Emerging Therapies for Neovascular Age-Related Macular Degeneration

Emerging Therapies for Neovascular Age-Related Macular Degeneration Drugs in the Pipeline Peter K. Kaiser, MD Topic: Discuss the emerging therapies that could improve the treatment of neovascular age-related macular degeneration (AMD). Clinical Relevance: Current antiangiogenic therapies require frequent injections, and not all patients respond to these therapies. Thus, there is a need to identify additional therapies that could improve the treatment of neovascular AMD. Methods: Review of medical literature and ongoing clinical trials as well as their results in the area of neovascular AMD treatment. Results: There are numerous areas of investigation into new treatment for AMD, including the newly approved aflibercept eye; sustained-release compounds that may allow for fewer injections, combination therapy with anti–vascular endothelial growth factor (VEGF) therapy and ionizing radiation, and investigational drugs that address different targets along the angiogenic signaling cascade, or other pathways related to the pathophysiology of neovascular AMD altogether. Conclusions: Despite the outstanding advances made in the treatment of neovascular AMD with anti-VEGF therapies, patients still require numerous injections and office visits. Future therapies, however, have the potential not only to reduce patient visits and injections, but also to improve outcomes by targeting additional pathways, increasing target affinity, and lengthening treatment durability. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2013;120:S11–S15 © 2013 by the American Academy of Ophthalmology.

The process of angiogenesis begins when proangiogenic growth factors, particularly vascular endothelial growth factor (VEGF)-A, diffuse into tissues and bind to receptors on endothelial cells. The activated endothelium then secretes various cytokines that mediate basement membrane degradation in concert with a loosening of tight junctions, leading to increased vessel permeability and fluid leakage. This extracellular matrix degradation is followed by endothelial cell proliferation and migration and the formation of vascular buds. The buds elongate and remodel to form tubes and, eventually, new vessels. The vessel maturation process is completed as smooth muscle cells called pericytes are recruited and attach to the exterior of the new vessels, providing structural support.1,2 Anti-VEGF treatments used to treat neovascular agerelated macular degeneration (AMD) block VEGF in the extracellular space. However, as highlighted in the preceding articles, this may require monthly injections or, at the very least, monthly assessments to determine whether patients have responded to the treatment as evidenced by improved or sustained visual acuity. These injections and assessments may be required indefinitely, placing a significant burden on patients and their caregivers (Bhisitkul Statement of Potential Conflict of Interest and Funding/Support: See page S15. © 2013 by the American Academy of Ophthalmology Published by Elsevier Inc.

RB. Year 7 outcomes for ranibizumab-treated subjects in ANCHOR/MARINA: a multicenter, prospective cohort study. Paper presented at: ARVO Annual Meeting, May 6 –10, 2012; Fort Lauderdale, FL). Thus, as already discussed, it is important to identify options that can provide the same or better visual acuity improvement as monthly antiVEGF therapy while minimizing patient and provider burden. It has been postulated that a higher dose of ranibizumab may offer similar efficacy as the monthly protocol, but may require fewer injections than the standard dose. However, the Ranibizumab Administered Monthly or on an AsNeeded Basis in Patients with Subfoveal Neovascular AMD trial, which compared the standard 0.5-mg dose of ranibizumab to a 2-mg dose given either monthly or with a loading dose followed by treatment as needed, demonstrated inconclusive results for both standard and higher dosage comparison and in both as-needed arms (Busbee BG, et al. Efficacy and safety of 2.0-mg or 0.5-mg ranibizumab in patients with subfoveal neovascular AMD: HARBOR study. Program and abstracts of the American Academy of Ophthalmology Annual Meeting, October 22– 25, 2011; Orlando, FL). Anti-VEGF agents with a higher affinity for VEGF molecule, such as aflibercept, which recently was approved for marketing in the United States, offer another option.3 Aflibercept is a fusion protein composed of key extracellular ISSN 0161-6420/13/$–see front matter http://dx.doi.org/10.1016/j.ophtha.2013.01.061

