Angeline Mariani Derham, MD and David M. Brown, MD, FACS

Pegaptanib

Pharmacology

Pegaptanib sodium (Macugen) is a 50 kDa pegylated modified oligonucleotide aptamer that adopts a 3-dimensional shape to selectively inhibit extracellular vascular endothelial growth factor (VEGF)₁₆₅, the major VEGF-A isoform in the eye.¹ Aptamers are single-stranded nucleotides that bind with high affinity and specificity to predetermined target molecules such as proteins and peptides.² These aptamers are selected in vitro using the systematic evolution of ligands by exponential enrichment technique to isolate oligonucleotide ligands that bind to a variety of proteins.³ Because VEGF is a secreted protein that binds to and activates receptors located predominantly on the surface of vascular endothelial cells, a selective antagonist in the form of a modified aptamer mitigates VEGF-induced angiogenesis, vascular permeability, and inflammation.⁴

Therapeutic Efficacy

Pegaptanib, approved by the United States (US) Food and Drug Administration (FDA) in 2004, was the first anti-VEGF agent approved for ocular use. It is currently approved for the treatment of neovascular age-related macular degeneration (AMD) as a 0.3 mg intravitreal injection every 6 weeks.¹

The first preclinical and phase Ia evaluation of the pegylated aptamer was conducted by the Eyetech Study Group in 2002. They found that patients with neovascular AMD had no adverse outcomes related to the drug and 80% of patients experienced stable or improved vision 3 months after the injection.⁵ A larger subsequent trial involving 1186 patients with neovascular AMD proved efficacy of pegaptanib across 3 dosages, 0.3 mg, 1.0 mg, and 3.0 mg, compared to sham injection, but were unable to find a dose-response relationship.6 Various randomized trials have since been conducted displaying therapeutic benefits from pegaptanib in patients with macular edema secondary to retinal vein occlusions, Von Hippel-Lindau disease, diabetic macular edema, and diabetic retinopathy.^7–10

Despite its early advantage, the emergence of additional anti-VEGF agents with wider isoform antagonism has limited the use of pegaptanib. More recent clinical trials focus on pegaptanib as a supplemental therapy, such as preoperative injection to improve surgical outcomes of patients with proliferative diabetic retinopathy. The concept behind this use is that the selectivity of pegaptanib may result in regression of neovascularization with a diminished tractional response compared with pan-anti-VEGF agents that can result in a “crunch” tractional retinal detachment phenomenon.¹¹

Conclusions

The first intravitreal anti-VEGF agent to be approved by the FDA, pegaptanib was a monumental discovery in the treatment of AMD. It was quickly replaced with newer, broader-acting anti-VEGF agents; however, there is continued interest in using pegaptanib as a supplemental treatment.

Ranibizumab

Pharmacology

Ranibizumab (Lucentis), the first VEGF inhibitor designed specifically for ocular use, is a 48 kDa recombinant humanized immunoglobulin G1 kappa monoclonal antibody fragment that binds to and inhibits VEGF-A.¹² Its lack of a fragment crystallizable region results in a more rapid systemic clearance.¹³ It is produced by an Escherichia coli expression system in a growth medium containing tetracycline. The advantage of protein expression in E coli is the ability to express and purify a desired recombinant protein in large quantities.¹⁴

Therapeutic Efficacy

Approved by the FDA in 2006, ranibizumab was the second anti-VEGF agent approved for ocular use. It is currently approved for the treatment of neovascular AMD, diabetic macular edema, diabetic retinopathy, macular edema following retinal vein occlusion, and more recently, choroidal neovascularization secondary to pathologic myopia.

