New therapeutic targets in the treatment of age-related macular degeneration | Archivos de la Sociedad Española de Oftalmología (English Edition)

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Del Carpio-Orantes, E.R. Contreras-Sánchez, R.I. Luna-Ceballos" "autores" => array:3 [ 0 => array:2 [ "nombre" => "L." "apellidos" => "Del Carpio-Orantes" ] 1 => array:2 [ "nombre" => "E.R." "apellidos" => "Contreras-Sánchez" ] 2 => array:2 [ "nombre" => "R.I." 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Muñoz-Ramón, P. Hernández Martínez, F.J. Muñoz-Negrete" "autores" => array:3 [ 0 => array:4 [ "nombre" => "P.V." "apellidos" => "Muñoz-Ramón" "email" => array:1 [ 0 => "Pablomuram@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "P." "apellidos" => "Hernández Martínez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "F.J." "apellidos" => "Muñoz-Negrete" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Oftalmología, Hospital Universitario Ramón y Cajal, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Universidad de Alcalá de Henares, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Nuevas dianas terapéuticas en el tratamiento de la degeneración macular asociada a la edad" ] ] "textoCompleto" => "IntroductionAge-related macular degeneration (AMD) is a disease that compromises the macular region of the retina and produces progressive loss of central vision.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> At present, AMD is the main cause of poor vision and blindness in developed countries and it is expected to affect approximately 200 million people worldwide in 2020 and 300 million by 2040.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>AMD is a disease with considerable socioeconomic and individual repercussions due to the quality of life limitations it entails. Patients with AMD exhibit higher levels of stress, lower levels of satisfaction and activity and higher rates of depression compared to controls within the same age.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> In addition, several studies have found an association between AMD and increased number of falls,<a class="elsevierStyleCrossRef" href="#bib0020">4</a> higher cognitive deficit risk (including Alzheimer’s disease)<a class="elsevierStyleCrossRef" href="#bib0025">5</a> as well as a 20 % increase in mortality for any cause.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>Despite the fact that the etiopathogeny of AMD is not yet well known, the consensus is that AMD is a multifactorial disease involving genetic predisposition, the complement pathway, neoangiogenesis processes, an inflammatory component and retinal extracellular matrix remodeling processes. As the name indicates, the main risk factor in AMD is age while the main modifiable risk factor is tobacco smoking. In addition, the existence of other risk factors with less evidence has been proposed, including aggregate solar exposure, the color of the iris or the consumption of alcohol.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>The best know classification of AMD divides the disease in 2 forms according to the nature of each:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">1Dry AMD, characterized by degeneration of the retina pigment epithelium (RPE) cells, without involving choroidal neovascularization.</li><li class="elsevierStyleListItem" id="lsti0010">2Neovascular AMD, the defining characteristic of which is the development of neovessels at the level of the choroids.</li></ul>At present, the only available pharmacological therapy is vascular endothelial growth factor (VEGF) inhibitors, indicated only for the neovascular form. As will be discussed below, VEGF inhibitors are expensive drugs<a class="elsevierStyleCrossRef" href="#bib0035">7</a> with uncomfortable posology, prone to complications, only partially efficient and in addition do not provide benefits for the dry form of the disease. The present review aims at discussing the most promising therapeutic targets identified to date for AMD and the breakthroughs achieved by new drugs being researched in ongoing clinic trials (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Limitations of current treatment for age-related macular degenerationAt present, the majority of patients with AMD are not candidates for any pharmacological treatment capable of modifying the course of the disease or reverting its damages. This is because in dry AMD, the most prevalent form of the disease, none of the drugs have demonstrated benefits.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> The only interventions that can be carried out in dry AMD involve controlling modifiable risk factors, predominantly giving up smoking, recommending nutritional supplements based on fatty acids, lutein, zeaxanthin, copper and zinc.