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Role of Pegaptanib in the Current Management of Exudative Age-related Macular Degeneration
Role of Pegaptanib in the Current Management of Exudative Age-related Macular Degeneration
Timothy L Comstock, Ophthalmic Medical Affairs Consultant, Amherst, NY, US
Teresa L Brevetti, Department of Ophthalmology, SUNY Downstate Medical Center, Brooklyn, NY, US

Age-related macular degeneration (AMD) is a progressive maculopathy that affects an estimated 8.7% of adults worldwide and can lead to irreversible central vision loss.1–4 Phenotypically, AMD is classified as either non-neovascular (dry, non-exudative) or neovascular (wet, exudative) AMD.5 Neovascular AMD (nAMD) represents an advanced form of the disease and involves the growth of abnormal blood vessels beneath the neurosensory retina or the retinal pigment epithelium (RPE), which can lead to leakage of intra- and/or subretinal fluid, exudates from new blood vessels, fibrous scarring of the macula and progressive loss of central vision.2,6,7 Although less than 10% of patients with AMD have the neovascular phenotype, a great majority (80–90%) of AMD-related blindness develops in patients with nAMD.8 

The aetiology of AMD is multifactorial, but a key component is the accumulation of drusen, which results in hypoxia and the expression of pro-angiogenic factors (e.g. vascular endothelial growth factor [VEGF]) that promote new vessel development.9 Clinical studies have established the integral role of VEGF-A in both ischemic and choroidal neovascularization,6 and inhibition of VEGF-A is currently considered the most effective treatment for nAMD, improving both anatomical and visual outcomes.2,7

VEGF inhibitors

Pegaptanib sodium (Macugen®; Bausch + Lomb; Bridgewater, NJ, US) was the first antiangiogenic agent used for the treatment of ocular neovascular disease (Figure 1),10,11 and was approved by the US Food and Drug administration in 2004 for the treatment of nAMD.12 Unlike other non-selective VEGF inhibitors (e.g. bevacizumab,13 ranibizumab14 and aflibercept15), pegaptanib is a small oligonucleotide aptamer that specifically inhibits the 165 isoform of VEGF (VEGF165).10–12,16 While this selectivity may limit the efficacy of pegaptanib in nAMD compared with non-selective (or ‘pan’) VEGF inhibitors,2,17–20 it may provide an alternative therapeutic option in patients who experience tolerability issues with, or are otherwise unable to receive, pan-VEGF therapy.

Figure 1: Sequence and predicted secondary structure of pegaptinib10

2’-O-methylated purines are shown in red, 2’-fluorine-modified pyrimidines are shown in blue and unmodified ribonucleotides are shown in black. The site of attachment of a 40-kDa polyethylene glycol moiety is shown.

Safety issues with VEGF inhibition

As VEGF is involved in a wide variety of physiological processes, it has been hypothesised that non-selective blockade of VEGF may contribute to an increased risk of ocular and systemic vascular events by impairing regulation and maintenance of the normal microvasculature.21 The selective blockage of VEGF165 with pegaptanib could therefore help reduce this risk.

Adverse ocular events

A review of available clinical evidence for pegaptanib and the pan-VEGF inhibitor ranibizumab by Tolentino et al. 2011, reported no ocular safety concerns with pegaptanib, but a low frequency of ocular inflammation with ranibizumab.21 In addition, recent studies have reported retinal arteriolar vasoconstriction,22,23 altered retrobulbar blood flood velocity,24 choroidal thinning and/or reduced central macular thickness,23,25 increased cup-to-disc ratio and cup volume,26 reduced retinal nerve fibre layer thickness,26 and decreased cellular metabolic activity and increased cytotoxicity of retinal cells with intravitreal pan-VEGF inhibitors.26 

Geographic atrophy

Preclinical evidence suggests that prolonged anti-VEGF treatment may interfere with maintenance of the choriocapillaris and result in areas of RPE loss and choroidal remodeling.27 Accordingly, development of geographic atrophy, involving breakdown of RPE and the capillary lamina of the choroid, is increasingly being recognised following long-term treatment with pan-VEGF inhibitors and has been reported in clinical trials of bevacizumab, ranibizumab, and aflibercept (Table 128–43). In particular, an analysis of data from the multicentre, randomised Comparison of AMD Treatment Trials (CATT) showed that treatment with ranibizumab was associated with a 43% increase in the risk of geographic atrophy at 2 years compared with bevacizumab in patients with nAMD (20.9% versus 16.9%; p=0.02).44–46 Subsequent studies have also reported an association between the intensity of therapy and the development of geographic atrophy/extent of RPE loss among patients with treatment-naïve nAMD receiving intravitreal ranibizumab.38,39

In contrast, to our knowledge there are no published reports of geographic atrophy associated with pegaptanib treatment in patients with nAMD, and a retrospective analysis of colour fundus photographs from patients enrolled in the pivotal trials of pegaptanib (VISION trials) found no evidence of increased risk of progression of geographic atrophy, RPE abnormalities, disc notching or increased cup-to-disc ratio over 2 years of treatment with pegaptanib versus placebo.47 Therefore, pegaptanib maintenance therapy may benefit patients at greater risk of developing geographic atrophy, such as those of advancing age,40–42 or with worse visual acuity,40–42,44 geographic atrophy lesions in the fellow eye,40,43,44 elevated cholesterol, coronary artery disease, various retinal and choroidal factors including haemorrhage, and larger choroidal neovascularisation lesions.38,40,41,44,48 

