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New Treatment Modalities for Neovascular Age-Related Macular

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New Treatment Modalities for Neovascular Age-Related Macular REVIEW ARTICLE New Treatment Modalities for Neovascular Age-Related Macular Degeneration Patricio G. Schlottmann, MD,* Arturo A. Alezzandrini, MD, PhD,† Marcelo Zas, MD, PhD,‡ Francisco J. Rodriguez, MD,§ José D. Luna, MD,¶ and Lihteh Wu, MD∥ Choroidal neovascularization (CNV) due to neovascular Abstract: Age-related macular degeneration (AMD) is considered one AMD (nAMD) is responsible for most AMD-related severe vi- of the main causes of severe vision loss in older adults. The neovascular 09/09/2020 on BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3GqhOzspyl8wzdGoAiDZ01F7vOf+c0L5VOYO2r67BVps= by https://journals.lww.com/apjoo from Downloaded sion loss. Anti‒vascular endothelial growth factor (anti-VEGF) form (nAMD) is an advanced stage, which is responsible for the most se- agents, delivered intravitreally, block the angiogenic process, the Downloaded vere vision loss. Vascular endothelial growth factor (VEGF) is at present growth of abnormal blood vessels in the eye, to prevent loss of the main factor that leads to the development of a neovascular membrane vision and, in some cases, improve vision.3 from and the increased leakage from the membrane to the retina. At present, https://journals.lww.com/apjoo Over the past decade, the only effective treatments that pre- anti-VEGF therapy is the only treatment that achieves vision gains in vented vision loss in most patients were anti-VEGF agents.4 These many patients and halts progression in most of them. VEGF blockade agents reduce the growth of new blood vessels from existing blood can be achieved with several molecules and various treatment regimens, vessels by blocking the activity of the essential positive regula- which have been studied with excellent results. Unfortunately, real-world tory factor, VEGF. The result of the action of the VEGF molecule by data has shown to be far less efficacious than clinical trials. This gap BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3GqhOzspyl8wzdGoAiDZ01F7vOf+c0L5VOYO2r67BVps= inducing growth of new vessels is known as angiogenesis. between clinical trials and real-world results is an unmet medical need Angiogenesis is a multistep, tightly regulated process that that supports the necessity of new treatment modalities for nAMD. Of is controlled by a dynamic balance of positive and negative fac- the various treatments being studied, anti-VEGFs of higher efficacy and tors.5 Factors that induce angiogenesis are VEGF, angiopoietins, longer durability are those more advanced in their development. Brolu- fibroblast growth factors, transforming growth factor-alpha and cizumab and abicipar pegol are 2 new anti-VEGF drugs that had positive -beta, hepatocyte growth factor, interleukin-8, and connective tis- results in phase 2 studies and are being tested in phase 3 trials at present. sue growth factor. Those that inhibit or modulate angiogenesis are Other promising therapies are antiangiopoietin 2 molecules, which are in vasostatin, angiostatin, endostatin, plasminogen kringle 5, throm- phase 2 development. At earlier stages of development but with promis- bospondin, and pigment epithelium derived factor.6,7 ing results are squalamine, anti–VEGF-C and -D, and gene therapy. The The large family of VEGF molecules includes VEGF-A, -B, future will give retina specialists a broad armamentarium with which pa- -C, -D, and -E and placental growth factor (PlGF). It is believed tients may achieve high visual gains for the long term with a low treat- the main type responsible for angiogenesis is VEGF-A, interact- ment burden. ing with VEGF receptor (VEGFR) 1 and 2. Other types of VEGF play different roles and do not directly stimulate angiogenesis or Key Words: neovascular, AMD, new, treatment, VEGF changes in permeability.8 Several agents manage at present to modulate angiogen- (Asia-Pac J Ophthalmol 2017;6:514–519) esis/permeability by blocking VEGF and preserving or improv- ing vision in most patients. The first drug to be approved that showed gains in vision of patients affected by neovascular AMD ge-related macular degeneration (AMD) is described as the was ranibizumab. The ANCHOR and MARINA trials were the Amost frequent cause of uncorrectable severe vision loss in pivotal studies that compared the use of ranibizumab versus pho- on people older than 55 years of age in the developed world. As todynamic therapy in classic membranes (ANCHOR) and versus 09/09/2020 many as 30% of adults 75 years of age or older develop signs placebo in occult membranes (MARINA), yielding vision gains of senile retinal degeneration, and the prevalence of AMD is in- for the ranibizumab groups and vision loss in the comparator creasing due to an aging population.1,2 groups.9,10 Another drug that showed efficacy initially when used systemically and then intravitreally was bevacizumab. Although never approved for this specific indication, the drug was used as From the *Organización Medica de Investigación, Buenos Aires, Argentina; 