<a class="elsevierStyleCrossRef" href="#bib0045">9</a>In what concerns the neovascular form of AMD, the treatment paradigm changed radically in the first years of the current century with the introduction of the first anti-VEGF drugs, 2 of which are approved for treating neovascular AMD (aflibercept [Bayer, Leverkusen, Germany] and ranibizumab [Novartis, Basel, Switzerland]) and a third drug (bevacizumab [Roche Pharma, Basel, Switzerland]) the off-label use of which is common due to its good results.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> Even though said drugs are able to stop the progression of the disease and improve visual acuity in a high percentage of patients, there is a significant proportion of cases in which they are not effective. In addition, we must add a number of drawbacks including the following<a class="elsevierStyleCrossRef" href="#bib0055">11</a>:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0015">1Uncomfortable administration for the patient as well as for the doctor (the need to puncture the eye, requirement of surgical theater or a room specially adapted for administration, etc.).</li><li class="elsevierStyleListItem" id="lsti0020">2Administration pathway comprising risks. Even though anti-VEGF drugs are very safe, the necessity of administering them on a regular basis increases the probability of some of the complications associated to administration, the most feared of which is endophthalmitis<a class="elsevierStyleCrossRef" href="#bib0060">12</a> which has an incidence per patient ranging between 0.019 and 1.6 %; and the most common complication being conjunctival hemorrhage which arises in approximately 10 % of cases.<a class="elsevierStyleCrossRef" href="#bib0065">13</a></li><li class="elsevierStyleListItem" id="lsti0025">3Partial efficacy. As described above, some patients do not respond positively to anti-VEGF drugs, while others initially exhibit a positive response but subsequently develop tachyphylaxis or resistance to treatment.<a class="elsevierStyleCrossRef" href="#bib0070">14</a></li><li class="elsevierStyleListItem" id="lsti0030">4There is a gap between the efficacy demonstrated in clinic trials and the actual effectiveness in daily clinic practice.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> This could be due to factors such as careful selection of patients included in clinic trials and the difficulties in daily clinic practice to administer injections at exact intervals of 4 or 8 weeks as occurs in research studies.</li><li class="elsevierStyleListItem" id="lsti0035">5High cost of treatment,<a class="elsevierStyleCrossRef" href="#bib0080">16</a> involving a significant burden for publicly funded health systems such as that of Spain, in addition to limiting access to treatment in countries with a scarcity of resources or based on private health systems.</li><li class="elsevierStyleListItem" id="lsti0040">6From the pharmacodynamics viewpoint, anti-VEGF act as VEGF action suppressants. Even though this molecule is crucial in the pathogeny of choroidal neovascularization, it also exhibits beneficial trophic effects on the choriocapillaries that participate in maintaining the adequate function of the retina. Increased choriocapillary atrophy has been found in patients treated with anti-VEGF.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> In this regard, efforts should be focused on the modulation of the VEGF pathway (enhancing its beneficial effects and inhibiting the negative ones) instead of the indiscriminate suppression thereof as is the case with the currently available therapeutic armamentarium.</li></ul>Considering the above, an ideal treatment for AMD should be easy and comfortable to administrate for the patient as well as for the doctor. It should also exhibit high tolerance and safety (i.e., low adverse effects rates) and it should be able to develop long-lasting action and low resistance rates. In addition it should be readily available, economically sustainable and able to be administered on an outpatient basis. The following sections of this review describe some of the drugs in development that aspire to fulfill one or more of said conditions.Physiopathology of neovascularization in age-related macular degenerationEven though in its final stages, the RPE atrophy that characterizes dry AMD could culminate in loss of vision due to the degeneration of overlying photoreceptors, with increased visual morbidity of the disease being the consequence of the development of choroidal neovascularization.The neoangiogenic stimulus is regulated by a number of molecules that are released in response to the RPE lesion.