February 2014, Issue 66

Treatment of Exudative AMD That Responds Poorly to Initial Anti-VEGF Therapy

Michael W. Stewart, MD Associate Professor of Ophthalmology Chairman, Department of Ophthalmology Mayo Clinic Florida

Treating exudative age-related macular degeneration (AMD) with drugs that prevent binding of vascular endothelial growth factor (VEGF) to its cognate receptors improves macular morphology and visual acuity in over 70% of eyes.^1-3 Only 5% of treated eyes lose more than 15 letters of vision but 55% to 71% have persistent fluid (retinal edema, subretinal fluid, or retinal pigment epithelial detachment) despite monthly injections of ranibizumab (Lucentis, Genentech, S. San Francisco, CA/Roche, Basel, Switzerland) or bevacizumab (Avastin, Genentech, S. San Francisco, CA/Roche, Basel, Switzerland).¹ Additionally, a small proportion of eyes that respond favorably to initial therapy subsequently develop tachyphylaxis.⁴ The remainder of this article will discuss treatment strategies for suboptimal responders.

Primary non-responders should prompt the surgeon to question the accuracy of the original diagnosis and perform a reassessment with optical coherence tomography (OCT) (including enhanced depth imaging), fluorescein angiography and, in some cases, indocyanine angiography (ICG). These ancillary tests can help to rule out masquerade conditions such as central serous chorioretinopathy, polypoidal choroidal vasculopathy and macular dystrophies, for which other therapies may be more appropriate.

Quadrupling the dose of an anti-VEGF drug to treatment-naïve eyes is not associated with a similar increase in the magnitude of vision improvement,^2,3 but switching poorly responsive eyes from 0.5 mg ranibizumab to 2.0 mg ranibizumab further improves macular thickness by -33 μm to -40 μm and visual acuity by +3.3 to +4.1 letters at 3 to 6 months.^5,6 Unfortunately, a 2.0 mg ranibizumab dose is not commercially available, and the incremental efficacy of lower doses (e.g. 1.0 mg/0.1 ml) in poorly responsive eyes is unknown. Higher drug doses/volumes of available anti-VEGF drugs increase the intraocular pressure and frequently mandate anterior chamber paracenteses to re-establish central retinal artery perfusion.

Increasing the frequency of anti-VEGF injections improves visual acuity and retinal thickness in some eyes that respond poorly to monthly ranibizumab. Injecting bevacizumab every 2 weeks, or alternating it with ranibizumab, increases VEGF binding capacity beyond what is achieved with monthly injections of higher doses.⁷ Once a favorable anatomic result has been achieved, the treatment interval can often be extended beyond one month.

Probably the most commonly used strategy for incomplete responders involves switching anti-VEGF drugs. Poorly responding patients have been switched successfully from bevacizumab to ranibizumab and vice versa. More recently, it has been reported that switching patients from bevacizumab or ranibizumab to aflibercept (Eylea, Regeneron, Tarrytown, NY) improves macular thickness in most eyes and stabilizes or modestly improves visual acuity in many eyes.⁸ Although reasons for this are unclear, aflibercept's greater binding affinity for VEGF-A isoforms (KD=0.45 pM for VEGF165), binding of placental growth factor and VEGF-B, less immunogenicity (all human protein sequences), or simply switching drugs may all be contributing factors.

Complete coverage of blood vessels by pericytes confers VEGF-resistance to choroidal neovascular membranes (CNVM), and an additional vestment of myofibroblasts creates arteriolization, which may be responsible for 25% of anti-VEGF resistance. Whereas photodynamic therapy (PDT) does not improve vision significantly or decrease anti-VEGF treatment burden in most eyes with neovascular AMD, ICG-guided PDT may benefit eyes with advanced, anti-VEGF resistant CNVM.⁹

Fortunately, most eyes with exudative AMD respond well to each of the three commonly used anti-VEGF drugs, but poor responders may benefit from these alternative management strategies.


Disclosure:
Allergan: advisory board
Boehringer-Ingelheim: consultant
Regeneron: advisory board

References:
1. Martin DF, Maguire MG, Ying G-S. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364:1897-1908.
2. Busbee BG, Ho AC, Brown DM, et al. Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology. 2013;120:1046-1056.
3. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration. Ophthalmology. 2012;119:2537-2548.
4. Gasperini JL, Fawzi AA, Khondkaryan A, et al. Bevacizmab and ranibizumab tachyphylaxis in the treatment of choroidal neovascularization. Br J Ophthalmol. 2012;96:14-20.
5. Fung AT, Kumar N, Vance SK, et al. Pilot study to evaluate the role of high-dose ranibizumab 2.0 mg in the management of neovascular age-related macular degeneration in patients with persistent/recurrent macular fluid <30 days following treatment with intravitreal anti-VEGF therapy (the LAST Study). Eye (Lond). 2012;26:1181-1187.
6. Brown DM, Chen E, Mariani AF, Major JC. Superdose anti-VEGF (SAVE) trial: 2.0 mg intravitreal ranibizumab for recalcitrant neovascular age-related macular degeneration-primary end point. Ophthalmology. 2013;120:349-354.
7. Stewart MW, Rosenfeld PJ, Penha FM, et al. Pharmacokinetic rationale for dosing every 2 weeks versus 4 weeks with intravitreal ranibizumab, bevacizumab, and aflibercept (vascular endothelial growth factor Trap-eye). Retina. 2012;32:434-457.
8. Ho VY, Yeh S, Olsen TW, et al. Short-term outcomes of aflibercept for neovascular age-related macular degeneration in eyes previously treated with other vascular endothelial growth factor inhibitors. Am J Ophthalmol. 2013;156:23-28.
9. Cousins S. ICG-directed photodynamic therapy for patients with refractory wet AMD. Presented at Retina 2014, Poipu, HI, January 20, 2014. .