Article Date: 3/1/2006

Peer Reviewed
Anti-VEGF Agents for Macular Edema Secondary to Retinal Vascular Disorders
RAJA NARAYANAN, MD • BARUCH D. KUPPERMANN, MD, PhD

Recent studies have implicated vascular endothelial growth factor (VEGF) in human eye diseases characterized by increased vascular permeability.1,2 Levels of ocular VEGF are correlated tightly with both the growth and permeability of new vessels.1,3,4 Furthermore, introduction of VEGF into normal primate eyes induces the same pathologic processes seen in diabetic retinopathy, including microaneurysm formation and increased vascular permeability.2,5,6 Vitreous samples from patients with diabetic macular edema (DME) contain elevated VEGF levels.7,8 These observations provide a sound rationale for the targeting of VEGF in ocular disorders with underlying manifestations of ocular neovascularization and/or increased vascular permeability, including DME, macular edema due to branch retinal vein occlusion (BRVO), and central retinal vein occlusion (CRVO).

DIABETIC MACULAR EDEMA

Recently, the results of a phase 2 trial to evaluate the safety and efficacy of pegaptanib sodium injection (Macugen, Eyetech Pharmaceuticals, Inc.) in the treatment of DME were published.9 In a randomized, double-masked, multi-center trial, individuals were enrolled who had a best-corrected visual acuity (VA) between 20/50 and 20/320 in the study eye, and DME involving the center of the macula. Intravitreous pegaptanib (0.3 mg, 1 mg, 3 mg) or sham injections were given at study entry, week 6, and week 12 with additional injections and/or focal photocoagulation as needed for another 18 weeks. Median VA was better at week 36 with 0.3 mg (20/50), as compared with sham (20/63) (P=.04). A larger proportion of those receiving 0.3 mg gained VAs of �10 letters (approximately 2 lines) (34% vs. 10%; P=.003) and �15 letters (18% vs. 7%; P=.12). Mean central retinal thickness decreased by 68 μm with 0.3 mg vs. an increase of 4 μ with sham (P=.02). Larger proportions of those receiving 0.3 mg had an absolute decrease of both �100 μm (42% vs. 16%; P=.02) and �75 μm (49% vs. 19%; P=.008). Photocoagulation was deemed necessary in fewer subjects in each pegaptanib arm (0.3 mg vs. sham, 25% vs. 48%; P=.04). In this trial, patients injected with pegaptanib had better VA, were more likely to have reduction in macular edema, and were less likely to need additional therapy with photocoagulation at follow-up. Ranibizumab (Lucentis, Genentech) is a recombinant, humanized, Fab fragment of the anti-VEGF antibody. Two pilot studies in the US and 1 in Europe are currently underway, determining the safety and efficacy of another anti-VEGF antibody, ranibizumab in the treatment of DME.

Recent studies have suggested that intravitreal triamcinolone acetonide (Kenalog, Bristol-Myers Squibb) (IVTA) may be useful in temporarily improving VA in patients with diffuse DME.10-13 Patients in study groups receiving IVTA compared with patients in control groups showed a significant improvement in VA during follow-up. There is convincing evidence that the effect of IVTA in the treatment of DME.13 In a prospective, placebo-controlled, randomized clinical trial of 69 eyes of 43 patients, 34 eyes were randomized to receive IVTA (4 mg) and 35 eyes were randomized to receive a placebo injection. Eighteen of 33 eyes (55%) treated with triamcinolone gained 5 or more letters in best corrected VA compared with 5 of 32 eyes (16%) treated with placebo (P=.002). Macular edema was reduced in 25 of 33 treated eyes (75%) vs. 5 of 32 untreated eyes (16%; P<.0001). Optical coherence tomography (OCT) showed a mean reduction of central retinal thickness of 152 μm in the 21 treated eyes that were examined, compared with a reduction of 36 μm in the 20 placebo-treated eyes.13 The Diabetic Retinopathy Clinical Research Network (DRCRnet) is a collaborative network dedicated to facilitating multi-center clinical research of diabetic retinopathy, DME and associated conditions. The DRCR.net supports the identification, design, and implementation of multi-center, clinical research initiatives focused on diabetes-induced retinal disorders. The DRCR.net was formed in September 2002 and currently includes over 100 participating sites (offices) with over 300 physicians throughout the US. Currently, enrollment is almost complete for a large randomized clinical trial comparing focal laser for DME to triamcinolone acetonide in a hydrogel formulation (Allergan).

