Article Date: 1/1/2014

The Role of Pegaptanib In the Treatment of Exudative AMD And Diabetic Retinopathy

The Role of Pegaptanib In the Treatment of Exudative AMD And Diabetic Retinopathy

Briefly the standard of care, pegaptanib could find a niche.

MICHAEL J. TOLENTINO, MD • MICHAEL S. TOLENTINO

Michael J. Tolentino, MD, practices with the Center for Retina and Macular Disease in Winter Haven, FL. Michael S. Tolentino is also employed by the Center for Retina and Macular Disease. The first author reports financial interests in Regeneron, Genentech, and Valeant. He can be reached at Miket@crmd.net.

Pegaptanib sodium (Macugen, Valeant Pharmaceuticals, Bridgewater NJ) was the first anti-VEGF therapy approved by the FDA for the treatment of exudative AMD, signaling the beginning of a new era for the treatment of this blinding condition.

The approval occurred in 2004, and for a short period of time, pegaptanib became the standard of care.

However, off-label use of bevacizumab (Avastin, Genentech, South San Francisco, CA) quickly usurped its position. While not approved by the FDA or formally tested for safety or efficacy, bevacizumab ultimately became the most used drug for this condition based solely on its anecdotal efficacy.

Currently, ranibizumab (Lucentis, Genentech) and aflibercept (Eylea, Regeneron, Tarrytown, NY) are the only two other anti-VEGF drugs approved for exudative AMD. Clinical trial results have suggested that these approved medications appear more efficacious, but studies directly comparing them to pegaptanib head-to-head have not been undertaken.

Because of the presumed superior efficacy of bevacizumab, ranibizumab, and aflibercept over pegaptanib, the use of the latter has declined rapidly and now represents only a small fraction of the market share of intravitreally injected drugs.

Is there any room for pegaptanib in the treatment of retinal diseases responsive to anti-VEGF therapies? And if so, when and where should it be used?

ADVANTAGES AND DISADVANTAGES

The potential utility of pegaptanib lies in the differences in molecular composition and targets between pegaptanib and the other anti-VEGF drugs. Because direct clinical comparison is unlikely in the future, we will attempt to summarize these differences and explain the characteristics of pegaptanib that differentiate it.

Pegaptanib is an aptamer that selectively binds to VEGF165. Unlike the other currently available anti-VEGF drugs, which are protein-based binding molecules, an aptamer is a biochemically stabilized, nucleic acid–based molecule. This structural difference makes aptamers less immunogenic.

The aptamer’s composition has molecular and clinical advantages and disadvantages. The advantages include decreased initiation or amplification of inflammatory processes implicated in AMD and DR, such as complement activation, or humoral immunity.1 In clinical trials, this advantage is impossible to detect without the availability of sensitive biomarkers.

The weaker binding characteristics of aptamers compared to antibodies, Fab fragments, or fusion proteins represent its primary disadvantage. The weaker binding to the target molecule VEGF translates into a shorter physical and functional half-life.2

Clinically, the weaker binding of VEGF translates into an inability to eliminate intraretinal or subretinal fluid completely on OCT or to improve vision in the majority of patients.3

A Safety Edge

While pegaptanib’s selective binding to VEGF165 attenuates its clinical efficacy, it does provide a safety advantage. Experimental models have definitively demonstrated that chronic pan-VEGF suppression results in photoreceptor, retinal ganglion cell, and RPE degeneration. These experimental results represent the potential for chronic VEGF suppression to initiate and propagate geographic atrophy and possibly optic nerve degeneration.4,5 Pan-VEGF suppression during ischemic retinal insult also increases apoptotic cell death, which will worsen vision loss in ischemic retinopathies.6

Systemically administered bevacizumab has been demonstrated clinically to increase the risk of ischemic events, such as strokes, heart attacks, hypertension, gastrointestinal perforation, and bleeding.7–9

Several mechanisms have been implicated in the development of these theoretical ophthalmic complications. The most compelling mechanism is the role VEGF has in choriocapillary/retinal blood vessel homeostasis, as well as retinal and neuronal cell survival.10

A Specific Isoform

Because of the vascular maintenance and neuroprotective properties of VEGF, the development of exudative AMD is believed to be an abortive attempt at restoring homeostasis of the choriocapillaris and protecting the neuronal components of the eye from oxidative and ischemic stress.

