Newer Treatments in Wet ARMD

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1 Newer Treatments in Wet ARMD Lalit Verma MD Lalit Verma MD, Arindam Chakravarti MD Centre For Sight, New Delhi It is a proven fact that anti- vascular endothelial growth factor (VEGF) monotherapy is effective in the treatment of neovascular age-related macular degeneration (AMD). There is equally no doubt that anti-vegf monotherapy induces disease resistance in neovascular AMD. Long-term visual outcomes of anti-vegf monotherapy in the clinical setting, are disappointing. The HORIZON extension study 1 analyzed patients with choroidal neovascularization (CNV) secondary to AMD who had received ranibizumab (Lucentis, Genentech) every 4 weeks for 2 years as participants in phase 3 trials of the drug. When patients who received 2 years of monthly therapy in the original trials were subsequently treated on an as-needed (prn) basis for an additional 2 years in HORIZON, their mean visual acuity returned almost to baseline. Similar limitations in the long-term outcomes of patients treated with anti-vegf therapies have been observed in other trials such as the SECURE and SEVEN-UP studies 2,3. More recently, in the CATT study 4 comparing ranibizumab and bevacizumab (Avastin, Genentech) with monthly and prn dosing schedules, the 2-year results showed similar insights. Patients in the crossover arms of this study received monthly anti-vegf treatment whether ranibizumab or bevacizumab and were then switched to prn treatment after 1 year. In the second year of the study, the response in these patients was similar to the response of those who had been treated prn from the beginning of the study. In other words, these studies suggest that anti-vegf monotherapy does not result in disease modification; it induces no structural advantage in neovascular AMD. It may be that patients with CNVM secondary to AMD would need anti-vegf monotherapy indefinitely. What are our options? Newer Drugs VEGF trap-eye VEGF Trap-Eye (Aflibercept) is a recombinant fusion protein consisting of human VEGF receptor extracellular domains fused to Fc portion of human IgG1, it is a dimeric glycoprotein. Protein MW- 97 kda and contains 15% glycosylation to give total MW of 115 kda. It binds to VEGF-A, VEGF-B, and placental growth factors 1 and 2 with high affinity. This ability to bind other VEGF family members distinguishes VEGF trap from antibodies specific for VEGF. Phase 2 experience of VEGF Trap Eye in AMD showed a positive functional and anatomical effect in patients with Wet AMD. In August 2007, Regeneron and Bayer Health Care initiated a Phase 3 trial evaluating VEGF trap-eye in wet AMD. Two similarly designed, phase-3 studies of VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD [VIEW 1, VIEW 2] 5 of neovascular age-related macular degeneration (AMD) compared monthly and 2 monthly dosing of intravitreal aflibercept injection. Patients were randomized to intravitreal aflibercept 0.5 mg monthly, 2 mg monthly, 2 mg every 2 months after 3 initial monthly doses or ranibizumab 0.5 mg monthly. The primary end point was non-inferiority of the aflibercept regimens to ranibizumab in the proportion of patients maintaining vision at 52 weeks. Intravitreal aflibercept dosed monthly or every 2 months after 3 initial monthly doses produced similar efficacy and safety outcomes as monthly ranibizumab. These studies demonstrate that aflibercept is an effective treatment for wet AMD with the every 2 month regimen offering the potential to reduce the risk from monthly intravitreal injections and the burden of monthly monitoring. www. dosonline.org l 17

2 The VIEW trials used a capped 3 month treat-and-observe strategy in year 2 but did not test treat-and-extend, thereby requiring retina surgeons to investigate this strategy with post-approval trials. However the popularity of this approach among both patients and physicians suggests that the aflibercept will be used in this manner, with the hope of extending the intervals longer than with either ranibizumab or bevacizumab. A phase III VEGF Trap Eye trial for central retinal vein occlusion has completed enrolment, and similar trials for diabetic macular edema and branch retinal vein occlusion have begun. The drug has been approved by FDA and is currently available in the market for treatment. It may help in larger spacing of treatment intervals leading to fewer