June 2011, Issue 52

Monotherapy Treatment Strategies for Neovascular AMD

Jaclyn L. Kovach, MD Assistant Professor of Clinical Ophthalmology Bascom Palmer Eye Institute University of Miami Miller School of Medicine

The past decade has been one of great progress for the treatment of neovascular age-related macular degeneration (AMD).  This monograph will review the evolution of evidenced-based anti-vascular endothelial growth factor (VEGF) treatment strategies, with a focus on bevacizumab and ranibizumab.

The pathogenesis of AMD is a complex interaction between lipofuscinogenesis, drusenogenesis, and inflammation which can lead to choroidal neovascularization.  Abnormal choroidal angiogenesis begins when ischemia and local inflammation disrupt a delicate interplay between numerous stimulators and inhibitors, including an imbalance between the pro-angiogenic VEGF and the anti-angiogenic pigment epithelium derived factor (PEDF).¹

The VEGF family is comprised of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F and placental growth factor.  The VEGF-A gene is organized into eight exons, separated by seven introns on chromosome 6p21.  Alternate gene splicing can generate 9 isoforms, the most prevalent of which is VEGF₁₆₅.  VEGF-A is a dimeric glycoprotein that mediates its effect by interacting with two tyrosine kinase receptors, VEGFR-1 and VEGFR-2 located primarily on endothelial cells.²

Bevacizumab
Bevacizumab (Avastin, Genentech/Roche South San Francisco, CA) is a full-length, humanized, monoclonal antibody that has 2 binding sites specific for all VEGF-A isoforms. The safety and efficacy of intravitreal bevacizumab was initially described in several case reports including a retrospective case series of 79 patients treated with monthly bevacizumab (1.25mg) until resolution of macular edema, subretinal fluid, and/or pigment epithelial detachment (PED).  After two months, intravitreal bevacizumab was well-tolerated and associated with an improvement in visual acuity, decreased retinal thickness and a reduction in angiographic leakage in most patients, the majority of whom had previous treatment with photodynamic therapy and/or pegaptanib.³  Over the past several years, the efficacy and tolerability of intravitreal bevacizumab has been touted by hundreds of articles. 

Ranibizumab
Ranibizumab (Lucentis, Genentech/Roche South San Francisco, CA) is an antibody fragment that binds to and inhibits all identified VEGF-A isoforms.  It was engineered to have 100X the binding affinity of bevacizumab, despite having only a single binding site.  With the absence of the Fc segment, the antibody fragment was designed to possess a shorter systemic half life, induce less of a theoretical inflammatory reaction, and demonstrate improved retinal penetration compared to bevacizumab.

In October 2006, the results of the phase III Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration (MARINA) study, which evaluated the efficacy and safety of ranibizumab for the treatment of minimally classic or occult choroidal neovascularization, were published.  Seven hundred and sixteen patients were enrolled into this 2-year, prospective, randomized, double blind, sham-controlled study.  At 24 months, 92% of the patients receiving 0.3mg of ranibizumab and 90% of those receiving 0.5mg lost fewer than 15 letters, compared with 52.9% in the sham group.  Thirty-three percent of the 0.5mg group, 26.1% of the 0.3mg group, and 3.8% of the sham group gained at least 15 letters on the ETDRS chart.⁴

The Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR) study was a multicenter, randomized double-blind study that enrolled 423 patients to compare the efficacy and safety of ranibizumab with that of photodynamic therapy with verteporfin in patients with predominantly classic lesions.  At 12 months, 94.3% of patients in the 0.3mg group and 96.4% in the 0.5mg group lost fewer than 15 letters from baseline compared with 64.3% in the verteporfin group.  Forty percent of the 0.5mg group and 35.7% of the 0.3mg group gained at least 15 letters compared to 5.6% in the verteporfin group.⁵  The results of the MARINA and ANCHOR trials proved that dramatic gains in visual acuity were possible, but with monthly dosing regimens. 

Several studies in the years that followed tried to establish the dosing regimen that yielded the best visual acuity outcomes while minimizing treatment burden.  The PIER⁶ and EXCITE⁷ studies supported increased efficacy of monthly ranibizumab, the importance of timely treatment, and that regimented, generic quarterly dosing does not yield desirable visual outcomes. 