Another steroid, fluocinolone acetonide (Retisert, Bausch and Lomb Pharmaceuticals), has shown promising results in the treatment of DME and in macular edema due to vein occlusion. In a phase 2 study, 80 patients were enrolled and randomized to a 0.5 mg implant, a 2 mg implant, or standard of care treatment. At the 6-month follow-up, the proportion of eyes with maintained or improved VA was greater in the eyes that received the 0.5 mg implant than in those receiving standard of care treatment. However, at 12 months this difference was no longer statistically significant. Visual acuity was significantly better at 24 months, but not at 12 months because of the development of cataracts that once removed, allowed one to have an improvement of VA. At the 6-month follow-up, the proportion of eyes with a 2 or more step decrease in retinal thickening at the center of the fovea was greater in the eyes that received the 0.5 mg implant than in those receiving standard of care treatment. This difference remained statistically significant at the 12 and 24-month time points. Cataract and elevated intraocular pressure (IOP) were commonly observed in this study. According to the Retisert package insert, nearly all phakic eyes undergoing Retisert implantation will develop cataracts within 2 years after implantation. Additionally, over 60% of eyes will develop elevated IOP requiring topical therapy within 2 years, and over 30% of patients will require a surgical procedure to control IOP during that time (Retisert package insert, page 8). Largely because of the high rates of cataract progression and glaucoma, the fluocinolone acetonide implant is currently approved only for patients with uveitis, and further development for the DME is under review by the company.

The Posurdex (Allergan Inc.) drug delivery system is a sustained-release formulation for posterior-segment delivery of dexamethasone, made of a polylacticglycolic acid (PLGA) matrix. The safety and efficacy of the Posurdex delivery system was tested in a controlled phase 2, prospective, randomized multi-center study in which patients were randomly assigned to 1 of 3 treatment arms: a single Posurdex implant containing a 350 μg dose of dexamethasone, a single Posurdex implant containing 700 μg of dexamethasone, or observation without drug therapy. The phase 2 study followed 306 patients who were diagnosed with macular edema associated with 4 conditions: diabetes (172 patients), retinal vein occlusions (103 patients), uveitis (14 patients), and postcataract surgery (27 patients). A dose response curve was observed, with 19.4% of eyes showing a 3 line or greater improvement in VA at day 180 in the 700 mcg Posurdex group compared with 13.0% of eyes in the 350 mcg Posurdex vs. 8.0% of eyes in the observation group (P=.02). The change in retinal thickness in the 700-μg group was -142 μm, whereas the retinal thickness in the observation group increased by an average of 11 μm (P<.001). There were no treatment-related cases of endophthalmitis. Cataract progression was not different between groups, including the observation group. Increased IOP of at least 10 mm Hg over baseline was observed in 11% of eyes in the 700 mcg Posurdex group after the 7-day timepoint; these increases were all successfully managed by either observation or topical therapy. Phase 3 trials are currently underway for patients with DME and macular edema caused by vein occlusion.

BRANCH RETINAL VEIN OCCLUSION

Branch retinal vein occlusion is a common retinal vascular disease and often results in macular edema, which is the most frequent cause of visual impairment in patients with BRVO.14 Vascular endothelial growth factor and interleukin-6 (IL-6) may be involved in the pathogenesis of macular edema with BRVO. The aqueous levels of VEGF and IL-6 are significantly correlated with the degree of retinal ischemia, and that the aqueous level of VEGF is significantly correlated with the severity of macular edema, suggesting that VEGF and IL-6 may contribute to the pathogenesis of macular edema with BRVO.15

A recent prospective, comparative, nonrandomized clinical interventional study included 10 patients with BRVO (2 eyes with ischemic-type BRVO; 8 eyes with nonischemic occlusion), who received an intravitreal injection of 20 mg–25 mg of triamcinolone acetonide, and 18 patients in a control group without IVTA. The patients in the study group experienced a significant increase in VA, while the patients in the control group did not show a significant change in VA during the follow-up. Comparing the study and control groups with one another, the gain in VA was seen to be significantly more marked in the study group for the measurements obtained 1 and 2 months after baseline.16 This confirmed another study in which IVTA reduced macular edema in eyes with branch CRVO.17 The safety and efficacy of the Posurdex delivery system in the treatment of macular edema due to BRVO is listed above. Currently a phase 3 study evaluating the Posurdex delivery system for eyes with macular edema due to BRVO and CRVO is underway.

