibercept injection.

Results: A significant decrease in central macular thickness in spectral domain OCT (= or > 50 μm) was observed in 18 eyes (43.9%). In 17 eyes (41.46%) no changes in thickness were observed after the switch. In the remaining 6 eyes (14.63%) increased thickness was appreciated. There was an improvement in best-corrected visual acuity (= or>4 letters) in 22 patients (53.65%) while 15 (36.5%) maintained the same BCVA and the remaining 4 (9.75%) lost one line.

Discussion: Recent publications suggest that the use of Aflibercept in patients with AMD that do not have satisfactory response to treatment with Bevacizumab, could present better results. Despitethis, they have not yet obtained scientifically significant results. However, it is important to emphasize that both drugs have different mechanisms of action.

Conclusion: Although the number of patients, who had improved with the switch to Aflibercept, is not statistically significant, the rotation of antiangiogenic is a valid option in the absence of response.

Keywords: Age-related macular degeneration; Aflibercept; Bevacizumab; Therapeutic switch; Insufficient response

Keywords

Age-related macular degeneration; Aflibercept; Bevacizumab; Therapeutic switch; Insufficient response

Introduction

Age-related Macular Degeneration (AMD) is the leading cause of irreversible vision loss among individuals aged 50 or older in developed countries. It can be classified into two types: dry (atrophic) AMD and wet (exudative) AMD [1,2]. Advanced wet AMD is characterized by choroidal neovascularization (CNVM), the leakage of new blood vessels can cause edema and disorders in retinal architecture eventually causing blurred and distorted vision. If left untreated, the area of neovascularization can expand rapidly leading to the development of fibrous scarring. Recent studies show that within 3 years of onset of neovascularization, about 75% of untreated patients will present a visual acuity of 20/200 or worse [3].
Several risk factors for AMD have been identified, such as advanced age, genetic predisposition, history of cataract surgery, smoking history, diabetes, ethnicity. Vascular Endothelial growth factor-A (VEGF-A) has been implicated to play a major role in the pathogenesis of the wet AMD [4,5].
VEGF-A and placental growth factor (PIGF) are members of the VEGF family of angiogenic factors which may act as potent mitotic factors, vascular permeability and chemotactic for endothelial cells. Thus the development of new blood vessels is induced from the inner layers of the retina; these new vessels are immature and lose fluid and blood that cause edema and retinal architecture disorders (CNVM). Since VEGF plays an important role in the pathogenesis of CNVM, The treatment for exudative AMD has been revolutionized with intravitreal anti-VEGF therapy: Ranibizumab, Bevacizumab (off label) and Aflibercept [6,7].
Ranizumab, a fragment of monoclonal antibody directed against VEGF is indicated for the treatment of wet AMD and retinal pathologies. Bevacizumab, a humanized full-length monoclonal antibody targeting VEGF-A and all of its isoforms, is primarily designed and approved for the intravenous treatment of metastatic colorectal cancer [8,9] . Although bevacizumab is still off-label for wet AMD treatment, good efficacy and safety in masses of case series and cost-effective make it commonly used in clinical treatment [10].
Aflibercept is a soluble protein that acts as a decoy for all VEGF-A and PlGF isoforms with higher affinity than natural VEGF receptors. Unlike Bevacizumab, which forms multimeric immune complexes that are rapidly cleared from the circulation, Aflibercept forms a very stable complex, 1: 1 with VEGF molecule. By entrapping the VEGF dimer, aflibercept avoids two drug molecules binding to one VEGF dimer. This increase in binding affinity suggests that Aflibercept may have a longer duration in the eye, allowing less frequent administration.
The introduction of intravitreal anti-vascular endothelial growth factor (VEGF) blockade for neovascular age-related macular degeneration (AMD) in the last decade has had a significant beneficial impact on patients with neovascular AMD [11,12]. However, information on long-term functional outcomes on anti-VEGF therapy in neovascular AMD are sparse and limited by decreasing number of patients in follow-up.
The presented study aimed to evaluate eyes anatomically “insufficiently responders” to prior anti-VEGF therapy with Bevacizumab, and the results obtained with the switch to aflibercept..