injections and subsequent decrease in financial burden to the patient. Role of Platelet-derived growth factor Crucial evidence for anti-vegf resistance has been identified in the oncology literature for more than a decade. It has to do with pericytes, a type of cell that intimately covers and protects the neovascular complex as new vessels develop and mature. Pericytes supply VEGF and other cell survival factors to the proliferating endothelial cells and confer anti- VEGF resistance 6. Platelet-derived growth factor (PDGF) is responsible for pericyte recruitment, survival and maturation 7,8. Studies in the oncology literature have shown that PDGFdeficient mice lack microvascular pericytes, and they form microaneurysms that rupture in late gestation 8. Conversely, PDGF over expression in melanoma cells leads to increased pericyte proliferation and tumor growth 9. These insights from the oncology literature are crucial for our understanding of neovascularization in AMD. The growth of a neovascular complex is not random, but rather specifically directed by a group of specialized cells known as tip cells 10. These tip cells are the only unprotected endothelial cells in the neovascular complex; they express PDGF, which stimulates the maturation and recruitment of pericytes that cover the neovascular complex. Anti-VEGF monotherapy is typically effective in obliterating only these unprotected tip cells. The pericytes that have been recruited form a protective armor around the rest of the neovascular complex, allowing it to remain in place. When anti-vegf therapy is stopped, the tip cells become active and mitotic again, leading to continuation of disease progression. This physiologic process is suggested by the results of clinical studies of anti-vegf agents in neovascular AMD. The familiar curve showing visual acuity improvement is remarkably consistent among these studies. An initial improvement in visual acuity in the first 3 or 4 months of treatment is followed by a plateau that persists through the study indefinitely. This pattern correlates well with the time course of antipermeability induced by VEGF antagonists. The pathophysiology of neovascular membrane growth explains the shape of the curve. Anti-VEGF monotherapy acts primarily on fenestrated and unprotected endothelial cells in the first few months of treatment, causing a decrease in exudation and initial improvement in visual acuity. Thereafter, however, the rest of the neovascular complex is protected by the pericyte armor, resulting in the plateau. As soon as anti-vegf monotherapy is withdrawn, the tip cells regrow, the neovascular complex increases in size, and disease progression with leakage continues. To summarize, chronic anti-vegf treatment causes PDGF upregulation, leading to pericyte recruitment and neovascular membrane maturation. This concept is well known in the oncology literature, where the role of VEGF as a negative regulator of pericyte function and vessel maturation has been well described. Pachdakiet al 11 recently described submacular surgery and excision of neovascular membranes in an eye with CNV that was unresponsive to bevacizumab treatment. The membrane displayed well-formed neovascular units consistently exhibiting pericytes, the authors reported. Anti-PDGF Therapy If pericytes are the source of resistance to anti-vegf therapy in neovascular AMD, then there is a physiologic rationale for a combination of anti-pdgf and anti-vegf therapies. The objective would be for the anti-pdgf agent to chemically bind to and strip pericytes from the neovascular complex, rendering the CNV more vulnerable to anti-vegf treatment. Ophthotech has developed a PDGF inhibitor (Fovista, formerly E10030), a PEGylated DNA aptamer. Preclinical work has shown that this agent binds to PDGF and strips pericytes from CNV, and that the combination of this agent with an anti-vegf agent is more effective than anti-vegf therapy alone in multiple animal models of neovascularization 12. In an uncontrolled dose-ranging phase 1 study with a small sample size (N=22), the safety profile of this anti-pdgf agent was excellent, with no dose-limiting toxicities observed 13. Despite the severity of disease in patients recruited for the study, a number of patients gained significant vision. A number of patients also showed significant regression of neovascular complex. Based on these encouraging results, a large phase 2b study was conducted (clinicaltrials.gov NCT ). The results of this study were presented at the American Academy of Ophthalmology Annual Meeting recently. The goal of the study was to assess the safety and efficacy 18 l DOS Times - Vol. 19, No. 3 September, 2013