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> The best-known of these are the molecules comprising the VEGF sub-family, which in addition are the targets of the drugs being applied at present. However, an entire series of new molecules has been recently identified as joint participants with VEGF in the development of choroidal neovascularization. Accordingly, these new molecules are becoming new potential therapeutic targets for the development of drugs to enable improved management of AMD.<a class="elsevierStyleCrossRef" href="#bib0095">19</a>The VEGF sub-familyThe VEGF sub-family is a member of the platelet-derived growth factor (PDGF) family and comprises VEGF isoforms A, B, C and D as well as the placenta growth factor (PlGF). The best characterized molecule of this subfamily is VEGF-A, which seems to regulate the primary pathogenic stimulus in the development of choroidal neovascularization. Even though the role of the rest of isoforms is not entirely defined, experimental evidence indicates that the VEGF-C isoform could be as powerful as VEGF-A. in addition, the finding that blocking VEFG-A with anti-VEGF associates increased levels of the rest of sub-family isoforms in the vitreous has led the group of Cabral et al. to propose that VEGF-B, VEGF-C, VEGF-D and PlGF could be involved in the tachyphylaxis and resistance processes exhibited by some patients in treatment with anti-VEGF.<a class="elsevierStyleCrossRef" href="#bib0050">10</a>The drugs utilized at present that belong to this family include bevacizumab (Roche Pharma, Basel, Switzerland), ranibizumab (Novartis, Basel, Switzerland) and aflibercept (Bayer, Leverkusen, Germany). The first 2 only block the VEGF-A isoform while the latter has the property of blocking VEGF-B and PlGF as well.The new drugs in development that exhibit action on said molecules include conbercept (Chengdu Kanghong biotech Co. Ltd, Chengdu, China), brolucizumab (Novartis, Basel, Switzerland) and abicipar-Pegol (Allergan, Dublin, Ireland). In addition, the upstream inhibition of VEGF by means of silencing RNA (siRNA) or the downstream inhibition by means of oral tyrosine kinase inhibitors are also the subjects of research.The PDGF familyPDGF is a molecule with a powerful mitogen activity which also plays a crucial role in pericyte survival and adequate function.<a class="elsevierStyleCrossRef" href="#bib0100">20</a>In vitro experiments found that combined blockage of VEGF and PDGF was more efficient than the blockage of VEGF only in the prevention of angiogenesis of endothelial cells. This finding raised great expectations about the potential usefulness of said drugs for treating neovascular AMD.Pegpleranib (Ophthotech, Nueva York, USA) and rinucumab (Regeneron ltd, New York, USA) were developed with the intention of acting jointly on the VEGF and PDGF pathways. However, the results of phase III studies did not reveal additional benefits to those provided by VEGF in isolated therapy.<a class="elsevierStyleCrossRef" href="#bib0105">21</a> This failure can be partly explained by the fact that the action of PDGF on angiogenesis is complex as it operates at various levels. Accordingly, even though it is true that its action on endothelial cells triggers a powerful proliferative stimulus, it is also true that its action on pericytes is necessary for the survival and migration thereof along avascular axis in development. By blocking PDGF action, the new developing vessels are deprived of the stabilizing function carried out by pericytes, leading to capillary dilatation with worsened exudation and progression of choroidal neovascularization. Therefore, greater knowledge is needed about the involvement of PDGF in its various levels of action before designing new molecules targeting this pathway.Pigment epithelium-derived growth factorThe pigment epithelium-derived growth factor (PEDF) is a molecule released by the RPE cells that is able to inhibit the angiogenic stimulus of the hypoxia induced factor 1 (HIF-1) as well as diminishing VEGF levels and regulating the action of specific matrix metalloproteinases.<a class="elsevierStyleCrossRef" href="#bib0110">22</a>Even though there are no trials with drugs acting on said pathway in humans, choroidal neovascularization regression has been observed in animal models treated with virus-mediated PEDF gene transfer.<a class="elsevierStyleCrossRef" href="#bib0115">23</a>Angiopoietin familyThe action of angiopoietin on choroidal neovascularization is complicated and depends on the inflammatory environment in the eye at a given point in time. Accordingly, angiopoietin-1 is abundant in healthy vascular environments and exerts a positive action for maintaining homeostasis by inhibiting angiogenesis, diminishing vascular permeability and exudation as well as an attenuating fibrosis.<a class="elsevierStyleCrossRef" href="#bib0095">19</a>In turn, the action of angiopoietin-2 is more difficult to understand. This molecule can perform as an agonist or antagonist of the Tie-2 receptor depending on the environment on which it acts.