The chronic oxidation, inflammation, and eventual senescence of the pigment epithelial cells exert stress on retinal cells and degrade the choriocapillaris over time. The chronically produced reactive oxygen species and accumulation of complement complex proteins trigger the production of VEGF.11–14

This initial signaling of VEGF is an adaptive retinal stress reaction and a protective healing response. As the disease progresses, this protective response evolves into a pathology leading to the initiation of exudative AMD.

The conversion to a pathologic response is signaled by the upregulation of VEGF165, the pathologic initiator of neovascular diseases of the eye. VEGF165, which is both freely soluble and also bound through a heparin-binding domain, is the only isoform required to initiate VEGF-A–mediated inflammation and retinopathy.15

VEGF165 is sufficient to initiate and produce retinopathy identical to diabetic retinopathy.16,17 These isoform-unique properties support the theory that VEGF165 is the pathologic isoform, and its selective inhibition will attenuate pathology, while allowing other isoforms to continue their maintenance and protective functions.

The Downside of Pan-VEGF Blockage

While the basic science definitively points to VEGF165 as the pathologic isoform, clinical endpoints have not demonstrated that selective VEGF165 inhibition alone is adequate to resolve completely the subretinal or intraretinal fluid seen in exudative AMD. In contrast, evidence has mounted that nonselective VEGF inhibition may cause long-term toxicity.

In the patients who lost more than 15 letters of vision in the ANCHOR and MARINA studies of ranibizumab, geographic atrophy, and not continued neovascularization, appeared to be the causative factor in vision loss.18 The CATT study also suggested that patients receiving pan-VEGF suppression with geographic atrophy at baseline were less likely to experience improved vision.19 Patients on pegaptanib followed over the long term did not experience worsening of geographic atrophy.3

As a Maintenance Treatment

One potential use of pegaptanib is in an induction maintenance regime, in which patients receive panisoform inhibitors to dry their retinas, followed by maintenance of this dry state with pegaptanib. This combination harnesses the efficacy of pan-VEGF inhibitors while maintaining long-term safety. The LEVEL trial demonstrated the ability of pegaptanib to act as an effective maintenance injection when following a ranibizumab or bevacizumab induction regime.20

Because of the widespread discontinuation of selective VEGF inhibition, very few patients have received long-term follow-up on pegaptanib.

Figure 1 shows a patient who received long-term pegaptanib and maintained vision with exudative AMD. While the patient developed some level of geographic atrophy, it has not involved his central fovea and has not extended past the area of hemorrhage from his initial presentation.

Considering the experimental association of retina and RPE degeneration with pan-VEGF inhibition, pegaptanib may pose a theoretical safety advantage in patients who appear to be developing worsening geographic atrophy yet who need continuous anti-VEGF suppression.

images

Figure 1. A 72-year-old man who developed exudative AMD in his left eye in 2006 and was treated with pegaptanib. He presented with 20/200 vision and improved to 20/20 after several injections. He was also treated with bevacizumab three times over his first two years of treatment. Currently, he is receiving pegaptanib every eight to 12 weeks, using an inject-and-extend protocol for the last seven years. A, B. Fluorescein angiography and time-domain OCT of initial presentation in 2006. C. Most recent fluorescein angiography and autofluorescence pictures; and D. Most recent spectral-domain OCT. The patient has not developed central-involving geographic atrophy while receiving continuous pegaptanib treatment for more than seven years. The present distribution of GA has not extended past the area of initial fibrosis.

Better for Patients With Ischemic Events

Another situation in which pegaptanib could prove useful is in patients with recent ischemic events. Theoretically, selective VEGF inhibition with a noninflammatory molecule could prove beneficial in patients.

While the systemic side effects of pan-VEGF inhibition using an intravitreal route remain controversial, the oncology literature has demonstrated an increased risk of arteriothrombolic events, especially in the elderly population.21

Considering the overall short-term human experience with these treatments, obtaining clinical guidance from basic science and other fields of medicine may prove wise when it comes to treating our patients with exudative AMD.

DIABETIC EYE DISEASE

Diabetic retinopathy is a VEGF165-driven disease, as are all ischemic neovascular retinal diseases, such as RVO. VEGF165 is both a soluble and bound molecule, and this hybrid nature allows for its localization in the retina and its pathogenic role in ischemic retinopathy.