3 of a combination of the anti-pdgf agent E10030 plus ranibizumab compared with ranibizumab monotherapy in patients with CNV secondary to AMD. Patients were randomly assigned to 1 of 3 treatment groups: 0.3 mg E10030 plus ranibizumab 0.5 mg, 1.5 mg E10030 plus ranibizumab 0.5 mg, or ranibizumab 0.5 mg monotherapy. Investigators recruited 449 patients, making this the largest phase 2 superiority study in retina. Unlike other recent studies in this area, it was a superiority study, not a noninferiority study. The primary endpoint was mean change in visual acuity from baseline to week 24. Secondary endpoints included mean change in visual acuity at week 12, the proportion of patients gaining 15 or more letters of visual acuity at week 12 and week 24, and mean change in the area of occult CNV at week 24 as defined by fluorescein angiography. The baseline demographics of all 3 arms were comparable. The prespecified superiority primary endpoint of improvement in visual acuity at week 24 was met by both combination groups. The 1.5 mg combination group showed mean improvement of 10.6 letters of vision, the 0.3 mg combination group showed improvement of 8.74 letters, and the ranibizumab monotherapy group showed improvement of 6.52 letters (P=.019 for ranibizumab only in comparison with each combination group). It is notable that both combination groups met their prespecified primary endpoint of superiority. In fact, in the 1.5 mg combination arm there was a 62% additional benefit compared with ranibizumab monotherapy. To determine whether any particular subgroup of patients drove these positive study results, numerous prespecified subgroup analyses were conducted. For baseline lesion size, an arbitrary segregation point of 4 disc areas was chosen. Results in the combination arms were superior for lesion sizes both greater than and less than or equal to 4 disc areas. Additionally, whether the median lesion size of 1.21 disc areas or the mean lesion size of 1.78 disc areas was used as the segregation point, again the combination arms were superior. The effect of baseline visual acuity was also examined. For relatively good visual acuity of 20/60 to 20/80 or relatively poor visual acuity of 20/160 or worse, the combination arms were superior. Clinically relevant subgroups were also examined. In patients who gained 3, 4, and 5 lines of visual acuity, the combination arms were always superior to the monotherapy arm, with 27%, 71%, and 190% relative benefits, respectively. In patients who lost 5 letters or more or 10 letters or more, the combination regimens were protective. Biomarkers including OCT and fluorescein angiography were also examined. On OCT, of particular interest was subretinal hyper reflective material (SHRM), the thickness of which appears to correlate with visual function. Resolution of SHRM at week 24 showed a clear dose-related response. This clear dose-response effect was also seen in patients who gained 3 lines of visual acuity or more. On fluorescein angiography, there was a clear correlation between lesion regression and visual acuity gain, whether in patients with 3, 4, or 5 lines of visual acuity gain, with superior results in the combination arms. In patients who lost vision, there was a clear correlation with growth of the neovascular membrane, and again the combination regimens were protective. Regarding safety, there was no difference in ocular adverse events or systemic serious adverse events among the 3 treatment groups. There was also, importantly, no difference in mean intraocular pressure among the groups, despite requiring 2 injections in the combination arms. In this large phase 2 clinical trial of E10030 anti- PDGF agent in combination with an anti-vegf agent, both combination arms met their prespecified primary endpoint of superiority over anti-vegf monotherapy (P=.019). Results showed a 62% additional benefit of combination therapy over monotherapy.lessons from the oncology literature suggest that it makes good physiologic sense to combine anti- PDGF and anti-vegf therapies. If the results of this large phase 2b trial are confirmed in a planned pivotal