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Ophthalmology Volume 120, Number 5, Supplement, May 2013 domains from VEGF receptor 1 and 2 fused to the immunoglobulin fragment part of human immunoglobulin G-1. Interaction of fragment with the neonatal fragment receptor of immunoglobulin G-1 prolongs the half-life of the molecule. Similar to ranibizumab, aflibercept binds to all VEGF isoforms (A, B, C) with a 10-fold higher affinity than ranibizumab for VEGF. It also binds to placental growth factor.4 Figure 1 demonstrates the predicted biologic activity of aflibercept versus ranibizumab based on half-life and binding affinity.5 The compound was evaluated in 2 identical, phase 3, multicenter, randomized, international trials: VEGF Trap: Investigation of Efficacy and Safety in Wet AMD (VIEW) 1 and VIEW 2. Investigators randomized 2457 patients (n ⫽ 1217 in VIEW 1; n ⫽ 1240 in VIEW 2) to one of the following: monthly injections of 0.5 mg ranibizumab, monthly injections of 0.5 mg aflibercept, monthly injections of 2 mg aflibercept, or 2 mg aflibercept given every 8 weeks after receiving 3 initial monthly injections. The primary end point was to determine the proportion of patients who avoided moderate vision loss (⬍15 letters) on the various aflibercept and ranibizumab regimens.6 An integrated analysis of the 2 trials found that all aflibercept regimens were noninferior to monthly dosing of ranibizumab in terms of visual acuity outcomes. Nearly all eyes (95%–96%) treated with any aflibercept regimen met the primary end point, as did approximately 94% of ranibizumabtreated eyes. Aflibercept-treated eyes treated in the VIEW 1 study gained a mean of 6.9 to 10.9 letters of visual acuity compared with a mean gain of 8.1 letters in ranibizumabtreated eyes.6 Similar results were observed in eyes treated in the VIEW 2 study (7.6 –9.7 letters for aflibercept and 9.4 letters for ranibizumab).6 The recently approved dosing for aflibercept is 2 mg once every 8 weeks after receiving 3 initial monthly injections.7 Two-year results released in December 2011 by the manufacturer reported sustained improvement in visual acuity at 96 weeks versus baseline. An integrated analysis of the VIEW trials showed a visual acuity gain from baseline of 7.6 letters compared with 8.4 letters at week 52 in the aflibercept-treated eyes. This was with an average of 11.2 injections over 2 years and 4.2 injections during the second year. In the monthly ranibizumab group, the visual acuity gain from baseline at week 96 was 7.9 letters compared with 8.7 letters at week 52,

First-Order Decay Mathematical Model 35 30

10-9 x A Activity

Intravitreal 2-mg Aflibercept

Intravitreal Ranibizumab

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INTEGRATED DATA VIEW 1 + VIEW 2

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2Q4

0.5Q4

2Q8

Figure 2. Graphs showing the mean change in visual acuity at 1 year in the VEGF Trap: Investigation of Efficacy and Safety in Wet Age-Related Macular Degeneration 1 and 2 studies. ETDRS ⫽ Early Treatment Diabetic Retinopathy Study; LOCF ⫽ last observation carried forward; Q ⫽ every; R ⫽ ranibizumab. Courtesy of Peter K. Kaiser, MD, Cleveland Clinic Lerner College of Medicine. Adapted from US Food and Drug Administration. VEGF Trap-Eye (aflibercept ophthalmic solution). Ophthalmologic Drugs and Advisory Committee [briefing document]. Available at: http://www. fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ DermatologicandOphthalmicDrugsAdvisoryCommittee/UCM259143.pdf. Accessed July 9, 2012.9

with an average of 16.5 injections over 2 years and 4.7 injections during the second year. There were no significant differences in the incidence of ocular treatment-emergent adverse events, with the most frequent events overall (⬎10%) being conjunctival hemorrhage, eye pain, retinal hemorrhage, and visual acuity reduced.6,8 Figure 2 depicts the mean change in vision in VIEW I and VIEW 2 at 1 year. In addition to these visual acuity gains, patients in all groups experienced a very rapid and sustained reduction in central retinal thickness (Ho AC, et al. Subgroup efficacy analyses of the VIEW 1 and VIEW 2 studies of intravitreal aflibercept injection and ranibizumab for treatment of neovascular AMD. Paper presented at: ARVO Annual Meeting, May 6 –12, 2012; Fort Lauderdale, FL).6,9 No new safety issues were identified in these trials, including no significant differences in the occurrence of Antiplatelet Trialists’ Collaboration arterial thrombotic event rates between the groups.8