Smaller isoforms of VEGF, such as VEGF121 and VEGF110, are not bound by a heparin-binding site, so they clear rapidly through the vitreous, allowing for only transient roles in retinal edema and retinal neovascularization due to diabetes and RVO.

The large bound isoforms, such as VEGF193 and VEGF210, are bound and relatively insoluble. As a result, they cannot bind to the VEGF receptors found in the retinal and subretinal space. It is this ability to simultaneously bind and be soluble that makes VEGF165 the cause of persistent DME and RVO-associated macular edema.

The selective nature and the nonimmunogenic structure of pegaptanib make it an ideal molecule for diabetic retinopathy because while it does eliminate the prominent diabetic VEGF isoform, it is nevertheless only minimally inflammatory.

VEGF165 is the only VEGF isoform that is both necessary and sufficient to produce diabetic–like changes. It is also the only isoform that can localize and persist in the retina due to its unique heparin-binding domain.

DIABETES- AND ISCHEMIA-SPECIFIC ROLES

In diabetic and ischemic retinopathies, VEGF165 is the isoform that not only initiates but also propagates retinopathy. It is central in the feed-forward loop that results in the progression from diabetes to neovascular retinopathy.

This loop starts with the advanced glycation end product (AGE)–induced upregulation of VEGF165 in diabetes and with hypoxia in ischemic retinopathies.22 AGE binding with its receptor (RAGE) increases production of reactive oxygen species (ROS). Both AGE and ROS upregulate VEGF165.

The upregulation of VEGF165 results in the chemoattraction of white blood cells. The inflammatory properties of VEGF localize to the unique heparin-binding domain found exclusively in VEGF165. The attraction of white blood cells and the upregulation of intracellular adhesion molecules result in capillary blockage and resultant capillary nonperfusion of the retina.23

This capillary blockage produces ischemia and further production of VEGF-A, as well as increased chemoattraction. The inflammatory cells also bring in all of the isoforms of VEGF-A, as well as other inflammatory cytokines and growth factors. However, because of the inability to persistently localize in the retina, these other isoforms play a lesser role. Other non-VEGF cytokines and growth factors, such as angiopoietin-2, then increase in importance the longer that the diabetic retinopathy persists (Figure 2).

images

Figure 2. The pathogenesis of diabetic retinopathy begins with the glycation of proteins due to increasing levels of systemic glucose. Hemoglobin A1C represents one of the many advanced glycation end products (AGEs). AGEs, when bound to the receptor for advanced glycation end products (RAGE), also increase the production of reactive oxygen species (ROS). THe insulin resistance from diabetes results in exposure to increasing levels of insulin, either endogenous or exogenous. AGE, ROS, and insulin upregulate VEGF165. Potential treatments include inhibitors of RAGE, as well as non–insulin-increasing treatments, such as the glucagon-like protein-1 (GLP-1) agonist exenatide (Byetta, Bristol Myers-Squibb, New York, NY) or the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin (Januvia, Merck, Whitehouse Station, NJ). Low doses of VEGF165 can produce all findings of nonproliferative DR. Higher VEGF165 levels result in chemoattraction and capillary blockage by polymorphonuclear (PMN) leukocytes. These PMNs degranulate, delivering other VEGF isoforms to the retina, as well as growth factors such as angiopoietin 2 (Ang2), chemokines, and cytokines. The capillary nonperfusion results in hypoxia and a tremendous increase in VEGF upregulation. More VEGF increases inflammation and capillary nonperfusion, resulting in a feed-forward loop that amplifies the amount of VEGF165 delivered to the retina. The tremendous increase in VEGF and other inflammatory cytokines produces neovascularization of the retina and iris. Because VEGF165 is the predominant isoform in this disease, pegaptanib is useful in all stages of DR, as are other anti-VEGF molecules. Because of the proinflammatory nature of monoclonal antibodies, one should use bevacizumab with caution. Ranibizumab and afiibercept are safer pan-VEGF isoform inhibitors. Steroids play a useful role in stopping the inflammatory cascade that brings about an amplification of VEGF. Anti-Ang2 can synergistically work with anti-VEGF therapies to stop leakage and neovascularization.