The standard of care vs. corticosteroids for retinal vein occlusion (SCORE) study is an ongoing multi-center, randomized, phase 3 trial designed to assess the efficacy and safety of standard care vs. triamcinolone acetonide in a hydrogel formulation (Allergan Inc.) 1 mg or 4 mg intravitreal injection(s) for the treatment of macular edema associated with CRVO and BRVO. Recruitment is currently underway for this study.

CENTRAL RETINAL VEIN OCCLUSION

Cystoid macular edema is one of the major causes of decreased vision in patients with CRVO. With the exception of retinal laser coagulation in eyes with early iris neovascularization, other therapeutic options have not been proven effective in increasing VA after CRVO. Recent studies on IVTA have addressed macular edema due to CRVO.18 Bashshur and colleagues evaluated the efficacy of IVTA in the management of persistent macular edema secondary to non-ischemic CRVO.19 Twenty consecutive patients with a 3 to 4-month history of nonischemic CRVO received a single intravitreal injection of 4 mg of triamcinolone acetonide. The follow-up period ranged from 10 to 12 months. Treated patients were compared with a retrospectively matched group of patients managed with observation only. The study group showed a significantly better outcome than the control group. At the final follow-up, the treated group had a mean VA of 20/37, while the observation group had a mean VA of 20/110 (P=.001). A total of 60% of treated patients had a final VA of 20/40 or better vs. only 20% in the observation group (P=.01); 40% of untreated patients had a final VA <20/200, while none of the treated patients did (P<.001). At final follow-up, 75% of treated patients had complete resolution of macular edema on clinical examination versus only 20% of the untreated patients (P<.001). Two of the treated patients had recurrence of macular edema at 6 months, and 3 had elevated IOP. The authors concluded a treatment benefit from intravitreal triamcinolone in terms of VA and macular edema for nonischemic CRVO. The safety and efficacy of the Posurdex delivery system in the treatment of macular edema due to CRVO is listed above. As mentioned previously, a phase 3 study evaluating the Posurdex delivery system for eyes with macular edema due to BRVO and CRVO is underway.

There is also a report of macular edema improving with intravitreal injection of bevacizumab (Avastin, Genentech, South San Francisco, Calif) in a case of CRVO. Within
1 week of the bevacizumab injection, VA improved from 20/200 to 20/50 and OCT revealed resolution of the cystic maculopathy. The improvements were maintained for at least 4 weeks. Intravitreal injections of bevacizumab may provide another treatment option for patients with macular edema from vein occlusions.20

In addition to evaluating the safety and efficacy of pegaptanib sodium injection DME, there is an ongoing phase 2, randomized, double-masked, multi-center trial evaluating pegaptanib sodium in patients with macular edema secondary to CRVO. No results are yet available.

In summary, laser photocoagulation was the only available treatment option until recently to treat macular edema secondary to retinal vascular diseases. Currently, off-label use of triamcinolone acetonide and more recently bevacizumab have been utilized. However, without the benefit of randomized, controlled clinical trials the safety and efficacy of these treatments are not fully understood. Importantly, randomized controlled clinical trials are underway evaluating injections of intravitreal steroids and anti-VEGF agents, as well as steroid based drug delivery systems. We anticipate that in the near future, several options for which we have a clear understanding of safety and efficacy would be available to retinal physicians for the treatment of macular edema.

REFERENCES

1. Adamis AP, Miller JW, Bernal MT, et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol. 1994;118:445-450.

2. Tolentino MJ, Miller JW, Gragoudas ES, et al. Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology. 1996;103:1820-1828.

3. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1480-1487.

4. Malecaze F, Clamens S, Simorre-Pinatel V, et al. Detection of vascular endothelial growth factor messenger RNA and vascular endothelial growth factor-like activity in proliferative diabetic retinopathy. Arch Ophthalmol. 1994;112;1476-1482.