phase 3 trial, this combination therapy modality has the potential to dramatically and profoundly change our treatment model for patients with neovascular AMD. Rapamycin Therapy Broad gaps currently exist in the management of retinal diseases such as neovascular age-related macular degeneration (wet AMD) and diabetic macular edema (DME). For instance, fibrosis represents an important component in many retinal diseases, causing irreversible photoreceptor death and severe loss of vision. Yet fibrosis is not addressed in the current treatment of these diseases. Rapamycin also known as sirolimus is a highly evolutionary nuclear and cytoplasmic protein kinase which acts by inhibiting mtor. mtor regulates cell processes in response to the environment. Mammalian target of Rapamycin (mtor) signals through two protein complexes, mtorc1 and mtorc2. It regulates a variety of processes, including angiogenesis and immune homeostasis. Rapamycin has been found to inhibit VEGF-induced vascular permeability. Sirolimus (Rapamycin) inhibits the translation and activity of hypoxiainducible factor-1 alpha (HIF-1a), a stress-activated protein that activates numerous survival proteins involved in angiogenesis and hyperpermeability 14. mtor inhibitors are safe, have broad therapeutic effect, proven clinical utility, and down regulates the hypoxic response. Rapamycin also inhibits formation of mtorc and reduce VEGF expression in RPE cells, inhibits various forms of ocular angiogenesis, has potent anti-inflammatory effect, and inhibits fibrotic www. dosonline.org l 19

4 process. In addition, sirolimus has the potential to be an excellent combination agent, improving overall outcomes or prolonging the intervals between anti-vegf injections. Kolosova et al 15 investigated the effect of rapamycin on spontaneous retinopathy in senescence-accelerated OXYS rats, an animal model of age-related macular degeneration. Rats were treated with either 0.1 or 0.5 mg/kg rapamycin, which was given orally as a food mixture. In a dosedependent manner, rapamycin decreased the incidence and severity of retinopathy. Rapamycin improved some histological abnormalities associated with retinopathy. Thus, in retinal pigment epithelial cell layers, rapamycin decreased nuclei heterogeneity and normalized intervals between nuclei. In photoreceptor cells, associated neurons, and radial glial cells, rapamycin prevented nuclear and cellular pyknosis. More important, rapamycin prevented destruction of ganglion neurons in the retina. Rapamycin (Sirolimus) is locally administered with minimum systemic effects. A clear, liquid sirolimus product (Perceiva) is administered through a subconjunctival or, alternatively, intravitreal injection using a standard 30-gauge needle. Sirolimus or rapamycin is being evaluated in three separate phase 2 trials, a monotherapy trial by National Eye Institute for geographic atrophy, a second trial in combination with ranibizumab (EMERALD trial) for wet ARMD and the DIAMOND trial for diabetic macular edema. In the NEI study, participants initially received a 20 (micro gm) L440 intravitreal injection sirolimus in the study eye at baseline and every two months thereafter unless contraindicated. As of September 2012, sirolimus intravitreal injections were no longer administered to participants. Both the study and fellow eyes will be observed every two months until the study terminates. The study will not terminate until all participants have been followed through Month 12. The primary outcome is the rate of change in area of geographic atrophy based on masked grading in the study eye and fellow eye at Month 12 compared to baseline. Secondary outcomes will include changes in best-corrected visual acuity (BCVA), changes in drusen area based on masked digital grading of fundus photography, absolute and relative changes in area of GA measured using fundus photography and autofluorescence imaging, and development of exudative AMD measured using optical coherence tomography (OCT). The DIAMOND and EMERALD trial have finished enrolment of patients. Two phase 1 studies have been completed: one for diabetic macular edema and one for wet AMD. A total of 50 patients, the majority (82%) of whom had failed previous laser photocoagulation, were enrolled into the DME trial. Likewise, in the wet AMD study, 30 patients, many with considerable fibrosis, were enrolled. In both dose-escalation