Diabetic Retinopathy

The central role of VEGF165 in ischemic and diabetic retinopathy is clear in the demonstrated clinical efficacy of pegaptanib in both types of retinopathy.

Pegaptanib has demonstrated similar efficacy in diabetic retinopathy by reducing retinal thickness and improving vision in DME, commensurate with the results with other anti-VEGF drugs.24 In PDR, not only does pegaptanib produce resolution of neovascularization, but it can also normalize the appearance of the retina (Figure 3).25

While similar in efficacy, the enhanced safety profile of pegaptanib, due to both its molecular structure and its target selectivity, provides an improved margin of safety in patients who are typically sicker than the general population and who need ocular treatment initiated at a much earlier age.

images

Figure 3. A. Fluorescein angiogram of a 52-year-old woman with PDR and neovascular disease. B. Fluorescein angiogram of the same eye three weeks after pegaptanib injection.

A Safer Long-term Strategy

Diabetic retinopathy is an inflammatory disease. Using an inflammatory molecule such as bevacizumab is akin to trying to control a fire with diluted kerosene, while pegaptanib, and to a lesser extent aflibercept and ranibizumab, is like using water. Diluted kerosene, in the short term, may control the fire but will likely fuel the fire in the long term by activating the inflammatory cascade.

While in the short term, bevacizumab, which is an inflammatory full-length humanized antibody, is efficacious and appears safe, diabetic retinopathy is a life-long condition, and physicians should bear in mind its potential long-term side effects.

Another consideration is the potential for tachyphylaxis, in which bevacizumab becomes ineffective after long-term use in DME. Ultimately, the inflammatory nature of bevacizumab outweighs its anti-VEGF properties. One should consider switching to a less inflammatory anti-VEGF agent, such as pegaptanib, ranibizumab, or aflibercept.

Pegaptanib’s minimally immunogenic molecular structure gives this drug a theoretical advantage in terms of long-term safety, especially compared to bevacizumab.

Because of the similar efficacy of pegaptanib in diabetic retinopathy and the potentially improved margin of safety, retinal physicians should consider the drug in diabetic patients who have a large ischemic component to their retinopathy or who have severe micro- and macrovascular disease.

Selective inhibition of VEGF in ischemic retinas does not promote or amplify retinal apoptosis, which appears to occur experimentally when an ischemic retina receives pan-VEGF blockade.

CONCLUSION

While no longer considered the first-line anti-VEGF treatment for exudative AMD, diabetic retinopathy, or RVO, pegaptanib sodium nevertheless has unique properties that differentiate it from the other available therapies.

In exudative AMD, it can be combined with pan-VEGF inhibitors when concern exists regarding expansion of center-involving geographic atrophy. For patients with a history of cardiovascular or cerebrovascular events and for physicians concerned with the potential of pan-VEGF isoform inhibition to exacerbate these problems, pegaptanib provides an acceptable alternative to balance safety with efficacy.

In diabetic retinopathy, little is lost in terms of efficacy when using pegaptanib. The drug may be ideal in patients with diabetes, who have large areas of retinal ischemia, or in those with glaucoma, in whom physicians are often concerned with the experimentally demonstrated promotion of the apoptosis of retina ganglion cells by pan-VEGF inhibition.6

Pegaptanib is a useful tool in our armamentarium against these conditions. Our use of pegaptanib allows us to practice both the art and science of medicine. Furthermore, it allows for an alternative for physicians and patients who are concerned about the theoretical safety considerations with other anti-VEGF therapies. RP

REFERENCES

1. Boomer RM, Lewis SD, Healy JM, Kurz M, Wilson C, McCauley TG. Conjugation to polyethylene glycol polymer promotes aptamer biodistribution to healthy and inflamed tissues. Oligonucleotides. 2005;15:183-195.

2. Nimjee SM, Rusconi CP, Sullenger BA. Aptamers: an emerging class of therapeutics. Ann Rev Med. 2005;56:555-583.

3. Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR; VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351:2805-2816.

4. Saint-Geniez M, Maharaj AS, Walshe TE, et al. Endogenous VEGF is required for visual function: evidence for a survival role on muller cells and photoreceptors. PLoS One. 2008;3:e3554.

