Neovascular age-related macular degeneration (known as wet AMD) is the leading cause of blindness in the elderly1 and is characterized by proliferation and leakage of abnormal blood vessels in the eye.2 Vascular endothelial growth factor (VEGF) is one of the most important cellular factors promoting the growth and proliferation of blood vessels, and has therefore become the major target for wet AMD therapies. Ranibizumab (Lucentis®), bevacizumab (Avastin®), both of which target VEGF-A; pegaptanib (Macugen®), a selective inhibitor of VEGF165; and aflibercept (Eylea®), which inhibits VEGF-A as well as placental growth factor (PGF)3 have become established treatments for wet AMD, although bevacizumab is not licensed for ophthalmic use. These anti-VEGF drugs are injected into the vitreous, where they bind to abnormal VEGF proteins and prevent them from stimulating further blood vessel growth and leakage. However, regular intravitreal injections are burdensome for patients and practitioners. Furthermore, a proportion of patients do not respond to anti-VEGF therapies, and treatments become less effective with repeated intravitreal injections.4 This has prompted a search for novel therapeutic targets.
In mammals, VEGF-A belongs to a family that also includes VEGF-B, -C, and -D. Of these, VEGF-A is the most potent cause of angiogenesis. New agents targeting VEGF-A include abicipar pegol (Allergan),5 a pegylated-designated Ankyrin repeat protein (DARPin); and brolucizumab (Alcon Laboratories),6 a single-chain, antibody fragment inhibitor of VEGF-A. These are being investigated in phase III clinical studies. In addition, PAN-90806 (Panoptica), a topical small molecule anti-VEGF-A agent, showed promise in a phase I/II clinical trial. However, it has been suggested that resistance to VEGF-A therapies may be related to other VEGF family members and that combining them with agents targeting other forms of VEGF may provide more complete VEGF inhibition. OPT-302 (Ophthea), a soluble form of VEGF receptor 3 that inhibits VEGF-C and VEGF-D, has shown promising findings in combination with ranibizumab in a phase I/IIa trial.7
As our understanding of the molecular processes underlying wet AMD has increased, it has become clear that, in addition to VEGF, other factors, such as platelet-derived growth factor (PDGF), may participate in the control of the angiogenic process. A growing body of evidence suggests that dual inhibition of VEGF and PDGF may be more effective than targeting VEGF alone. Tumor models have shown that angiogenesis involves both VEGF and PDGF activity.8In addition, PDGF is involved aspects of wet AMD pathology, such as fibrosis. However, several of these agents in advanced clinical development have failed to show any benefits when added to established anti-VEGF-A agents: these include E10030 (also known as pegpleranib, Fovista®, Ophthotech) and rinucumab (Regeneron). Despite these disappointing findings, the clinical development of other PGDF inhibitors is continuing, including DE-120 (Santen) and X-82 (Tyrogenex)9 which block both PDGF and VEGF, and OHR-102 (squalamine®, Ohr Pharmaceuticals), which targets intracellular calmodulin to inhibit the downstream effects of VEGF, PDGF, and basic fibroblast growth factor, and has shown promise in combination with ranibizumab.10 The latter two have attracted particular attention since X-82 is administered orally and OHR-102 is applied topically (see Table 1).
Another pathway responsible for vascular leakage and neovascularisation is the angiopoietin pathway. Two direct inhibitors of angiopoietin-2 are being investigated: RG7716 (Genentech)11and nesvacumab (Regeneron Pharmaceuticals).12Another substance, AKB-9778 (Aerpio Therapeutics) activates Tie-2, which is found on endothelial cells and is a key component of the angiopoietin pathway. A phase II clinical study showed that subcutaneous injections of AKB-9778 combined with ranibizumab was more effective than ranibizumab alone in diabetic macular edema (DME).13
Integrins are transmembrane protein that are involved in regulating cellular adhesion, kinase signalling pathways, endothelial cell migration, and apoptosis, VEGF receptor-2 activation, and vascular development, making them potential targets for wet AMD therapy. Two integrin inhibitors, volociximab (Ophthotech), and Luminate (Allegro Ophthalmics), have demonstrated good safety in phase I trials.14
Other molecules involved in cellular proliferation are also being investigated for wet AMD. In a phase II study, the mammalian target of rapamycin (mTOR) inhibitor sirolimus appears promising when administered intravitreally.15
Finally, transforming growth factor-beta has emerged as a useful therapeutic target as it promotes escape from VEGF inhibition in endothelial cells. DE-122 (Santen), a transforming growth factor-beta inhibitor, is being investigated in combination with anti-VEGF agents.
In summary, although anti-VEGF treatments have transformed the treatment of wet AMD, they are far from perfect and there remains a need for novel molecular targets to overcome the non-responsiveness, observed in some patients, to anti-VEGF treatment. However, the numbers of investigational agents that have failed late-stage clinical development illustrate the challenges of wet AMD therapy. Intravitreal injections with current anti-VEGF medications are likely to remain the standard treatment for wet AMD for the foreseeable future. However, emerging therapies have the potential to reduce the injection frequency, as well as improving visual outcomes. If these novel therapeutic options are marketed, it will also become important to better characterize patients to tailor treatment to the individual.
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6. Bandello F, Weichselberger, A., Weissgerber, G., et al, Safety and efficacy of RTH258, a single-chain anti-vascular endothelial growth factor (VEGF) antibody fragment, in patients with neovascular age-related macular degeneration (NAMD): results from 2 phase II studies. Presented at: European School for Advanced Studies in Ophthalmology Retina Academy; October 22-24, 2015; Barcelona, Spain.
7. Opthea Reports Positive Phase 1/2A Clinical Results for OPT-302 in wet AMD http://www.marketwired.com/press-release/opthea-reports-positive-phase-1-2a-clinical-results-for-opt-302-in-wet-amd-asx-opt-2207063.htm Accessed 12 April 2017.
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11. Chakravarthy U, Schwab, D, Cech, P. et al, The novel bispecific monoclonal anti-VEGF/anti-Ang2 antibody RG7716 shows promise in wet age-related macular degeneration patients with suboptimal response to prior anti-VEGF monotherapy, Presented at the Association for Research, Vision and Ophthalmology (ARVO) 2016 Annual Meeting 01-05 May 2016 Seattle, WA
12. Brown DM, Phase 1 study of combination therapy with nesvacumab and aflibercept for neovascular AMD and diabetic macular edema. , Presented at tha American Academy of Ophthalmology annual meeting; Oct. 14-18, 2016; Chicago, IL
13. Campochiaro PA, Khanani A, Singer M, et al., Enhanced Benefit in Diabetic Macular Edema from AKB-9778 Tie2 Activation Combined with Vascular Endothelial Growth Factor Suppression, Ophthalmology, 2016;123:1722-30.
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15. Bracha PC, J., Harless, A. et al, intravitreal Sirolimus vs. anti-VEGF in chronic neovascular AMD with persistent retinal fluid: 1-year follow-up, to be presented at the Presented at the Association for Research, Vision and Ophthalmology (ARVO) 2017 Annual Meeting, May 7-11 2017, Baltimore, MD