Currently, two anti-VEGF treatment regimens are favored, but neither has been proven superior: as needed (or “prn”) therapy vs. treat and extend therapy. 

Ranibizumab: As Needed
The PrONTO study was an open-label, prospective, single-center uncontrolled study that investigated a variable-dosing regimen for the treatment of wet AMD with intravitreal ranibizumab over two years.  In the PrONTO study, with a variable-dosing regimen based on several factors (including changes in best-corrected ETDRS VA, optical coherence tomography [OCT], etc), VA outcomes were comparable with the ranibizumab phase III clinical studies, but with fewer intravitreal injections.⁸  The SAILOR trial showed that quarterly visits were insufficient to monitor and capture disease progression and the SUSTAIN study indicated that flexible, guided dosing with fewer ranibizumab injections and monthly monitoring can maintain efficacy outcomes.⁹  In the HORIZON extension study, a delay in the initiation of treatment was associated with poor visual outcomes and less frequent dosing in years 3 and 4 was associated with visual decline.¹⁰  Overall, these studies support frequent follow-up and individualized retreatment to achieve the best visual acuity gains with the traditional as-needed treatment regimen.

Ranibizumab: Treat and Extend
Gupta et al. reported a retrospective, interventional, case series of 92 eyes that had undergone treatment with the treat and extend ranibizumab regimen.  At the end of 2 years, 32% had gained at least 3 lines of vision and received a mean of 8.36 and 7.45 injections the first and second years, respectively.  This treatment approach was associated with fewer patient visits and injections, and less direct annual medical cost compared with monthly injections as in the phase III clinical trials.¹¹

Bevacizumab: As Needed
Unlike ranibizumab, no large, prospective trials exist to guide treatment or formally document bevacizumab efficacy.  The ABC trial is a prospective, double masked, multicenter, randomized-controlled trial of 131 patients randomized to 3 loading doses of bevacizumab at 6 week intervals followed by as needed treatment at six week intervals or standard treatment at the start of the trial (PDT or pegaptanib).  Thirty-two percent of patients in the bevacizumab group gained 15 or more letters with a mean VA increase of 7 letters and a median of 7 injections.  There was a mean decrease of 9.4 letters in the standard care group.¹²  

Bevacizumab: Treat and Extend
Gupta et al. reviewed 166 eyes of 159 patients in a retrospective case series of patients treated with a treat and extend regimen of bevacizumab or ranibizumab for an average follow-up of 1.5 years.  Patients received monthly injections until “dry” on OCT.  Treatment intervals were extended by 2 weeks at a time unless exudation was seen on OCT.  Visual outcomes and recurrence rates were similar for patients who received ranibizumab or bevacizumab.  At 1 year, 32-35% of patients gained at least 3 lines of vision and 45-52% of patients had no recurrence over the course of the study.  Bevacizumab had a longer mean period of extension, compared to ranibizumab.  The treat and extend regimen was associated with lower medical costs when compared to the MARINA, ANCHOR, and PrONTO clinical trials, with a reduced mean number of injections and lower medical costs in the bevacizumab group.¹³

Even though large, randomized controlled trials are lacking, smaller studies support frequent follow-up and retreatment.  The treat and extend regimen may prove to be more cost-effective.

Anti-VEGF Non-Responders
While a remarkable 30-40% of patients treated monthly with ranibizumab gained at least 3 lines of vision and 90% achieved stabilization of vision, as many as 10% of patients lost a significant amount of vision over 2 years of monthly therapy.^4,5  Within this group are eyes that demonstrate persistent macular fluid/blood, leakage on fluorescein angiography, and vision loss, i.e. anti-VEGF non-responders.  Perhaps more aggressive forms of wet AMD, including retinal angiomatous proliferation (RAP), or tachyphylaxis to anti-VEGF agents play a role.  Mimics of wet AMD have to be considered, including idiopathic central serous chorioretinopathy, idiopathic polypoidal choroidal vasculopathy, and inflammatory-induced neovascular proliferation.  The therapeutic approach can be adjusted in these patients to include alternating bevacizumab and ranibizumab every 2 weeks to allow sustained anti-VEGF blockade, or combination therapy including photodynamic therapy and intravitreal steroids.¹⁴