studies, a single subconjunctival or intravitreal injection resulted in visual acuity improvement and reduction of OCT that lasted at least 90 days. Other agents Palomid 529, an inhibitor of both mtorc1 and mtorc2 pathway, recently has been shown to possess similar effect on both ocular neovascularization and on VEGF-induced vascular permeability. Everolimus, another mtor inhibitor is also being tried for the treatment of neovascular AMD. Anti-TNF-a agents can directly neutralize the circulating TNF-a and prevent the binding of TNF to its receptors, p55 and p75. TNF-a antagonists also bind to transmembrane TNF-a, thereby inducing complement-dependent cytotoxicity and antibody-dependent cytotoxicity. The binding of anti-tnf-a agents with transmembrane TNF-a initiates outside-to-inside signal transduction, resulting in apoptosis, suppression of cytokine production, and cell growth arrest in proinflammatory cells. Consequently, the number of activated cells is significantly reduced at the inflamed site 16. Infliximab is a chimeric immunoglobin IgG1 monoclonal antibody composed of a constant human Fc region and a variable mouse Fab region. It is a TNF-alpha inhibitor that has been found to have a role in VEGF inhibition in certain trials. TNF-alpha is a potent pro-inflammatory cytokine. TNF alpha has a role in promoting angiogenesis, at least in part through upregulation of molecules, such as VEGF25 and its receptor VEGFR and PDGF-B. Preclinical studies in rodent models have demonstrated the efficacy of agents targeting TNF-alpha in reducing laser-induced CNV. Two small case series reported that intravenous injection of infliximab, a monoclonal antibody directed against TNF-alpha, provided clinical benefit for patients with neovascular AMD and diabetic macular edema. The intravitreal approach is being examined in a Phase I trial in patients with neovascular AMD and diabetic macular edema. Daclizumab is a fully humanized IgG1 monoclonal antibody directed against the a-chain (Tac/CD25) of the IL-2 receptor (IL-2R). Blockage of IL-2R results in decreased activation and proliferation of T-cell clones. Daclizumab also inhibits IFN-a expression in both CD4+ and CD8+ T cells. A pilot prospective study evaluated the use of systemic daclizumab in four patients with neovascular AMD for 6 months. The results showed that daclizumab appeared to decrease the need for anti-vegf intravitreal injections by approximately half. The effects of intravenous injection of daclizumab in neovascular AMD are being assessed in a phase II clinical trial. Daclizumab may become a promising adjunctive therapy in neovascular AMD, especially for patients who do not respond to the conventional anti-vegf agents. Controlling gene expression via small interfering RNA (sirna) has opened the doors to a plethora of therapeutic possibilities, with many currently in the pipelines of drug 20 l DOS Times - Vol. 19, No. 3 September, 2013

5 Table 1: Current Investigative Agents in Wet AMD S.N. Clinical Trial Details of trial and mechanism of action of trial drug Trial phase 1 Bevasiranib Gene silencing Phase I and Phase II trials of Bevasiranib have been completed 2 TG100801Eye Drops Targegen 3 PTK787 Pill For AMD Novartis 4 Talaporfin Sodium PDT Light Sciences LLC 5 Ophthotec (E10030/Fovista) 6 REDD14NP Quark 7 Sirolimus (Rapamycin) 8 ATG003 Eye Drops TG100801, a compound is a small molecule, topically applied compound that acts to inhibit vascular permeability (VEGF mediated retinal leakage), angiogenesis, and inflammation simultaneously. Clinical trial involved 44 healthy volunteers without AMD. It was designed to assess the safety and tolerance of the eye drop. Studied safety and tolerance of a tablet of Vitalanib, taken over three months and the effect on wet macular degeneration. Study was undertaken to determine the safety of photodynamic therapy (PDT), using the drug talaporfin sodium (LS11). Twenty-seven patients were enrolled Compares outcomes between patient groups receiving standard Lucentis treatment and those receiving Lucentis and E E10030 blocks PDGF, that seems to contribute to wet AMD. Open-Label, Dose Escalation Trial of PF delivered by a single intravitreal injection to patients with choroidal neovascularization (CNV) Secondary to Wet AMD. Drug designed to interfere with a gene that seems to be active in creating AMD Sirolimus is designed to stop the growth of blood vessels in the macula. It is an antifibrotic agent and acts by inhibiting mtor. Patients received either one of three treatments: sirolimus at a lower dose in combination with Lucentis, sirolimus at a higher dose in combination with Lucentis or placebo in combination with Lucentis. Double-masked, randomized, placebocontrolled study of the safety and effectiveness of ATG003 (topical mecamylamine) in patients receiving maintenance injections of either Lucentis or Avastin. 