5. Tolentino MJ, McLeod DS, Taomoto M, et al. Pathologic features of vascular endothelial growth factor-induced retinopathy in the nonhuman primate. Am J Ophthalmol. 2002;133:373-385.

6. Tolentino MJ, Miller JW, Gragoudas ES, et al. Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in a nonhuman primate. Arch Ophthalmol. 1996;114:964-970.

7. Funatsu H, Yamashita H, Noma H, et al. Increased levels of vascular endothelial growth factor and interleukin-6 in the aqueous humor of diabetics with macular edema. Am J Ophthalmol. 2002;133: 70-77.

8. Brooks HL Jr, Caballero S Jr, Newell CK, et al. Vitreous levels of vascular endothelial growth factor and stromal-derived factor 1 in patients with diabetic retinopathy and cystoid macular edema before and after intraocular injection of triamcinolone. Arch Ophthalmol. 2004;122:1801-1807.

9. Macugen Diabetic Retinopathy Study Group. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology. 2005;112:1747-1757.

10. Jonas JB, Akkoyun I, Kreissig I, Degenring RF. Diffuse diabetic macular oedema treated by intravitreal triamcinolone acetonide. A comparative non-randomized study. Br J Ophthalmol .2005;89:321-326.

11. Massin P, Audren F, Haouchine B, et al. Intravitreal triamcinolone acetonide for diabetic diffuse macular oedema: preliminary results of a prospective controlled trial. Ophthalmology. 2004;111:218-224.

12. Jonas JB, Kreissig I, Söfker A, Degenring RF. Intravitreal injection of triamcinolone acetonide for diabetic macular oedema. Arch Ophthalmol. 2003;121:57-61.

13. Sutter FK, Simpson JM, Gillies MC. Intravitreal triamcinolone for diabetic macular oedema that persists after laser treatment: 3-month efficacy and safety results of a prospective, randomized, double-masked, placebo-controlled clinical trial. Ophthalmology. 2004;111:2044-2049.

14. Michels RG, Gass JD. The natural course of retinal branch vein obstruction. Trans Am Acad Ophthalmol Otolaryngol. 1974;78:166-177.

15. Noma H, Funatsu H, Yamasaki M, et al. Pathogenesis of macular edema with branch retinal vein occlusion and intraocular levels of vascular endothelial growth factor and interleukin-6. Ameri J Ophthalmol. 2005;140:256-261.

16. Jonas JB, Akkoyun I, Kamppeter B, Kreissig I, Degenring RF. Intravitreal triamcinolone acetonide as treatment of branch retinal vein occlusion. Eye. 2004;19:65-71.

17. Jonas JB, Degenring R, Kamppeter B, Kreissig I, Akkoyun I. Duration of the effect of intravitreal triamcinolone acetonide as treatment of diffuse diabetic macular oedema. Am J Ophthalmol. 2004;138:158-160.

18. Ip MS, Gottlieb JL, Kahana A, et al. Intravitreal triamcinolone for the treatment of macular oedema associated with central retinal vein occlusion. Arch Ophthalmol. 2004;122:1131-1136.

19. Bashshur ZF, Ma'luf RN, Allam S, Jurdi FA, Haddad RS, Noureddin BN. Intravitreal triamcinolone for the management of macular oedema due to non-ischaemic central retinal vein occlusion. Arch Ophthalmol. 2004;122:1137-1140.

20. Rosenfeld PJ, Fung AE, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for macular edema from central retinal vein occlusion. Ophthalmic Surg Lasers Imaging. 2005;36:336-339.

Raja Narayanan, MD, is a clinical instructor at the University of California, Irvine. Baruch D. Kuppermann, MD, PhD, is an associate professor of ophthalmology and biomedical engineering, chief of the retina service, and vice-chair of clinical research at the University of California, Irvine. Dr. Narayanan has no financial interest in the information contained in this article. Dr. Kuppermann is a consultant for Allergan, Bausch&Lomb, Eyetech, and Genentech. Dr. Kuppermann can be reached by e-mail at bdkupper@uci.edu. Dr. Narayanan can be reached by e-mail at dr_narayanan@hotmail.com.



Retinal Physician, Issue: March 2006