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Investigational Approaches

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120

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Figure 1. Modeling of prolonged biologic activity of intravitreal aflibercept. Reprinted with permission from Stewart MW, Rosenfeld PJ. Br J Ophthalmol 2008;92:667– 8.5

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Although bimonthly injections certainly are less burdensome on patients than monthly injections, it would still be ideal to provide patients with an even longer interval between treatments. Several sustained-release products that deliver the active drug via biodegradable polymers, nanoparticles or microparticles, encapsulated cell technology,

Kaiser 䡠 Emerging Therapies for Neovascular AMD reservoir implants, or gene therapy are under investigation.10 One such therapy uses an adeno-associated viral vector to produce the soluble VEGF receptor 1 (sFLT01). It inhibited retinal revascularization in murine models, with evidence of anti-VEGF activity persisting up to 1 year in rodents and nonhuman primates.11 The compound is now being investigated in a phase 1 safety and tolerability study.12

Combination Therapy Combination therapy with anti-VEGF therapy and ionizing radiation offers another option to reduce treatment frequency. Ionizing radiation provides strong inhibitory effects on new and established neovascular vessels by inducing double-stranded DNA breaks, resulting in antiangiogenic, anti-inflammatory, and antifibrotic effects.13,14 In addition, oncology trials demonstrate a synergistic, antiangiogenic effect when both radiotherapy and anti-VEGF agents are used.15–18 Although radiation has been used previously to treat AMD, it was never widely adopted because it did not provide a significant, reproducible effect on visual acuity, while difficulty delivering targeted doses led to complications in some patients.19 –22 New options, however, such as epimacular brachytherapy and robotic stereotactic radiotherapy, enable safer, targeted delivery of the most appropriate dosage, minimizing damage to surrounding structures and improving outcomes.23–26 Epimacular brachytherapy, for instance, delivers ␤ radiation to the lesion through a 20-gauge sclerotomy after a pars plana vitrectomy. The phase 1/2 study with epimacular brachytherapy enrolled 34 treatment-naïve patients who received either 15-Gy or 24-Gy ␤ radiation. Neither group experienced any adverse effects, yet the higherdosage group demonstrated a significantly higher visual acuity improvement on the Early Treatment Diabetic Retinopathy Study visual chart (10.3-letter gain vs. 1.0-letter loss).25 In a second trial also involving 24 treatment-naïve patients, participants were treated with a single dose of the 24-Gy brachytherapy and 2 injections of ranibizumab (1 at surgery, the other 1 month later), followed by ranibizumab injections as needed. After 12 months, the mean improvement in visual acuity was a gain of 8.9 letters, with 91% of patients maintaining their vision and 68% demonstrating stable or improved vision. In addition, 70% of patients did not require an additional anti-VEGF injection.24 However, results of the phase 3 Choroidal Neovascularization Secondary to AMD Treated with Beta Radiation Epiretinal Therapy trial, which compared epiretinal brachytherapy plus ranibizumab with ranibizumab alone, found that the combination was not noninferior to monotherapy with ranibizumab (Dugel PU. CABERNET: for treatment of naïve neovascular macular degeneration. Paper presented at: Angiogenesis 2012, February 4, 2012; Miami, FL).

Investigational Drugs Numerous new compounds also are under investigation that, if approved, will enable clinicians to individualize

Table 1. Compounds in Preclinical or Clinical Studies for Neovascular Age-Related Macular Degeneration Compound

Target

Fovista Sonepcizumab ATG003 AdGVPEDF.11D Pazopanib Vatalanib AL39324 OC-10X Combretastin A4 Volociximab JSM6427 JNJ-26076713 Compstatin (POT-4) sCR1 Eculizumab ACR1905 JPE-1375 PMX53