9 ASap (POT-4) POT-4 affects the complement protein C3 The objective of this study is to provide initial safety and tolerability information of intravitreal POT-4 for treatment of patients with AMD Phase 1 Phase I/II study Phase I study Phase 2 b study Phase 1 study 3 ongoing phase II trials including one for geographic atrophy Phase II study Pilot Phase I study Current Status Phase III clinical trial is now recruiting available yet. available yet available yet Data present in last AAO Congress Completed Recruitment over for NEI trial on geographic atrophy, recruitment ongoing for wet AMD trial Recruiting available yet www. dosonline.org l 21

6 S.N. Clinical Trial Details of trial and mechanism of action of trial drug 10 CABERNET Strontium-90 Beta Radiation Implant Trial 11 Thera Sight TM Ocular Brachytherapy System for Wet AMD 12 COBALT Bevasiranib & Lucentis Combination Therapy 13 Pazopanib Eye Drops Versus Ranibizumab Intravitreal Injections for the Treatment of Neovascular Age- Related Macular Degeneration A tiny source of radiation is placed inside the eye near the macula, held there for about 4 minutes and then removed. The radiation destroys the abnormal blood vessels and prevents the growth of blood vessels to stop the progression of wet macular degeneration vision loss. Enrolled 457 subjects at 45 clinical centers worldwide, patients received either the standard injection of Lucentis or the radiation plus Lucentis. A radioactive button mounted on an applicator wand is positioned behind the eye and held in place touching the outer surface of the eye for 5 to 20 minutes. The radioactive button produces low-energy x-rays that interfere with the abnormal new blood vessels, potentially reducing further vision loss. Bevasiranib is a small interfering RNA molecule (Cand5) designed to silence the gene that prompts blood vessel growth. The purpose of the study is to compare the safety and effectiveness of Bevasiranib compared to Lucentis. patients randomized to receive intravitrealbevasiranib sodium followed by three Lucentis injections or Lucentis injections alone for 4 weeks. Pazopanib is a tyrosine kinase inhibitor of multiple receptors including vascular endothelial growth factor receptors and platelet-derived growth factor receptors. Trial phase Phase III trial Phase I Phase III Phase IIb Current Status Results are now available. After 2 years, the study could not show epiretinal brachytherapy to be non-inferior to Lucentis. Recruiting Ongoing, recruitment over. Recruiting development for various ocular diseases. Despite the potential of sirna technologies, barriers to intracellular delivery significantly limit their clinical efficacy. However, recent progress in the field of drug delivery strongly suggests that targeted manipulation of gene expression via sirna delivered through nanocarriers can have an enormous impact on improving therapeutic outcomes for ophthalmic applications. sirna-027 is a small interfering RNA targeting vascular endothelial growth factor receptor-1, in patients with choroidal neovascularization (CNV) resulting from neovascular age-related macular degeneration (AMD). It has been studied in a prospective, open-label, single-dose, dose-escalation phase 1 trial. A single intravitreal dose of sirna-027 up to 1600 microgm/eye was well tolerated in patients with CNVM resulting from neovascular AMD that had been refractory to other therapies. Stabilization or improvement in visual acuity and foveal thickness was observed. No dose-response or dose-limiting effects were noted. Current treatments for wet macular degeneration often require repeated injections in the eye monthly or less often. Epiretinal brachytherapy can reduce the number of injections needed to just two injections over a period of 12 months. A tiny source of radiation is placed inside the eye near the macula, held there for about 4 minutes and then removed. The radiation destroys the abnormal blood vessels and prevents the growth of blood vessels to stop the progression of wet macular degeneration vision loss.in a 22 l DOS Times - Vol. 19, No. 3 September, 2013