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> In a healthy environment, angiopoietin -2 facilitates vascular stability. It has been demonstrated that an environment with a high ANG-2/VEGF ratio is able to promote the regression of new vessels.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> However, in an environment in which inflammatory cytokins and other proangiogenic have already acted, angiopoietin-2 performs as an antagonist of the Tie-2 receptor, developing synergetic action with VEGF in stimulating choroidal neovascularization.Other involved moleculesIn addition to the molecules discussed above, other substances can actively participate in choroidal angiogenesis even though the exact mechanisms of action are unknown at this date. For instance, it is known that a member of the epidemic growth factor (EGF) family, specifically the EGF-like growth factor which is capable to join heparin (HB-EGF), increases its levels in the vitreous in response to treatment with bevacizumab.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> This could point to its participation in the development of resistance to treatment with anti-VEGF. The same occurs with other markers such as endothelin-1, folistatin, hepatocyte-derived growth factor (HGF) or interleukin 8 (IL-8). Among these, the role of endothelin-1 is well-known as vasoconstrictor and therefore flow regulator in smaller gauge vessels as those of the retina.<a class="elsevierStyleCrossRef" href="#bib0095">19</a>Another molecule worthy of note is the hypoxia inducible growth factor 1 (HIF-1), a transcription factor that increases in response to oxygen deprivation in several tissue types including the retina, stimulating the transcription of multiple pro-angiogenic molecules including VEGF.<a class="elsevierStyleCrossRef" href="#bib0130">26</a>Finally, it is worth pointing out that a considerable part of receptors on which pro-angiogenic molecules act have an intrinsic tyrosine kinase activity. Accordingly, tyrosine kinase inhibitors which are already approved for non-ophthalmological indications are becoming an additional therapeutic option for neovascular AMD, as explained below.New drugs for treating neovascular age-related macular degenerationBrolucizumabBrolucizumab (Novartis, Basel, Switzerland) is a new monoclonal antibody in advanced development that targets the VEGF isoform A (VEGF-A). From the pharmacological viewpoint, its main advantage in relation to existing drugs is its small size: 26 kDA against 115 kDA for aflibercept and 48 kDa for ranibizumab. This feature enables the concentration of brolucizumab up to 120 mg/ml so that an intravitreal 0.05 ml injection would supply 6 mg of brolucizumab. At the molar level, i.e., in what concerns the number of molecules, this is equivalent to 12 times the dose of the standard 2 mg of aflibercept and 22 times the 0.5 mg dose of ranibizumab. Theoretically, higher anti-VEGF molecule concentrations in the vitreous could involve longer clearing time of the drug and therefore extended duration of action.<a class="elsevierStyleCrossRef" href="#bib0135">27</a>In what concerns clinic evidence, the preliminary results of 2 phase III clinical trials (HAWK and HARRIER)<a class="elsevierStyleCrossRef" href="#bib0140">28</a> have been published. These studies compared brolucizumab 3 or 6 mg every 8 or 12 weeks after the loading phase with aflibercept every 8 weeks.Said studies included 1818 patients who were randomized for receiving brolucizumab every 4 weeks during 12 weeks (loading phase) followed by brolucizumab every 12 weeks or aflibercept every 4 weeks during 12 weeks (loading phase) followed by aflibercept every 8 weeks, as indicated in the technical specifications. The patients in the brolucizumab branch of the study could initiate an administration pattern every 8 weeks in case the response was regarded as insufficient.The study completed the main objective of no inferiority as regards best corrected visual acuity in the group treated with brolucizumab against the aflibercept group in the protocol analysis.In the Kaplan-Meier analysis, 49.4 % of patients randomized to brolucizumab 3 mg in HAWK, 55.6 % of those randomized to brolucizumab 6 mg in HAWK and 51.0 % of those allocated to brolucizumab 6 mg in HARRIER maintained the administration regime of every 2 weeks at follow-up week 48. In addition, over 80 % of patients without activity during the first 2 weeks of treatment maintained the administration frequency of 12 weeks at follow-up week 48.In what concerns safety data, the side effects profile was similar in all treatment branches, with conjunctival hemorrhage being the most frequent adverse effect in line with the experience from years of treatment with intravitreal drugs.