VEGF-Trap-Eye
VEGF Trap-Eye (VTE) (Regeneron, Tarrytown, NY) is a soluble fusion protein consisting of 2 extracellular cytokine receptor domains and a human Fc region of immunoglobulin G (IgG).  VEGF Trap-Eye includes specific extracellular components of VEGF receptors 1 and 2 fused to the constant region (Fc) of IgG1, which results in 2 identical arms, each constructed from select pieces of both VEGFR1 and VEGFR2.  These components were selected based on their high affinity for both VEGF-A and placental growth factor (PlGF).  The binding affinity of VEGF Trap to VEGF is 10-fold higher than bevacizumab.  The 2mg dose of VTE at 83d has been proven to have a similar biologic activity to ranibizumab at 30 days.

VIEW1 is a phase III non-inferiority study conducted in North America that randomized 1217 patients to VTE 0.5mg monthly dosing, VTE 2 mg monthly, VTE 2mg every two months following 3 monthly doses, or ranibizumab 0.5mg monthly.  The 2mg q4wk was significantly better than ranibizumab q4wk in the mean change in best-corrected visual acuity from baseline to week 52.  Differences between other VTE groups and ranibizumab q4wk were non-significant.  The difference in the decrease in central retinal thickness was not significant between the groups.  Overall, dosing monthly or every two months with VTE was non-inferior to monthly ranibizumab and was well-tolerated with a favorable safety profile. The VIEW 2 study enrolled 1240 patients from Europe, Latin America, Asia, and Australia and yielded results consistent with the VIEW1 study.

The treatment of neovascular AMD has been revolutionized with the discovery of anti-VEGF agents that have enabled patients to regain vision thought permanently lost to the damaging effects of this blinding disease.  The evolution of drug development and the refinement of treatment protocols will continue to foster more efficacious and cost-conscious treatment strategies in the years to come. 

REFERENCES
1. Nowak JZ. Age-related macular degeneration (AMD): pathogenesis and therapy. Pharmacological Reports. 2006;58:353-363.
2. Shams N, Ianchulev T. Role of vascular endothelial growth factor in ocular angiogenesis. Ophthalmol Clin N Am. 2006;19:335-344.
3. Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology. 2007 Feb;114(2):400. 
4. Rosenfeld PJ, Brown DM, Heier JS et al.  Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006; 355(14):1419-1431.
5. Brown DM, Kaiser PK, Michels M et al.  Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl Med. 2006;355(14):1432-44.
6. Abraham P, Yue H, Wilson L. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER study year 2. Am J Ophthalmol. 2010 Sep;150(3):315-324.
7. Schmidt-Erfurth U, Eldem B, Guymer R et al. Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: The EXCITE study. Ophthalmology. 2010 Dec 9 Epub ahead of print.
8. Lalwani GA, Rosenfeld PJ, Fung AE et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO study. Am J Ophthalmol. 2009 Jul;148(1):1-3.
9. Mitchell P, Korobelnik J-F, Lanzetta P et al. Ranibizumab (Lucentis) in neovascular age-related macular degeneration: evidence from clinical trials. Br J Ophthalmol.  2010;94(1):2-13.
10. Ranibizumab safe and effective over long term in HORIZON extension study. Ophthalmology Times. May 6,2009
11. Gupta OP, Shienbaum G, Patel AH et al. A treat and extend regimen using ranibizumab for neovascular age-related macular degeneration clinical and economic impact. Ophthalmology. 2010 Nov;117(11):2134-40.
12. Tufail A, Patel, PJ, Egan C, et al. Bevacizumab for neovascular age-related macular degeneration (ABC Trial): Multicentre randomized double masked study. BMJ. 2010 Jun 9;340:c2459.
13. Treat-and-extend therapy: a popular, cost-effective approach to treating neovascular AMD. PCONSuperSite. February 1,2011.
14. Slakter JS. What to do when anti-VEGF therapy fails. Retinal Physician.  June 2010.