For patients with neovascular AMD, ranibizumab is approved as a monthly 0.5 mg intravitreal injection, with less frequent injections allowable after the first 3 or 4 months.¹² There were 4 large, randomized phase III studies evaluating the safety and efficacy of ranibizumab in neovascular AMD. In Study AMD-1 (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD [MARINA]) and Study AMD-2 (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD [ANCHOR]), patients received monthly 0.3 mg ranibizumab, 0.5 mg ranibizumab, sham injections, or verteporfin (photodynamic therapy, PDT) for 2 years. MARINA patients had minimally classic or occult neovascularization, whereas ANCHOR patients had predominantly classic neovascularization. Both studies showed ranibizumab to be effective and safe in neovascular AMD patients with differing anatomically categorized disease.15,16 In Study AMD-3 (PIER), patients received 0.3 mg ranibizumab, 0.5 mg ranibizumab, or sham injections monthly for 3 consecutive doses, followed by a mandated dose every 3 months for a total of 24 months. This study treated a wider variety of lesion subtypes and also showed an improvement in ranibizumab-treated patients compared to sham.^17,18 These trials advocated for the use of ranibizumab in all angiographic subtypes of neovascular AMD and across lesions of all sizes.^15–18 Study AMD-4 (HARBOR) was a dose-response study in which 1098 patients received monthly or pro re nata (PRN) ranibizumab injections of either 0.5 mg or 2.0 mg following 3 initial monthly injections. Although all groups experienced visual improvement, the 2.0 mg monthly group did not meet the prespecified superiority comparison and the 0.5 mg and 2.0 mg PRN groups did not meet the prespecified noninferiority comparison. This study confirmed that 0.5 mg doses of ranibizumab monthly provides the best results in patients with neovascular AMD.^19–20

For patients with diabetic macular edema or diabetic retinopathy, ranibizumab is approved for a monthly 0.3 mg intravitreal injection.¹² This indication was evaluated in 2 pivotal parallel trials (RISE and RIDE) in which 759 patients were assigned to monthly ranibizumab 0.3 mg or 0.5 mg or sham injection for 24 months.²¹ All outcome measures were superior in ranibizumab-treated patients as compared to sham, and these benefits were maintained at 36 months.²²

For patients with choroidal neovascularization secondary to pathologic myopia, ranibizumab was recently approved as a 0.5 mg intravitreal injection with allowable repeated treatment at monthly intervals.¹² The clinical benefit of ranibizumab in these patients was demonstrated in a randomized phase III trial known as RADIANCE. In this trial, intravitreal ranibizumab was found to be superior to intravenous verteporfin plus PDT. Improvements in vision were sustained for up to 12 months in ranibizumab recipients and were mirrored by improvements in anatomic outcomes.²³

For patients with macular edema following retinal vein occlusion, ranibizumab is approved as a monthly 0.5 mg intravitreal injection.¹² Study RVO-1 (Branch Retinal Vein Occlusion: Evaluation of Efficacy and Safety [BRAVO]) and Study RVO-2 (Central Retinal Vein Occlusion Study: Evaluation of Efficacy and Safety [CRUISE]) were parallel studies that analyzed the use of ranibizumab for patients with center-involved macular edema following branch (397 patients) and central (392 patients) retinal vein occlusions, respectively. Both studies had a treatment period of 6 months of monthly 0.3 mg or 0.5 mg ranibizumab or sham injection followed by a 6-month observation period. Results demonstrated a greater improvement in best-corrected visual acuity (BCVA) in both treatment groups compared to sham.^24–27

Conclusions

Ranibizumab is a safe treatment strategy for a variety of retinal diseases, including neovascular AMD, diabetic macular edema, diabetic retinopathy, choroidal neovascularization secondary to pathologic myopia, and macular edema following retinal vein occlusion. It was the first anti-VEGF agent designed and approved for ocular use. Ongoing research focuses on adjusting dosing regimen and treatment schedule.