<a class="elsevierStyleCrossRef" href="#bib0140">28</a>Taking into account the above data, brolucizumab could provide an efficacy and safety profile similar to that of aflibercept but with a more comfortable administration both for doctors and patients.According to the data of the pharmaceutical company developing the drug, brolucizumab is up for approval by the US Food and Drug Administration (FDA) presumably by late 2019.Abicipar-PegolAbicipar (Allergan, Dublin, Ireland) is one of a new class of drugs known as DARPin (designed ankyrin repeat protein) characterized by proteins with a design similar to that of ankyrin having a great capacity to bond to a given molecule.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> Abicipar is able to join all the soluble forms of VEGF-A to block their action.Recently the results of a phase II clinical trial (REACH)<a class="elsevierStyleCrossRef" href="#bib0150">30</a> have been published. This study included 64 patients with the objective of comparing the efficacy and safety of abicipar compared to ranibizumab with a 20-week follow-up. The study concluded that abicipar is not inferior to ranibizumab in visual acuity gain at 12 weeks and exhibits increased capacity to resolve the accumulation of intra- and subretinal fluid in a shorter period of time (a higher percentage of patients treated with abicipar exhibited dry retina at 4 and 8 weeks in comparison with ranibizumab). In addition, the results of said studies suggest that an abicipar administration regime of 8–12 weeks could be as effective as ranibizumab every 4 weeks.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> However, abicipar exhibited higher post-administration intraocular inflammation incidence than ranibizumab. Two phase III studies comparing abicipar every 8 or 12 weeks after a loading dose with ranibizumab every 4 weeks are in progress (NCT02462928 and NCT02462486).ConberceptConbercept (Chengdu Kanghong biotech Co. Ltd, Chengdu, China) is a monoclonal antibody distributed in China that has the theoretical advantage of acting against VEGF-A, VEGF-B and VEGF-C forms in addition to PlGF. However, there are no clinic studies with sufficient quality to compare the efficacy of conbercept against the anti-VEGF drugs marketed in the Western world.<a class="elsevierStyleCrossRef" href="#bib0155">31</a>Tyrosine kinase inhibitorsTyrosine kinase inhibitors are well-known drugs due to their indications in oncology. An important advantage of these inhibitors is oral administration. As many pro-angiogenic molecule receptors that participate in the development of choroidal neovascularization have an intrinsic tyrosine kinase activity (including VEGF and PDGF receptors or the angiopoietin Tie-2 receptor), it has been proposed that these drugs could be efficient for treating neovascular AMD.At present there is only one published Phase 1 study that concludes that X-82 (Tyrogenex, Rockville, USA) is safe for oral administration in patients with AMD. Phase II trials to assess the efficacy of these drugs as intravitreal monotherapy or anti-VEGF co-adjuvants for AMD have not started yet.<a class="elsevierStyleCrossRef" href="#bib0160">32</a>Axitinib (Pfizer, New York, USA) is another medicament in this category that is being researched for treating neovascular AMD.<a class="elsevierStyleCrossRef" href="#bib0165">33</a>FaricimabAs discussed above, the action of angiopoietin on the induction of neovessels is complex. The ANG-1 isoform contributes to the stability of vessels while the ANG-2 isoform is involved in aberrant angiogenesis. Faricimab is a new monoclonal antibody that combines anti-VEGF and anti-ANG-2 action and which has demonstrated in a phase II trial (STAIRWAY) in a 12–16 week administration regime after a loading dose to be not inferior to ranibizumab (Novartis, Basel. Switzerland) every 4 weeks. At present there are 2 phase III studies in progress (TENAYA-NTC03823287 and LUCERNE-NTC03823300) aiming at the confirmation of these results.Nesvacumab is another monoclonal antibody with selective action against ANG-2 that was researched in the past in combination with ranibizumab.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> However, the phase II trial that was studying this drug was suspended due to lack of efficacy.Topical formulationsDue to the ease of topical pathway administration, a significant effort has been made in recent years to develop drugs for neovascular AMD treatment. The most relevant are:<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0045">•Pazopanib (GlaxoSmithKline, Brentford, United Kingdom) and regorafenib (Bayer Healthcare, Leverkussen, Germany), multikinase inhibitors approved for treating a range of solids tumors. The targets include the downstream inhibition of VEGF and PDGF receptors. This led to researching these drugs in combination with anti-VEGF (in the case of pazopanib) or in monotherapy (regorafenib) in patients with neovascular AMD. However, the primary endpoint of the study was not reached and at the time of writing there are no new studies in progress.