The Era of anti- - - VEGF Kirk L. Halvorson, OD

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1 The Era of anti- - - VEGF Kirk L. Halvorson, OD Introduction: Anti- - - Vascular Endothelial Growth Factor (Anti- - - VEGF) medication is a relatively a new line of medications used in treating a variety of ocular pathology. Some anti- - - VEGF medications are gaining FDA approval as a first line medication for exudative macular degeneration, retinal vein occlusions, and diabetic macular edema while being used off label for other exudative retinal conditions. Since the introduction of anti- - - VEGF medications on the market, there has been a decline in the amount of retinal laser treatment and intravitreal steroids used to treat these retinal conditions. It s important for primary eye care providers to understand how these medications are being utilized as to better provide the patient realistic expectations of their care. What is VEGF? Vascular endothelial growth factor is one of the major cytokines involved in angiogenic and vascular permeability retinal pathologies. The family of VEGF includes; VEGF- - - A, VECF- - - B, VEGF- - - C, VEGF- - - D, VEGF- - - E, and placental growth factor (PIGF). It is VEGF- - - A, the main cytokine targeted by the majority of currently available medications, that binds to VEGF receptor 1 and VEGF receptor 2 and activates angiogenesis and vascular permeability in response to ischemia and tissue damage (Mahar, Hanfi, Kahn 2009). One of the newer anti- - - VEGF medications is targeting PIGF as well, which is thought to induce vascular permeability, chemotaxis and angiogenesis. Not all VEGF is bad, as it has been shown that VEGF plays a role in normal vascular development and it also has retinal neuroprotection, raising concerns over the long- - - term use of anti- - - VEGF medications (Kim and D Amore 2008). Intravitreal anti- - - VEGF medications Pegapfinib sodium (Macugen. Pfizer and OSI/Eyetech Pharmaceuticals, Inc.) was first to be FDA approved for exudative macular degeneration in December The medication works by inhibiting the major VEGF- - - A isoform, 165, and was shown to be superior to photodynamic therapy (PDT), which was standard of care at that time (Shapiro 2012). The dosage is one intravitreal injection every 6 weeks. Bevacimubab (Avastin, Genentech Inc) was initially FDA approved as an adjunct therapy for colon cancer in February The medication started to be used off label shortly after the approval of pegapfinib sodium and is still readily used off label. It is a humanized anti- - - VEGF antibody that is designed to block all VEGF- - - A isoforms (Shapiro 2012). Ranibizumab (Lucentis, Genentech Inc) is also humanized anti- - - VEGF antibody designed to block all VEGF- - - A isoforms. Since Lucentis is a smaller variant of Avastin it was initially thought to have better retinal penetration, therefore being more effective. It was FDA approved for exudative macular degeneration in June 2006, with a dosing schedule of one injection every 6 weeks (Shapiro). It has since been approved for macular edema from retinal vein occlusion in June 2010 and diabetic macular edema in August 2012, both with a dosing schedule of one injection every 4 weeks. Aflibercept (Eylea, also known as Trap eye, Regeneron, Inc) is the newest anti- - - VEGF medication to be FDA approved. It inhibits all isoforms of VEGF- - - A and PIGF, and has been reported to have an increased binding affinity compared to bevacimubab and ranibizumab. To separate itself, Regeneron was able to gain FDA approval in November 2011 for exudative macular degeneration with a dosing schedule of one injection every 8 weeks, after three monthly injections. It was then approved for macular edema from