Bevacizumab (Avastin) is a 140 kDa recombinant humanized monoclonal antibody that binds to VEGF-A.28 It is a much larger molecule than ranibizumab, which theoretically may limit efficacy and contribute to a weaker binding affinity. Nevertheless, it has been proven to penetrate the retina²⁹ and comparative trials have showed near equivalence in clinical efficacy.^30,31

Therapeutic Efficacy

Bevacizumab, initially designed for non-ocular use, was approved by the FDA in 2004 for metastatic colorectal cancer.³² It is currently approved for treating a range of cancers, including angiosarcoma, cervical cancer, endometrial cancer, ovarian cancer, glioblastoma, renal cell carcinoma, colorectal cancer, and small-cell lung cancer, and is used off-label for metastatic breast cancer and a variety of ocular diseases including neovascular AMD.^28,33 Because no industry-sponsored ophthalmology trials were conducted, ocular use of bevacizumab is strictly off-label. As it is less expensive than both ranibizumab and aflibercept, it is an appealing alternative to the FDA-approved medications, especially in patients undergoing monthly injections in one or both eyes.

Postinjection endophthalmitis is a risk for any intravitreal injection, but because bevacizumab is not provided as an individual dose, it must be compounded by a local pharmacy into ready-to-use syringes. For this reason, publicized outbreaks of endophthalmitis have been caused by contamination at the time of compounding.³⁴ Nevertheless, studies have shown that after controlling for age, race, sex, injection-related diagnosis, and year of injection, there is no significant association with development of endophthalmitis after an injection of bevacizumab compared to ranibizumab.³⁵

With regard to systemic adverse events, a meta-analysis of 9 studies found no difference in adverse events between bevacizumab and ranibizumab in the first 2 years of treatment, but did find a higher risk of gastrointestinal disorders in patients treated with bevacizumab in their secondary analysis.³⁶ In the United Kingdom-based Age-Related Choroidal Neovascularization (IVAN) trial, fewer patients in the bevacizumab group experienced arteriothrombotic events or heart failure than in the ranibizumab group. Another interesting finding was that patient median serum VEGF concentrations at one year were lower for bevacizumab than for ranibizumab.³⁷

A large multicenter study, the Comparison of Age-related Macular Degeneration Treatments Trials (CATT), aimed to elucidate whether bevacizumab and ranibizumab were clinically equivalent and whether monthly vs as-needed treatments were clinically equivalent. After the 2-year endpoint, CATT found that visual outcomes between the 2 groups were statistically insignificant but that anatomic markers for dry eyes as measured by optical coherence tomography were more common in eyes treated with ranibizumab.³⁰

Aflibercept (Eylea) is a 115 kDa glycosylated dimeric human VEGF receptor fusion protein created with Trap technology in which portions of 2 receptors (extracellular domains of VEGF-R1 and VEGF-R2) are fused with the immunoglobulin constant region of human immunoglobulin G1.38,39 This creates a soluble decoy receptor with a ligand-binding affinity more potent than the individual native endogenous receptors. Aflibercept binds to VEGF-A, VEGF-B, and placental growth factor and demonstrates higher binding affinity for VEGF-A when compared to previously designed anti-VEGF agents.⁴⁰

Therapeutic Efficacy

Aflibercept was approved by the FDA for the treatment of neovascular AMD in 2011. Since then, it has also been approved for macular edema following retinal vein occlusion, diabetic macular edema, and diabetic retinopathy on different scheduled regimens. In addition, it has been approved in various countries outside the US for the treatment of choroidal neovascularization secondary to myopia.