<a class="elsevierStyleCrossRefs" href="#bib0175">35,36</a></li><li class="elsevierStyleListItem" id="lsti0050">•Squalamine (Ohr pharmaceuticals, New York, USA) is a molecule that was first isolated from sharks that aroused great interest for treating a range of diseases including AMD due to its ability to modulate a large amount of intracellular signaling pathways. However, a phase III study (Mako study - NTC 02727881) on squalamine in combination with ranibizumab was unable to demonstrate additional benefits to monotherapy ranibizumab treatment, for which reason its development is on hold at present.</li><li class="elsevierStyleListItem" id="lsti0055">•LHA-510 (Alcon, Geneva, Switzerland) and PAN-90806 (PanOptica, Bernardsville, USA) are topical drugs in early clinic research phase for monotherapy treatment of neovascular AMD.<a class="elsevierStyleCrossRef" href="#bib0185">37</a></li></ul>Other drugsEven though the medicaments discussed above are the most promising drugs with the highest possibilities of reaching the market in the near future, other drugs are also worthy of note, including:<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0060">•Bevasinarib (Opko Health, Miami, USA) is a member of the class known as silencing RNA molecules (siRNA). This is a dual RNA strand designed to join the VEGF messenger RNA molecule with intravitreal administration in order to block its translation.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> This would achieve a lower VEGF expression. Even though the siRNA technology holds a lot of promise for the future of pharmacology, clinic studies with bevasinarib was suspended and at present there are no additional molecules under research.</li><li class="elsevierStyleListItem" id="lsti0065">•Another example of interrupted trials due to lack of efficacy are those related to pegpleranib and rinucumab, PGDF inhibitors. As discussed above, the action of PDGF on choroidal neovascularization is complex and the action of this molecule would be focused on modulation instead of induction of angiogenesis. Accordingly, a more selective approach than simple inhibition would be required to act on this pathway.</li><li class="elsevierStyleListItem" id="lsti0070">•OPT-302 (Opthea, Victoria, Australia) is a soluble form of the VEGFR-3 receptor that is capable of sequestering the VEGF-3 isoform which is increased in the vitreous of patients treated with VEGF-A inhibitors.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> This drug could help overcome the resistance experienced by some patients against anti-VEGF treatments because it depends at least partially on an offsetting increase of VEGF isoforms that are different to VEGF-A.</li></ul>Gene therapyGene therapy could also find applications for the treatment of choroidal neovascularization through the induction of the expression in the patient retina of a micro-environment that is able to restore the homeostasis altered by the disease. At present the transfer of genes encoding VEGF inhibiting molecules and other pro-angiogenic factors to retina cells compromised by neovascular membranes is in pre-clinic research.<a class="elsevierStyleCrossRef" href="#bib0195">39</a>In this line of research, the most promising therapies are:<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0075">•ADVM-022 / ADVM-032 (Adverum biotechnologies, Menlo Park, USA): this is a vector that encodes DNA necessary for the production of aflibercept and ranibizumab, respectively. At the time of writing, there is a phase 1 trial in progress (NTC 0374884).<a class="elsevierStyleCrossRef" href="#bib0185">37</a></li><li class="elsevierStyleListItem" id="lsti0080">•RGX-314 (Regenxbio, Rockville, USA) is a vector that is able to induce the expression of a molecule with anti-VEGF capacity similar to ranibizumab in retinal cells subject to gene transfer. The administration of this drug requires vitrectomy to enable subretinal inoculation of the drug. The safety and tolerability of the drug shall be studied in a phase I/IIa trial (NTC 03066258) that is in the recruitment stage at the time of writing.