 Adverse systemic events

Another concern related to prolonged administration of intravitreal VEGF inhibitors, especially pan-VEGF inhibitors, is the risk of systemic absorption and adverse systemic effects. Indeed, clinical studies have reported reductions in plasma VEGF following intravitreal administration of pan-VEGF inhibitors.49,50 A review of available clinical evidence for pegaptanib and the pan-VEGF inhibitor ranibizumab by Tolentino et al. 2011, reported no systemic safety concerns with pegaptanib, but a low frequency of systemic events, including a slightly elevated risk of non-ocular haemorrhage and stroke, with ranibizumab.21 Further, a recent review of the systemic safety of intravitreal VEGF inhibitors (pegaptanib, ranibizumab, bevacizumab and aflibercept) in nAMD, using data from prospective clinical trials and retrospective case studies,51 noted a trend towards an increased risk of arterial thromboembolic events, stroke, cardiac failure and non-ocular haemorrhage with anti-VEGF therapy, especially among patients treated with bevacizumab.51 A meta-analysis of randomized clinical trials of VEGF inhibitors in patients with diabetic macular oedema (who are at high risk for vascular disease) who received injections for at least 2 years also suggested a possible increased risk for death and stroke associated with aflibercept and ranibizumab; however, bevacizumab and pegaptanib were not included in the analysis.52 Conversely, a retrospective, pooled analysis of data from nine sponsor-administered, randomized trials of pegaptanib in patients with AMD with or without diabetes found that patients with diabetes did not have a clinically relevant increase in rates of vascular adverse events during pegaptanib therapy.53

Role of pegaptanib in maintenance therapy for age-related macular degeneration

Many patients with exudative AMD will require long-term maintenance therapy with VEGF inhibitors, and pegaptanib may have a role as maintenance therapy following initial induction with a pan-VEGF inhibitor.54–56 This “induction-maintenance” strategy was assessed in the phase IV, prospective, open-label, uncontrolled LEVEL (Evaluation of Efficacy and Safety in Maintaining Visual Acuity with Sequential Treatment of Neovascular AMD) study.54 The mean improvement in visual acuity achieved during induction therapy was sustained over 54 weeks of pegaptanib treatment, and mean centre point thickness remained relatively stable (Figure 2).54 Similar results were also reported in the prospective, multicentre, LEVEL-J study evaluating pegaptanib maintenance therapy following induction in 75 Japanese patients with nAMD.57 Mean retinal thickness and central macular thickness remained stable over 54 weeks of observation, and improvement in mean logMAR visual acuity achieved during induction was sustained throughout the study.57

Figure 2: Mean visual acuity during induction therapy (ranibizumab, bevacizumab, or other agents or a combinations of agents)54

Subsequent maintenance therapy with pegaptanib (A) and mean centre point thickness during maintenance (B), N=568 patients with subfoveal neovascular age-related macular degeneration. Reused with permission from Friberg et al. 201054

Pegaptanib “rescue therapy” following tachyphylaxis with pan-VEGF inhibitors

Tachyphylaxis, or loss of clinical efficacy, has been reported for ranibizumab, bevacizumab, and aflibercept,58–61 often necessitating a switch to an alternative therapy such as pegaptanib. The clinical efficacy of this approach has been demonstrated in a prospective study by Shiragami et al. who assessed the efficacy of switching to pegaptanib in patients with persistent exudative AMD following an initially positive response to treatment with ranibizumab or ranibizumab combined with photodynamic therapy.62 Overall, of 296 eyes of 296 patients, 50 eyes of 50 patients (16.9%) developed tachyphylaxis.62 Following switching to pegaptanib, complete resolution of exudative change was achieved in 54% of eyes and partial reduction in 42% of eyes.62

Conclusion

In conclusion, clinical evidence suggests that pegaptanib may have a more favourable long-term safety profile than pan-VEGF inhibitors in patients with risk factors for thromboembolic events (e.g. diabetes, cardiovascular disease) or risk factors for geographic atrophy, and may also be considered as maintenance therapy following induction with alternative therapies.


Keywords: Geographic atrophy, exudative age-related macular degeneration, intravitreal, neovascular age-related macular degeneration, pegaptanib, vascular endothelial growth factor (VEGF) inhibitor  

Acknowledgments: Medical writing assistance was provided by Stuart Wakelin of Touch Medical Media, and funded by Bausch & Lomb, Incorporated.

Disclosures: Timothy L Comstock is a paid consultant to Bausch & Lomb, Incorporated. Teresa Brevetti is an employee of Bausch & Lomb, Incorporated

Support: The preparation of this Insight funded by Bausch & Lomb, Incorporated.

Review: This article is independent from the touchOPHTHALMOLOGY journals and has not been approved by the journal’s peer review process.

Publication date: March 1, 2019

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