2 central retinal vein occlusion in September 2012 and is currently looking to gain approval for diabetic macular edema. Exudative Macular Degeneration Age related macular degeneration is the leading cause of severe vision loss in those over age 55 and it comes in two forms; exudative and non- - - exudative. The exudative form results in the majority of vision loss in AMD patients and accounts for about percent of AMD cases (Schreiber 2012). Years of chronic stress upon retinal tissue may eventually lead to damage of the retinal pigmented epithelium (RPE) and Bruch s membrane, thereby increasing VEGF production. With exudative macular degeneration, vessels that originate from the choroid break through Bruch s membrane, leading to sub- - - retinal/sub- - - RPE hemorrhage or serous fluid and subsequent possible scarring. Previous treatments for exudative AMD include laser photocoagulation and photodynamic therapy where the goal of the treatment was to slow progression. One of the first pivotal anti- - - VEGF treatment studies is the VISION study. It demonstrated that Macugen resulted in a slower rate of vision loss and required less photodynamic therapy treatment compared to no treatment. Additionally, from this study Macugen demonstrated less efficacy after a year and that there were no significant differences in efficacy in doses higher than 0.3mg. Some of the other pivotal studies looking at anti- - - VEGF medications for exudative AMD are the MARINA and ANCHOR study. Both of these studies helped Lucentis gain FDA approval for exudative AMD by showing, not only that Lucentis prevented vision loss better than traditional methods, but that people treated with Lucentis gained statistically significant vision as quickly as one month. 2 years into the MARINA trial, the mean acuity gain for those treated with 0.3mg were 6.4 letters and 6.6 letters for those treated with 0.5mg compared to those who weren t treated lost an average of 14.9 letters. Similar results were shown in the ANCHOR trial, the 0.3mg group showed a mean gain of 8.1 letters, a gain of 10.7 letters in the 0.5mg group, and those not treated showed a mean loss of 9.8 letters. The results are summarized in Table 1. The 2 year CATT study looked at Avastin and Lucentis as treatment for exudative AMD. This study demonstrated that the two medications had similar efficacy and there is a dramatic difference in cost between the two medications ($25, $45,000 for Lucentis, $ $1,200 for Avastin). Another interesting finding in this study was that the monthly Lucentis group was more likely to develop geographic atrophy. The CATT study also looked at as needed injections compared to monthly and demonstrated a 2.4 letter loss of acuity when dosing as needed. There were additional studies that looked at extending treatment time between injections, since monthly injections often times seem overwhelming. While reducing the amount of injections decreases the burden for the patient, studies haven t demonstrated the same visual outcomes when reducing treatments with Lucentis or Avastin. Some of the newest studies, VIEW 1 and VIEW 2, looked at providing adequate treatment while lessening the total number of injections (Heier et. al., 2012). These two studies helped Eylea gain FDA approval for an injection every 8 weeks after 3 monthly loading doses by showing similar efficacy to monthly Lucentis injections.

3 TABLE 1 Study Brief description Medication Dosing schedule Mean letter gain ANCHOR 24 month trial Lucentis 0.3mg Monthly +6.4 showing advantage of Lucentis 0.5mg Monthly +6.6 Lucentis over PDT PDT Monthly MARINA 24 month trial Lucentis 0.3mg Monthly +8.1 showing advantage of Lucentis 0.5mg Monthly Lucentis Sham Monthly CATT 24 month trial Lucentis Monthly +8.8 showing similar Lucentis PRN +6.7 outcomes when comparing Lucentis vs Avastin Monthly +7.8 Avastin Avastin PRN +5.0 Diabetic Macular Edema Diabetic retinopathy is the leading cause of blindness in ages in the United States (ADA, 2013). Microvascular damage from hyperglycemia can lead to microaneurysms, retinal hemorrhages, cotton wool spots, hard exudates, venous beading, and intra- - - retinal microvascular abnormalities. These microvascular damages may eventually lead to hypoxia, which, in turn, increases VEGF production. As previously stated, VEGF production can lead to increased vascular permeability resulting in macular edema, and the development of new blood vessel growth resulting in neovascularization of the disc, iris, or retina. Studies that have looked at diabetes and VEGF production have shown elevated amounts of VEGF in proliferative diabetic retinopathy and diabetic macular edema. Diabetic macular edema is the most frequent cause of visual impairment in patients with diabetic retinopathy. The likelihood of a patient having diabetic macular edema increases with the length of the disease, from % for someone recently diagnosed with diabetes compared to % for someone that has 20 or more years with the condition (Nguyen and Brown 2012). The Early Treatment Diabetic Retinopathy Study (ETDRS) showed the benefits of preventative laser treatment for those that fall under the classification of clinically significant macular edema but it failed to show any significance at restoring vision. Intravitreal steroids initially showed promise, but long- - - term treatment shows only short- - - term effects. As with other conditions, both laser and intravitreal steroids are still used today, but their use has declined with the introduction of anti- - - VEGF medications. Since studies have shown increased levels of VEGF production with those who have diabetic retinopathy, trials began looking into treating diabetic macular edema patients with anti- - - VEGF medications. RISE and RIDE were two major trials that looked into the benefit of Lucentis injections for treating this condition. In the RISE trial the percentage of patients that gained at least 15 ETDRS letters were 44.8%, treated with 0.3mg, and 39.2%, treated with 0.5mg, compared to 18.1% of those in the sham group. The RIDE trial showed similar results, 33.6% of those treated with 0.3mg and 45.7% treated with 0.5mg gained at least 15 letters compared to only 12.3% of the sham group. The results are summarized in TABLE 2. The RISE and RIDE studies not only showed that Lucentis showed visual gain over time but also showed patients receiving the medication were less likely to receive laser treatment, both pan- - - retinal photocoagulation (PRP) and focal. Another interesting finding was that the RISE and RIDE trials showed a higher correlation of death and CVA with the treated group, although the DRCR study showed opposite results. For this reason, some physicians may elect to delay treatment if a