5. Saint-Geniez M, Kurihara T, Sekiyama E, Maldonado AE, D’Amore PA. An essential role for RPE-derived soluble VEGF in the maintenance of the choriocapillaris. Proc Natl Acad Sci U S A. 2009;106:18751-18756.

6. Nishijima K, Ng YS, Zhong L, et al. Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury. Am J Pathol. 2007;171:53-67.

7. Shah MA, Ilson D, Kelsen DP. Thromboembolic events in gastric cancer: high incidence in patients receiving irinotecan- and bevacizumab-based therapy. J Clin Oncol. 2005;23:2574-2576.

8. Pande A, Lombardo J, Spangenthal E, Javle M. Hypertension secondary to anti-angiogenic therapy: experience with bevacizumab. Anticancer Res. 2007;27:3465-3470.

9. Cohen MH, Gootenberg J, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab (Avastin) plus Carboplatin and Paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer. Oncologist. 2007;12:713-718.

10. Sakowski SA, Heavener SB, Lunn JS, et al. Neuroprotection using gene therapy to induce vascular endothelial growth factor-A expression. Gene Ther. 2009;16:1292-1299.

11. Kuroki M, Voest EE, Amano S, et al. Reactive oxygen intermediates increase vascular endothelial growth factor expression in vitro and in vivo. J Clin Invest. 1996;98:1667-1675.

12. Bora NS, Kaliappan S, Jha P, et al. Complement activation via alternative pathway is critical in the development of laser-induced choroidal neovascularization: role of factor B and factor H. J Immunol. 2006;177:1872-1878.

13. Cortright DN, Meade R, Waters SM, Chenard BL, Krause JE. C5a, but not C3a, increases VEGF secretion in ARPE-19 human retinal pigment epithelial cells. Curr Eye Res. 2009;34:57-61.

14. Nozaki M, Raisler BJ, Sakurai E, et al. Drusen complement components C3a and C5a promote choroidal neovascularization. Proc Natl Acad Sci U S A. 2006;103:2328-2333.

15. Ishida S, Usui T, Yamashiro K, et al. VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization. J Exp Med. 2003;198:483-489.

16. 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.

17. Tolentino MJ, McLeod DS, Taomoto M, Otsuji T, Adamis AP, Lutty GA. Pathologic features of vascular endothelial growth factor-induced retinopathy in the nonhuman primate. Am J Ophthalmol. 2002;133:373-385.

18. Rosenfeld PJ, Shapiro H, Tuomi L, Webster M, Elledge J, Blodi B; MARINA and ANCHOR Study Groups. Characteristics of patients losing vision after 2 years of monthly dosing in the phase III ranibizumab clinical trials. Ophthalmology. 2011;118:523-530.

19. Ying GS, Huang J, Maguire MG, et al; Comparison of Age-related Macular Degeneration Treatments Trials Research Group. Baseline predictors for one-year visual outcomes with ranibizumab or bevacizumab for neovascular age-related macular degeneration. Ophthalmology. 2013;120:122-129.

20. Friberg TR, Tolentino M; LEVEL Study Group, Weber P, Patel S, Campbell S, Goldbaum M. Pegaptanib sodium as maintenance therapy in neovascular age-related macular degeneration: the LEVEL study. Br J Ophthalmol. 2010;94:1611-1617.

21. Kozloff MF, Berlin J, Flynn PJ, et al. Clinical outcomes in elderly patients with metastatic colorectal cancer receiving bevacizumab and chemotherapy: results from the BRiTE observational cohort study. Oncology. 2010;78:329-339.

22. Lu M, Kuroki M, Amano S, et al. Advanced glycation end products increase retinal vascular endothelial growth factor expression. J Clin Invest. 1998;101:1219-1224.

23. Lu M, Perez VL, Ma N, et al. VEGF increases retinal vascular ICAM-1 expression in vivo. Invest Ophthalmol Vis Sci. 1999;40:1808-1812.

24. Sultan MB, Zhou D, Loftus J, Dombi T, Ice KS; Macugen 1013 Study Group. A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema. Ophthalmology. 2011;118:1107-1118.

25. González VH, Giuliari GP, Banda RM, Guel DA. Intravitreal injection of pegaptanib sodium for proliferative diabetic retinopathy. Br J Ophthalmol. 2009;93:1474-1478.



Retinal Physician, Volume: 11 , Issue: January 2014, page(s): 34 - 40