<a class="elsevierStyleCrossRef" href="#bib0185">37</a></li></ul>Sustained-release devicesPort delivery systemPort Delivery System (Genentech, San Francisco, USA) is an implantable device that provides sustained release of ranibizumab. It is inserted at the subconjunctival level at the height of pars plana and can be filled in with ambulatory treatment every 24 weeks. In a recent phase II clinical trial<a class="elsevierStyleCrossRef" href="#bib0200">40</a> the sustained administration of ranibizumab 100 mg/ml by means of the Port Delivery System demonstrated to be not inferior to monthly ranibizumab. At present 2 phase III trials are in progress (PORTAL and ARCHWAY).OthersAdditional sustained-release devices in early development include GB-102 (GrayBug Vision, Redwood city, USA), an sunitinib maleate implant (a tyrosine kinase inhibitor); NT-503 (Neurotech, Waukesha, USA), an intravitreous implant containing a genetically modified pigment epithelium cell line that produces a molecule with the ability of inhibiting VEGF-A; Hydrogel anti-VEGF depot (Ocular Therapeutix, Bedford, USA); Durasert (EyePoint Pharmaceuticals, Watertown, USA) or ENV-1305 (Envisia Therapeutics, Morrisville, USA).<a class="elsevierStyleCrossRef" href="#bib0185">37</a>New drugs for treating dry age-related macular degenerationDry macular degeneration is characterized by RPE alterations that involve progressively towards the final stage known as geographic atrophy. As a consequence of said alteration, overlying photoreceptors are deprived of the atrophic actions of the RPE cells and suffer degeneration which is ultimately responsible for the loss of vision found in these patients.RPE damage is due to a range of not entirely known factors, notably alterations in the mitochondrial function of RPE cells leading to oxidative stress, complement activation that establishes a chronic inflammation environment, lipofuscin deposits or insufficient blood supply for the choroids.<a class="elsevierStyleCrossRef" href="#bib0090">18</a>Taking the above into account, only 2 strategies can be considered for treating said pathology. On the one hand, actions aimed at slowing down genetic atrophy as much as possible and confining it to areas as removed as possible from the macula, and on the other hand treatments focused on regeneration of the RPE and degraded photoreceptors in the case of advanced stages of the disease.The drugs that have been tested to counteract geographic atrophy by controlling inflammation in dry AMD include those acting on complement cascade, the best-known of which is lampalizumab (Roche, Basel, Switzerland), a complement d-factor inhibitor. After finding contradictory results in phase II trials, phase III Chroma and Spectri studies concluded that there is no difference in atrophy progression compared to placebo.<a class="elsevierStyleCrossRef" href="#bib0205">41</a> Even so, other drugs with similar action mechanisms are at present in research. Perhaps the most promising research is on a C3 inhibitor known as APL-2 (Apellis pharmaceuticals, Kentucky, USA) which in monthly intravitreous administration has demonstrated in a phase II study its ability to diminish the progression rate of geographic atrophy.Other complement inhibitors such as POT-4 (Apellis pharmaceuticals, Kentucky, USA), ARC 1905 (Opthotech corporation, Princeton, USA), eculizumab and immunomodulators such as sirolimus or glatiramer acetate has been researched as possible strategies for diminishing geographic atrophy progression but without demonstrating clear benefits.<a class="elsevierStyleCrossRef" href="#bib0210">42</a>In what concerns neuroprotection strategies, the most relevant drugs are the ciliary neurotrophic factor (CNTF) and brimonidin. CNTF is being researched in several clinical trials for treating ischemic optic neuropathy, retinitis pigmentosa or glaucoma, and could also play a role in the interruption of atrophic AMD.<a class="elsevierStyleCrossRef" href="#bib0215">43</a> Brimonidin has demonstrated neuroprotective capacity on retinal cells in animal models.<a class="elsevierStyleCrossRefs" href="#bib0220">44–46</a> Recently, an intravitreal sustained release brimonidin device has demonstrated in a randomized prospective and triple blind clinic trial with 310 patients (Beacon study) its ability to diminish geographic atrophy progression in a statistically significant manner. The full results of this study are expected to be published in late 2019.Finally, in the longer term we may be able to utilize stem cells not only to slow down but also to revert atrophy progression utilizing pluripotential cells to regenerate pigment epithelium and lost photoreceptors.