Block PGDF Block production of S1P Block nAChR Produce PEDF Tyrosine kinase inhibitor Tubulin-binding agents Integrin blockers Complement inhibitors

nAChR ⫽ nicotinic acetylcholine receptor; PEDF ⫽ pigment epitheliumderived factor; PGDF ⫽ platelet-derived growth factor; sCR ⫽ short consensus repeats; S1P ⫽ sphingosine 1-phosphate. Data from Yuan A, Kaiser PK. Semin Ophthalmol 2011;26:149 –5529; Santulli RJ, et al. J Pharmacol Exp Ther 2008;324:894 –90130; Chi ZL, et al. Adv Exp Med Biol. 2010;703:127–3531; and Clinicaltrials.gov.32

therapy for patients through various drug combinations. Some exert their effects upstream of the angiogenic signaling cascade; others, such as the tyrosine kinase inhibitors, exert their effects downstream.27,28 Table 1 provides a more comprehensive list of investigational drugs, including their targets.29 –32 Several studies suggest that vessel maturation affects the response of blood vessels to anti-VEGF therapy, which may explain why mature AMD does not respond well to antiVEGF agents. This poor response is thought to be related to the presence of pericytes that surround capillaries and larger vessels, simultaneously secreting VEGF and protecting vessels from anti-VEGF therapy.33–35 Platelet-derived growth factor (PDGF) is involved in the recruitment of pericytes; thus, blocking its effects reduces pericyte protection, possibly increasing neovascular sensitivity to anti-VEGF therapy. In a phase 1 dose-escalating trial of 0.5 mg ranibizumab combined with 1 of 4 doses of the anti-PDGF aptamer E10030, 59% of patients (n ⫽ 22) experienced at least a 15-letter gain in visual acuity by week 12. Particularly interesting is that all patients demonstrated neovascular regression on fluorescein angiography, which has not occurred in any anti-VEGF trial.36 The recently released phase 2 study evaluated 3 different injection regimens, which were given every 4 weeks for 24 weeks: 0.3 mg anti-PDGF with 0.5 mg ranibizumab, 1.5 mg anti-PDGF with 0.5 mg ranibizumab, and a sham injection given in conjunction with ranibizumab 0.5 mg. Results showed that anti-PDGF combination therapy was superior to ranibizumab monotherapy, with 62% improvement in the combination arms (Dugel PU. Anti-platelet derived growth factor: where do we stand? Paper presented at: Retina Subspecialty Day, November 9 –10, 2012; Chicago, IL).

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Ophthalmology Volume 120, Number 5, Supplement, May 2013 In conclusion, despite the outstanding advances made in the treatment of neovascular AMD with anti-VEGF therapies, patients still require numerous injections and office visits. Future therapies, however, have the potential not only to reduce patient visits and injections, but also to improve outcomes by targeting additional pathways, increasing target affinity, and lengthening treatment durability. Acknowledgment. The author thanks Debra Gordon, MS, for writing and editing assistance, whose services were provided by Johns Hopkins in cooperation with ASiM. Responsibility for the content rests with the author.