4 patient has a recent vascular event. There were many other studies such as the BOLT, DRCR, RESTORE, READ , and RESOLVE, that showed the benefit of anti- - - VEGF for patients with diabetic macular edema, not only preventing vision loss but also gaining acuity in most instances. Many of the studies showed the correlation between reducing foveal thickness and increased acuity. Eylea will likely look to get approval for clinically significant macular edema in the near future. TABLE 2 Study Brief Description Medication Dose Gain > 15 ETDRS letters RISE 24 month trial that showed Lucentis 0.3mg 44.8% the benefit of Lucentis for Lucentis 0.5mg 39.2% diabetic macular edema Sham 18.1% RIDE 24 month trial that showed the benefit of Lucentis for diabetic macular edema Lucentis 0.3mg 33.6% Lucentis 0.5mg 45.7% Sham 12.3% Macular Edema from Retinal Vein Occlusion Retinal vein occlusion is second only to diabetic retinopathy, as the leading cause of vision loss due to retinal vascular disease. (Brown 2010) There are many theories about the pathophysiology, but retinal vein occlusions are thought to the result of thrombosis formation resulting in increased vascular pressure that eventually leads to fluid leakage. Some of the signs seen in retinal vein occlusion are hemorrhages, retinal edema, cotton wool spots, and capillary non- - - perfusion. Vascular endothelial damage and ischemia lead to increased VEGF production, creating the potential for neovascularization or more retinal edema. One of the two types of retinal vein occlusions, central retinal vein occlusion (CRVO), occurs when an occlusion is at or behind the lamina cribrosa and has a greater potential to be ischemic. The other type, branch retinal vein occlusion (BRVO), occurs at a proximal branch off the central retinal vein and is times more common than CRVO (Ehlers and Fekrat 2010). Age, hypertension, hyperlipidemia, arteriosclerosis, and diabetes are all risk factors for retinal vein occlusions. Previous treatments for these patients included monitoring, laser treatment (focal or grid), and intravitreal steroid injections. Some of the first studies that looked at treating macular edema from retinal vein occlusions with laser were the central retinal vein occlusion study (CVOS) and the branch retinal vein occlusion study (BVOS). The CVOS showed no benefit of grid laser when compared to observation, whereas the BVOS showed a benefit of laser treatment for those patients that fell under certain criteria. The Standard Care versus Corticosteroid for Retinal Vein Occlusion Study (SCORE) looked at treating macular edema from retinal vein occlusion with intravitreal triamcinolone. The SCORE trial reinforced laser treatment as the standard of care for BRVOs mostly because laser showed superior sustained efficacy and a better safety profile. It also showed the visual benefit of triamcinolone for those who have experienced a CRVO, although there is a concern with changes in intraocular pressures when using steroids. New studies have shown the efficacy of anti- - - VEGF medications for macular edema from retinal vein occlusions. The BRAVO and CRUISE trials helped Lucentis gain FDA approval for macular edema from BRVO and CRVO respectively. These 12 month clinical trials not only showed quick vision recovery, as early as one week, but they also showed quicker resolution of retinal hemorrhages and that patients may still benefit from medications even after longstanding macular edema. By 6 months into the BRAVO