11,12 †Oftalmos Instituto Oftalmológico, Universidad de Buenos Aires, Buenos an off-label treatment for neovascular AMD. Aires, Argentina; ‡Retina Section, Ophthalmology Department, Hospital de Later in 2012, aflibercept, a fusion protein, was approved Clinicas Jose de San Martin, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina; §Fundacion Oftalmologica Nacional, Department for the treatment of neovascular AMD based on the results of of Ophthalmology, Universidad del Rosario School of Medicine, Bogota DC, the VIEW 1 and 2 trials.13 This drug showed a similar efficacy Colombia; ¶Centro Privado Romagosa-Fundacion VER, Cordoba, Argentina; and was noninferior to ranibizumab. Conbercept is another anti- and ∥Asociados de Macula Vítreo y Retina de Costa Rica, San José, Costa Rica. VEGF agent that has been successfully used to treat neovascular Received for publication June 30, 2017; accepted August 17, 2017. 14 P.G.S. is a consultant for Novartis, Allergan, and Roche and a member of the AMD, but it is only approved for use and available in China. speakers bureau for Novartis and Allergan. The oncology formulation of aflibercept, ziv-aflibercept, has also The authors have no other funding or conflicts of interest to declare. Reprints: Patricio G. Schlottmann, MD, Uruguay 725 PB, Ciudad de Buenos Aires, been used successfully to treat nAMD patients, although its use C1015ABO, Argentina. E-mail: [email protected]. is off-label, similar to bevacizumab but less widespread.15 All Copyright © 2017 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 these agents have different costs and access levels depending DOI: 10.22608/APO.2017258 on whether they are licensed, but there is comparable efficacy 514 | www.apjo.org Asia-Pacific Journal of Ophthalmology • Volume 6, Number 6, November/December 2017 Copyright © 2017 Asia-Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited. Asia-Pacific Journal of Ophthalmology • Volume 6, Number 6, November/December 2017 New Treatment Modalities for nAMD among them.4,13 the use of vitamin and mineral supplementation for delaying pro- Despite having drugs that achieve positive results in clini- gression of AMD. This evidence has been largely drawn from a cal trials, with varying results according to the different treat- study with long follow-up in a well-nourished American popula- ment strategies, real-world results have been disappointing in tion, which may limit the generalizability of the results to other several reports, even from countries with good medical access.16 populations.23 Long-term follow-up of patients enrolled in clinical trials using There is a strong association between the risk of both geo- anti-VEGF for neovascular AMD also showed poor results af- graphic atrophy and CNV and pack years of cigarette smoking, ter 5 years of treatment.17 The main reason for low visual gains supporting a causal relation between smoking and AMD. Smok- is linked to reduced frequency of injections and increased time ing cessation may have a strong impact on AMD progression.24 between visits. These long-term clinical trial results tend to be It is not clear though, whether once a neovascular stage has been similar to real-world settings.18 It has been speculated that long- reached, quitting smoking has an impact on the number of injec- term results could have been better at a cost of heavy burdens to tions or visual gain. the health system and patients alike. At present neovascular AMD treatment has very positive re- sults in clinical trials and less successful results in real life. All NEW ANTI-VEGF MOLECULES treatments available today have the same or very similar mecha- Brolucizumab (RTH258, formerly ESBA1008, Alcon) is a nism of action, which is blockade of the VEGF molecule. humanized single-chain antibody fragment that inhibits all iso- forms of VEGF-A. It is the smallest of the anti-VEGF antibodies, with a molecular weight of 26 kDa, compared with 115 kDa for NEED FOR NEW TREATMENT MODALITIES aflibercept and 48 kDa for ranibizumab. By virtue of its design, Newer treatment strategies (Table 1) are needed to close the it is possible to concentrate brolucizumab up to 120 mg/mL, al- gap between clinical trial results and real-world settings. These lowing the administration of 6 mg in a single 50-mL intravitreal new treatment modalities should be able to have better efficacy, injection. On a molar basis, 6 mg of brolucizumab equals ap- longer duration of action, or simultaneous effects on angiogen- proximately 12 times the 2.0-mg dose of aflibercept and 22 times esis/permeability and the main physiopathologic cause for poor the 0.5-mg dose of ranibizumab. These attributes may confer po- long-term results: atrophy and scarring.19,20 tential advantages in the treatment of nAMD. A small molecular weight and high drug concentration gradient between the vitreous and retina may support drug distribution into the retina. Assuming EARLY DETECTION AND PREVENTION comparable half-life, higher molar doses of drug may be cleared Although there are currently no proven effective treatments more slowly from the eye, thus prolonging duration of action.
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