For patients with neovascular AMD, aflibercept is approved as a 2 mg intravitreal injection every 2 months following 3 initial monthly injections.³⁹ The phase I and II Clinical Evaluation of Anti-Angiogenesis in the Retina (CLEAR) trials examined the safety, pharmacokinetics, and biological activity of aflibercept in neovascular AMD patients^41–43 and the CLEAR IT 2 trial refined the dosing regimens for the subsequent VIEW trials.⁴² The VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW 1 and VIEW 2) trials were large, randomized, controlled phase III trials, enrolling 1217 and 1240 patients, respectively. VIEW 1 was conducted in the US and Canada, and VIEW 2 was conducted across Europe, Middle East, Asia-Pacific, and Latin America. Both trials were similarly designed to compare 3 different dosing regimens of aflibercept (0.5 mg every 4 weeks, 2 mg every 4 weeks, and 2 mg every 8 weeks after 3 initial monthly doses) compared to 0.5 mg ranibizumab every 4 weeks. They found all 3 dosing groups of aflibercept to be noninferior and clinically equivalent to ranibizumab at 52 weeks.⁴⁴ In the second year of the VIEW trials, all groups were found to be equally effective in improving BCVA and preventing BCVA loss at 96 weeks.⁴⁵

For patients with macular edema following retinal vein occlusion, aflibercept is approved as a 2 mg intravitreal injection administered monthly.³⁹ The parallel trials General Assessment Limiting Infiltration of Exudates in Central Retinal Vein Occlusion with VEGF Trap-Eye (GALILEO) (Europe and Asia-Pacific) and Controlled Phase III Evaluation of Repeated Intravitreal Administration of VEGF Trap-Eye in Central Retinal Vein Occlusion (COPERNICUS) (US, Canada, Columbia, India, and Israel) proved monthly 2 mg aflibercept injections followed by PRN treatment superior to sham injection in 365 patients with macular edema secondary to central retinal vein occlusion.46,47 The phase III VIBRANT trial (North America and Japan) randomized 183 eyes with macular edema following branch retinal vein occlusion to 2 mg aflibercept group or laser photocoagulation and sham groups. Patients in the aflibercept group received a 2 mg injection every 4 weeks through week 20, followed by every 8 weeks through week 48. Significantly greater visual and anatomic improvements in the aflibercept group were maintained by week 52.⁴⁸

For patients with diabetic macular edema, aflibercept is approved as a 2 mg intravitreal injection every 2 months following 5 initial monthly injections.³⁹ The VISTA (US) and VIVID (Europe, Japan, and Australia) studies randomized 872 patients with center-involved diabetic macular edema to aflibercept 2 mg every 4 weeks, 2 mg every 8 weeks after 5 initial monthly doses, or laser photocoagulation. Visual and anatomic gains were found to be superior in both aflibercept groups as compared to the laser group for both studies at 52 weeks⁴⁹ and maintained through week 100.⁵⁰ The Diabetic Retinopathy Clinical Research Network-led Protocol T trial was the first trial comparing 3 of the most widely used anti-VEGF agents for center-involved diabetic macular edema. A total of 660 patients were randomized to arms with 2 mg aflibercept, 0.3 mg ranibizumab, or 1.25 mg bevacizumab.⁵¹ Patients treated with aflibercept had significantly greater BCVA gains from baseline (13.3 letters) compared with those treated with either ranibizumab (11.2 letters, P = .03) or bevacizumab (9.7 letters, P < .001) at 1 year, required 1 fewer injection, and had a lower proportion of patients requiring rescue treatment with laser compared with the other 2 groups. At 2 years, treatment benefits observed in year 1 were maintained across all 3 treatment groups.⁵²

There is evidence to suggest that aflibercept is also a promising intervention for patients with recalcitrant disease. Small retrospective studies have shown that aflibercept therapy might be helpful for AMD patients exhibiting recurrent or resistant leakage despite prior anti-VEGF treatment.^53–55

Conclusions

Aflibercept has been shown to improve both visual and anatomic outcomes with an acceptable safety profile in patients with neovascular AMD, macular edema following retinal vein occlusion, diabetic macular edema, and choroidal neovascularization in myopia. It is the first anti-VEGF agent demonstrating similar results whether given every 8 weeks following a loading dose or dosed monthly in patients with neovascular AMD and diabetic macular edema. Although it provides an alternative treatment regimen, the high cost of this newest anti-VEGF agent may be prohibitive for some patients but potentially worthwhile if treatment intervals can be extended.

References

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