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15. Myers AL, Williams RF, Ng CY, et al. Bevacizumab-induced tumor vessel remodeling in rhabdomyosarcoma xenografts increases the effectiveness of adjuvant ionizing radiation. J Pediatr Surg 2010;45:1080 –5. 16. Willett CG, Duda DG, Czito BG, et al. Targeted therapy in rectal cancer. Oncology (Williston Park) 2007;21:1055– 65; discussion 1065, 1070, 1075 passim. 17. Willett CG, Kozin SV, Duda DG, et al. Combined vascular endothelial growth factor-targeted therapy and radiotherapy for rectal cancer: theory and clinical practice. Semin Oncol 2006;33(5 suppl 10):S35– 40. 18. Nieder C, Wiedenmann N, Andratschke N, et al. Current status of angiogenesis inhibitors combined with radiation therapy. Cancer Treat Rev 2006;32:348 – 64. 19. Sivagnanavel V, Evans JR, Ockrim Z, et al. Radiotherapy for neovascular age-related macular degeneration. Cochrane Database Syst Rev 2004(4):CD004004. 20. Finger PT, Gelman YP, Berson AM, et al. Palladium-103 plaque radiation therapy for macular degeneration: results of a 7 year study. Br J Ophthalmol 2003;87:1497–503. 21. Adams JA, Paiva KL, Munzenrider JE, et al. Proton beam therapy for age-related macular degeneration: development of a standard plan. Med Dosim 1999;24:233– 8. 22. Zambarakji HJ, Lane AM, Ezra E, et al. Proton beam irradiation for neovascular age-related macular degeneration. Ophthalmology 2006;113:2012–9. 23. Gertner M, Chell E, Pan KH, et al. Stereotactic targeting and dose verification for age-related macular degeneration. Med Phys 2010;37:600 – 6. 24. Avila MP, Farah ME, Santos A, et al. Twelve-month shortterm safety and visual-acuity results from a multicentre prospective study of epiretinal strontium-90 brachytherapy with bevacizumab for the treatment of subfoveal choroidal neovascularisation secondary to age-related macular degeneration. Br J Ophthalmol 2009;93:305–9. 25. Avila MP, Farah ME, Santos A, et al. Twelve-month safety and visual acuity results from a feasibility study of intraocular, epiretinal radiation therapy for the treatment of subfoveal CNV secondary to AMD. Retina 2009;29:157– 69. 26. Silva RA, Moshfeghi AA, Kaiser PK, et al. Radiation treatment for age-related macular degeneration. Semin Ophthalmol 2011;26:121–30. 27. Rasmussen H, Chu KW, Campochiaro P, et al. Clinical protocol. An open-label, phase I, single administration, doseescalation study of ADGVPEDF.11D (ADPEDF) in neovascular age-related macular degeneration (AMD). Hum Gene Ther 2001;12:2029 –32. 28. Moutray T, Chakravarthry U. Age-related macular degeneration: current treatment and future options. Ther Adv Chronic Dis 2011;2:325–31. 29. Yuan A, Kaiser PK. Emerging therapies for the treatment of neovascular age-related macular degeneration. Semin Ophthalmol 2011;26:149 –55. 30. Santulli RJ, Kinney WA, Ghosh S, et al. Studies with an orally bioavailable alpha V integrin antagonist in animal models of ocular vasculopathy: retinal neovascularization in mice and retinal vascular permeability in diabetic rats. J Pharmacol Exp Ther 2008;324:894 –901. 31. Chi ZL, Yoshida T, Lambris JD, et al. Suppression of drusen formation by compstatin, a peptide inhibitor of complement C3 activation, on cynomolgus monkey with early-onset macular degeneration. Adv Exp Med Biol 2010;703:127–35.

Kaiser 䡠 Emerging Therapies for Neovascular AMD 32. Clinicaltrials.gov. Complement inhibition with eculizumab for the treatment of non-exudative macular degeneration (AMD); NCT00935883. Available at: http://clinicaltrials.gov/ct2/show/ NCT01024998. Accessed December 6, 2011. 33. Carmeliet P, Collen D. Molecular basis of angiogenesis. Role of VEGF and VE-cadherin. Ann N Y Acad Sci 2000;902: 249 – 62; discussion 262– 4. 34. Benjamin LE, Hemo I, Keshet E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 1998;125:1591– 8.

35. Bergers G, Song S, Meyer-Morse N, et al. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 2003;111: 1287–95. 36. Boyer DS, Ophthotech Anti-PDGF in AMD Study Group. combined inhibition of platelet derived (PDGF) and vascular endothelial (VEGF) growth factors for the treatment of neovascular age-related macular degeneration (NV-AMD)— results of a phase 1 study. Invest Ophthalmol Vis Sci 2009; 50:E-Abstract 1260.

Footnotes and Financial Disclosures Originally received: May 10, 2012. Final revision: January 8, 2013. Accepted: January 25, 2013.

Manuscript no. 2012-679.

Cleveland Clinic Lerner College of Medicine, Cole Eye Institute, Cleveland, Ohio. Financial Disclosure(s): The author(s) have made the following disclosure(s):

Peter K. Kaiser - Consultant - Alcon Laboratories, Bayer, Genentech, Inc., Novartis Pharmaceuticals Corporation, Ophthotech Corporation, Oraya Therapeutics, and Regeneron Pharmaceuticals, Inc. Supported by an educational grant from Regeneron Pharmaceuticals, Inc, Tarrytown, NY. Correspondence: Peter K. Kaiser, MD, Cleveland Clinic Main Campus, Mail Code i32, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail: [email protected].

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