Materials and Methods

An observational retrospective study was conducted in “Oftalmos, Centro Oftalmológico de Alta Complejidad”.
We selected patients diagnosed with macular degeneration related to age (AMD) that had been rotated to intravitreal treatment with Aflibercept after having shown an inadequate response to treatment with Bevacizumab in the year 2014. Records of 41 patients treated for neovascular AMD were reviewed based on defined inclusion criteria. To select patients insufficiently responding to prior therapy, a two-step selection process was used. The first criterion required that the affected eye had received at least three intravitreal 1.25 mg Bevacizumab injections (Avastin®, Roche, Genetech, USA) with a period no longer than 4 weeks between each application prior to switching to Aflibercept, 2 mg (Eylea®, Bayer, Regeneron, USA). Secondly, the selected eyes had to have evidence of insufficient anatomic response to prior therapy, defined as any persisting or increasing sub- or intraretinal fluid observed in spectral-domain optical coherence tomography (OCT) using the Heidelberg Spectralis® system (Heidelberg Engineering, Heidelberg Germany).
Exclusion criteria was the following: patients who had not received at least one loading dose of three intravitreal injections of Aflibercept (2 mg) at an interval of 4 weeks between each. Three groups were put together according to the pathology diagnosed by OCT Spectralis. The first group of 27 patients had a diagnosis of choroidal neovascular membrane, the second with a total of 5 patients diagnosed with choroidal neovascular membrane associated with detachment of neuroepithelium, and the last group of 9 patients had been diagnosed with a pigment epithelial detachment (PED).
Evaluation included central macular thickness and maximum pigment epithelium (PED) height measured by spectral domain OCT and best-corrected visual acuity (BCVA) prior to the switch of therapy and 4 weeks after the last Aflibercept injection. Using the Spectralis OCT follow up scan functionality, the same areas were scanned at each visit, allowing small changes to be measured more accurately. All anatomical parameters were analyzed by two independent observers who had the same criteria to make the measures.
Evidence of any persisting sub- or intraretinal fluid in any of the scans was considered an insufficient response. OCT scans were compared based on “follow-up” mode of the eye-tracking-assisted Heidelberg Spectralis® system (AutoRescan), allowing precise comparison. The primary outcome was the change in central retinal thickness (CRT) measured by OCT 4 weeks after the third Aflibercept injection, compared to the time of change in therapy. Secondary outcome measures were the change in maximum height of a pigment epithelial detachment (PED) — if present — as well as the change in best-corrected visual acuity (BCVA) using Snellen visual acuity. The change in maximum height of the PED was measured via the software’s ruler tool in μm on the OCT image. Response to treatment was assessed using two criteria, one objective and other subjective. Objectively central macular thickness was measured through OCT Spectralis considering a significant decrease equal to or greater than 50 microns. Regarding the subjective evaluation, clinical improvement post rotation to Anti VEGF was considered a gain of 4 or more letters in the corrected visual acuity.

Results

Response to treatment was assessed using two criteria, one objective and other subjective. With a total of 41 eyes, on 18 (43.9%) there was a significant decrease whereas no changes were observed in 17 eyes. The 6 remaining eyes (14.63%) showed an increase in the thickness (Graphics 1, Table 1).
Graphics 1: Modification of central macular thickness.
Table 1: Visual Acuity Data.
Regarding the subjective evaluation, there was an improvement in best corrected visual acuity in 22 patients (53,65%), while 15 (36.5%) maintained the same VA and the remaining 4 (9.75%) lost 1 line of sight (Graphics 2, Table 1).
Graphics 2: Changes in Visual Acuity.
These patients are being follow up in our clinic monthly. The best results were observed in the patients with choroidal neovascular membrane associated with pigment epithelial detachment. The results obtained were stadistically significant (p<0.005).