7 previous study, 34 people with wet macular degeneration received a single treatment of NeoVista s epiretinal brachytherapy. Patients received the radiation and two injections of Avastin - one dose just before the radiation or at the time of radiation delivery and an additional injection of Avastin one month later, depending on which group they were in. The patients could receive additional injections of Avastin if the investigator felt it was needed. Seventy six percent of the patients in the study did not require additional injections of Avastin throughout the year. After 12 months, 94 percent of patients lost fewer than 15 letters, 39 percent gained 15 or more letters, and 12 percent gained 30 or more letters.in contrast to other forms of radiation therapy for wet AMD, NeoVista s approach targets the peak dose of energy directly to the lesion without damaging the normal blood vessels or other structures within the eye such as the lens and the optic nerve. No radiation related complications were reported. This was followed by CABERNET, a multicenter, randomized, controlled Phase III study that enrolled 457 subjects at 45 clinical centers worldwide (Table 1). In this research, patients received standard injection of Lucentis(ranibizumab) or the radiation plus Lucentis. After 2 years, the study could not show epiretinal brachytherapy to be non-inferior to Lucentis. Noninferiority was the primary endpoint for the clinical trial. Previous research had led to the hope that radiation treatment could be used with Lucentis to reduce the number of injections that were needed. References 1. Singer MA, Awh CC, Sadda S, et al. HORIZON: an open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology 2012;119(6): Silva R, Axer-Siegel R, Eldem B, et al. SECURE Study Group. The SECURE Study: Long-Term Safety of Ranibizumab 0.5 mg in Neovascular Age-related Macular Degeneration. Ophthalmology 2013;120(1): Bhisitkul RB, Rofagha S, Boyer DS, et al. Year 7 outcomes for ranibizumab-treated subjects in ANCHOR/MARINA: a multicenter, prospective cohort study. Paper presented at: Association for Research in Vision and Ophthalmology Annual Meeting; May 8, 2012; Fort Lauderdale, FL. 4. Martin DF, Maguire MG, Fine SL, et al. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group. Ranibizumab and bevacizumab for treatment of neovascular agerelated macular degeneration. Ophthalmology 2012;119(7): Heier JS, Brown DM, Chong V. Intravitreal aflibercept (VEGF trapeye) in wet age-related macular degeneration. Ophthalmology 2012;119(12): Reinmuth N, Liu W, Jung YD, et al. Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival. FASEB J. 2001;15(7): Benjamin LE, Hemo I, Keshet E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 1998;125(9): Lindahl P, Johansson BR, Levéen P, et al. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 1997;277(5323): Furuhashi M, Sjöblom T, Abramsson A, et al. Platelet-derived growth factor production by B16 melanoma cells leads to increased pericyte abundance in tumors and an associated increase in tumor growth rate. Cancer Res. 2004;64(8): Gerhardt H, Golding M, Fruttiger M, et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol. 2003;161(6): Pachydaki SI, Jakobiec FA, Bhat P, et al. Surgical management and ultrastructural study of choroidal neovascularization in punctate inner choroidopathy after bevacizumab. J Ophthalmic Inflamm Infect. 2012;2(1): Jo N, Mailhos C, Ju M, et al. Inhibition of platelet-derived growth factor B signaling enhances the efficacy of anti-vascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am J Pathol. 2006;168(6): Dugel PU. Anti-Platelet Derived Growth Factor: Where Do We Stand? Paper presented at: American Academy of Ophthalmology Annual Meeting; November 10, 2012; Chicago. 14. Hudson CC, Liu M, Chiang GG, et al. Regulation of hypoxiainducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol. 2002; 22: Kolosova NG, Muraleva NA, Zhdankina AA. Prevention of agerelated macular degeneration-like retinopathy by rapamycin in rats. Am J Pathol. 2012;181(2): Sfikakis PP. The first decade of biologic TNF antagonists in clinical practice: lessons learned, unresolved issues and future directions. Curr Dir Autoimmun. 2010;11: www. dosonline.org l 23