5 trial, patients treated with Lucentis (0.3mg, 0.5mg) were likely to gain at least 3 lines of acuity (55.2%, 61.1%) compared to those patients who were only observed (28.8%). The CRUISE trial showed similar results at 6 months, 46.2%, 47.7%, and 16.9% gained at least 3 lines of acuity respectively. These studies also showed patients may gain vision even without treatment and if treatment is postponed the patient may show benefit, although not as much as if the patient were treated immediately. The COPERNICUS and GALILEO studies looked at the benefit of Eylea for macular edema from CRVO only and helped the medication gain FDA approval. Both studies demonstrated significant visual gains with Eylea, 56.1% of patients treated in the COPERNICUS study and 60.2% treated in the GALILEO study gained at least 15 letters versus 12.5% and 22.1% of the sham group. Results are listed in Table 3. Table 3 Study Brief Description Medication Dose Gain > 15 ETDRS letters BRAVO 6 month trial that Lucentis 0.3mg Monthly 55.2% showed benefit of Lucentis 0.5mg Monthly 61.1% Lucentis for macular edema 2 BRVO Sham Monthly 28.8% CRUISE 6 month trial that Lucentis 0.3.mg Monthly 46.2% showed benefit of Lucentis 0.5mg Monthly 47.7% Lucentis for macular edema 2 CRVO Sham Monthly 16.9% COPERNICUS 6 month trial that Eylea 2.0mg Monthly 56.1% showed benefit of Eylea Sham Monthly 12.5% for macular edema 2 CRVO GALILEO 6 month trial that Eylea 2.0 mg Monthly 60.2% showed benefit of Eylea Sham Monthly 22.1% for macular edema 2 CRVO Anti- - - VEGF medications are playing a huge role in a variety of ocular diseases, namely exudative AMD, clinically significant macular edema, and macular edema from retinal vein occlusions. Studies have not only shown that they can help preserve vision, but that a majority of these patients actually gain vision compared to traditional treatments. Even though anti- - - VEGF medications seem to be a primary treatment for many diseases, there is still a place for laser treatment and intravitreal steroids. Newer studies are looking at long term anti- - - VEGF usage and its affects on ocular health, but for the meantime the benefits of these medications seem to outweigh any risks.

6 References American Diabetes Association: Diabetes Statistics basics/diabetes- - - statistics. Jan Brown DM, Campochiaro PA, et al Sustained Benefits from Ranibizumab for Macular Edema Following Branch Retinal Vein Occlusion: Month Outcomes of a Phase III Study. Ophthalmology.2011;118(8); Brown DM. Clinical Implications of the BRAVO and CRUISE Trials. Retina Today. April Campochiaro PA, Brown DM, et al. Sustained Benefits from Ranibiuzumab for Macular Edema following Central Retinal Vein Occlusion: Twelve- - - Month Outcome of a Phase III Study. Ophthalmology.2011;118(10); Ehlers JP, Fekrat S, Retinal Vein Occlusions: Beyond the Acute Event. Survey of Ophthalmology. 2011;56(4); Fung A. Influence of Baseline Characteristics and Dosing Outcomes of Anti- - - VEGF Therapy for Retinal Vein Occlusions. Retina Today. June Heier JS, Brown DM, et al. Intravitreal Aflibercept (VEGF Trap- - - Eye) in Wet Age- - - Relate Macular Degeneration. Ophthalmology.2012;119(12); Ho AH, Scott IU, et al. Anti- - - Vascular Endothelial Growth Factor Pharmocotherapy for Diabetic Macular Edema. Ophthalmology.2012;119(10); Ip MS, Scott IU, et al. Anti- - - Vascular Endothelial Growth Factor Pharmocology for Age- - - Related Macular Degeneration. Ophthalmology.2008;115(10): Kim LA, D Amore PA. A Brief History of Anti_VEGF for the Treatment of Angiogenesis. American Journal of Pathology 2012;181(2); Mahar PS, Hanfi AN, Kahn A. Angiogenesis and Role of Anti- - - VEGF Therapy. Pak J Opthalmology.2009;25(3); Miller JW, Le Couter J, et al. Vascular Endothelial Growth Factor A in Intraocular Vascular Disease. Ophthalmology.120(1); Nguyen QD, Brown DM, et al. Rinibizumab for Diabetic Macular Edema. Results from 2 Phase II Randomized Trials; RISE and RIDE. Opthalmology.2012;119(4): Penn JS, Madan A, et al. Vascular endothelial growth factor in eye disease. Progress in Retinal Eye Research.2008;27; Schreiber S. What is Macular Degeneration. American Macular Degeneration Foundation Shapiro A. Anti VEGF State of the Union. Retina Today.February Wykoff CC, Brown DM. CATT at 2 Years: The Facts. Medscape Ophthalmology. Aug Envoy KE, Abel SR. Afliberept: Newly Approved Treatment of Macular Edema Following Central Retinal Vein Occlusion. June2013;47(6);

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