Discussion

Recent reports suggest that the use of Aflibercept in patients with age related macular degeneration (AMD) without satisfactory response to treatment with Bevacizumab may present better results [12]. Despite this, scientifically meaningful results still were not obtained. It is important to highlight that both drugs have a different mechanism of action. Bevacizumab is a humanized anti- VEGF monoclonal antibody with recombinant full two binding sites to VEGF- A; effective against all isoforms of VEGF A.
Aflibercept is a recombinant fusion protein formed by portions of the extracellular domains of VEGF and VEGF -1 - 2 Human with Fc of human Ig G1 formulated as isosmotic solution. It is a dimeric glycoprotein with a molecular weight of 97 kDa and an additional 15% of the total molecular mass corresponding to the part of glycosylation (total weight of 115 kDa). It has affinity for all forms of VEGF and PIGF.
As mentioned above Aflibercept has several theoretical advantages over other blockers of VEGF: has a much higher affinity binding to VEGF; unlike Bevacizumab, which only bind to VEGF -A, also it binds to other members of the VEGF family, including VEGFB and placenta growth factor.
Several articles recently published in high ranking journals have reported the results of using Aflibercept in patients with wet AMD classified as poor responders Bevacizumab [13-16]. Although studies were not related, all of them were similar in design and presented a retrospective review of patients with wet AMD. All patients had received numerous injections of Bevacizumab, and had persistent or recurrent macular edema, so all were switched to treatment with Aflibercept.
In our series, 4 weeks after then last Aflibercept intravitreal injection, 18 eyes showed decrease on central macular thickness, 17 eyes showed no changes and 6 eyes showed an increase. Using the Spectralis OCT follow up scan functionality, the same areas were scanned at each visit, allowing small changes to be measured more accurately. Our data are in line with other studies evaluating Aflibercept in cases of neovascular AMD showing insufficient anatomic response to previous anti-VEGF therapy. There is consistency with regard to an anatomical improvement. However, not all studies show a significant gain in visual acuity. Most studies with limited or no vision gain explain their results with the longstanding disease.
It is unclear why all studies find reduced edema following a switch to Aflibercept. Theoretically, all VEGF should be bound by intensive anti-VEGF therapy. Better retinal penetration appears rather unlikely, especially when compared to the much smaller Ranibizumab molecule. The additional binding of the placental growth factor (PlGF) by Aflibercept, its higher binding affinity to VEGF compared to other VEGF inhibitors, or the development of auto-antibodies to prior anti-VEGF therapy, could serve as potential explanations [17-21].
Limitations of our study include small cohort, heterogeneous group of patients with different previous treatments and use of Snellen visual acuity. Patients did not have a routine fluorescein or green indocyanine angiogram before initiating treatment with Aflibercept. This may have helped identify areas of active neovascular tissue from scarring and would have helped identify the type of neovascularization that responds best when neovascularization that responds best when switched to Aflibercept (Figures 1 and 2)
Figure 1: Successive horizontal foveal spectral domain OCT of the right eye of a 70 year old woman previously treated with 4 intravitreal Bevacizumab injections. Since there was persistent subfoveal fluid she was switched from intravitreal Bevaxizumab to intravitreal Aflibercept. (A) Optical coherence tomography without prior treatment shows subfoveal PED with serous component. Visual acuity at baseline is 20/60(B) Optical coherence tomography 30 day after the fourth intravitreal Bevacizumab injections, showing a decrease in PED height, subretinal fluid(C) Optical coherence tomography 28 days after the fourth intravitreal Aflibercept injection, shows complete resolution of the serous component. Visual acuity at the final visit is 20/40.
Figure 2: Successive horizontal foveal spectral domain OCT of the left eye of a 65 year old man previously treated with 9 intravitreal Bevacizumab injections. Since there was persistent subfoveal fluid she was switched from intravitreal Bevaxizumab to intravitreal Aflibercept. (A) Optical coherence tomography without prior treatment shows subfoveal PED with fibrovascular and serous components. Visual acuity at baseline is 20/100(B) Optical coherence tomography 33 days after the ninth intravitreal Bevacizumab injections shows no decrease in the PED height and persistence of subretinal fluid (C) Optical coherence tomography 29 days after the fifth intravitreal Aflibercept injection, shows minimum decrease .Visual acuity at the final visit is 20/100.

Conclusion

Although the number of patients who had improved with the switch to Aflibercept, is not statistically significant, the rotation of antiangiogenic is a valid option in the absence of response.
Bevacizumab and Aflibercept had similar efficacy for bestcorrected visual acuity in the treatment of neovascular age-related macular degeneration. Aflibercept appears to be a valuable tool for the management of patients with poor responses to other antivascular endothelial growth factor drugs. These patients could have anatomic improvement, and the injection intervals could be extended. Recently published work are also limited by the small number of patients, but the results observed after the switch showed anatomical improvement and the need for fewer injections. This is because Aflibercept binds with greater affinity and speed than Bevacizumab to the endothelial growth agents; it is the most powerful anti- VEGF and only Aflibercept blocks the activation of VEGF receptor for PIGF and mediated endothelial cell migration.
Finally, we should mention that Ophthotech has initiated a pivotal Phase 3 clinical program to evaluate the safety and efficacy of Fovista® 1.5mg in combination with anti-VEGF drugs compared to anti-VEGF monotherapy for the treatment of newly diagnosed patients with wet AMD. The trial included patients at approximately 69 centers in North America, South America, Europe and Israel.
Fovista® is designed to target platelet derived growth factor (PDGF) and in combination with anti-VEGF drugs disrupt the formation of abnormal new blood vessels in wet AMD. It prevents PDGF from binding to its natural receptor on pericytes, thus causing pericytes to be stripped from newly formed abnormal blood vessels. Left unprotected, the endothelial cells are highly vulnerable to the effects of anti-VEGF drugs. Because of the ability of Fovista® to induce pericyte stripping from newly formed blood vessels, the administration of Fovista® in combination with anti-VEGF drugs is likely to inhibit abnormal new blood vessel growth associated with wet AMD more effectively than anti-VEGF drugs alone and may also enhance neovascular regression.
Pharmacology studies indicate that Fovista® binds to PDGF-BB, blocking the interaction of this growth factor with the pericyte cell surface receptor PDGF-ß. This results in stripping or death of the pericytes by interrupting the cell survival signals [22,23].

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