<a class="elsevierStyleCrossRef" href="#bib0195">39</a>ConclusionDue to prevalence, morbidity and socioeconomic implications, macular degeneration is one of the biggest challenges facing ophthalmologists in the 21st century. Significant pharmacological developments in the past few years have improved treatments for the neovascular form of the disease which accounts for the highest morbidity. Considering the positive results of pre-market clinic trials, in the next few years we could witness the arrival of a new generation of antiangiogenic drugs including brolucizumab, abicipar or faricimab that could improve the efficacy of currently available therapies or contribute to a more comfortable administration regime by increasing the intervals between intravitreal injections while maintaining efficacy. Sustained release implants of antiangiogenics such as the Port Delivery System are additional novelties that could become available in the coming decade.In turn, the main challenges for researchers in the next few years involve a full understanding of the reasons for the failure of anti-PDGF drugs as well as the development of oral and topical administration therapies such as tyrosine kinase inhibitors, oral macromolecule administration systems (anti-VEGF) or the formulation of antiangiogenics in the form of gels, drops or the like.In what concerns dry AMD, a range of drugs have been researched to slow down the development of geographic atrophy with poor results. At present, the most promising drugs are APL-2 and the brimonidin intravitreal implant. Both have demonstrated to slow down in a statistically significant manner the progression of geographic atrophy. Even so, we must await the full publication of research results to determine the extent in which these drugs could be significant in clinic practice.Conflict of interestNo conflict of interests was declared by the authors." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1300359" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1199738" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1300358" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1199739" "titulo" => "Palabras clave" ] 4 => array:3 [ "identificador" => "sec0005" "titulo" => "Introduction" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Limitations of current treatment for age-related macular degeneration" ] ] ] 5 => array:3 [ "identificador" => "sec0015" "titulo" => "Physiopathology of neovascularization in age-related macular degeneration" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "The VEGF sub-family" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "The PDGF family" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Pigment epithelium-derived growth factor" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Angiopoietin family" ] 4 => array:2 [ "identificador" => "sec0040" "titulo" => "Other involved molecules" ] ] ] 6 => array:3 [ "identificador" => "sec0045" "titulo" => "New drugs for treating neovascular age-related macular degeneration" "secciones" => array:8 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Brolucizumab" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Abicipar-Pegol" ] 2 => array:2 [ "identificador" => "sec0060" "titulo" => "Conbercept" ] 3 => array:2 [ "identificador" => "sec0065" "titulo" => "Tyrosine kinase inhibitors" ] 4 => array:2 [ "identificador" => "sec0070" "titulo" => "Faricimab" ] 5 => array:2 [ "identificador" => "sec0075" "titulo" => "Topical formulations" ] 6 => array:2 [ "identificador" => "sec0080" "titulo" => "Other drugs" ] 7 => array:2 [ "identificador" => "sec0085" "titulo" => "Gene therapy" ] ] ] 7 => array:3 [ "identificador" => "sec0090" "titulo" => "Sustained-release devices" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0095" "titulo" => "Port delivery system" ] 1 => array:2 [ "identificador" => "sec0100" "titulo" => "Others" ] ] ] 8 => array:2 [ "identificador" => "sec0105" "titulo" => "New drugs for treating dry age-related macular degeneration" ] 9 => array:2 [ "identificador" => "sec0110" "titulo" => "Conclusion" ] 10 => array:2 [ "identificador" => "sec0115" "titulo" => "Conflict of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-07-15" "fechaAceptado" => "2019-09-20" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1199738" "palabras" => array:6 [ 0 => "Age related macular degeneration" 1 => "Anti-VEGF" 2 => "Angiopoietin" 3 => "Brolucizumab" 4 => "Abicipar" 5 => "Faricimab" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1199739" "palabras" => array:6 [ 0 => "Degeneración macular" 1 => "Anti-VEGF" 2 => "Angiopoyetina" 3 => "Brolucizumab" 4 => "Abicipar" 5 => "Faricimab" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Age-related macular degeneration and specially neovascular age-related macular degeneration is the leading cause of low vision in developed countries. Even though the introduction of anti-VEGF drugs in recent years completely changed the management of this condition, its cost, the need for repeated intravitreal injections and loss of efficacy in the long term are still issues to deal with. Currently, a new generation of novel therapies under development tries to address some of this limitations. Among them some of the most prominent are new anti-VEGFs such as brolucizumab or abicipar, drugs against angiopoyetin-2 receptor such as faricimab, sustained-release systems or tyrosin kinase inhibitors.Regarding dry age-related macular degeneration, neuroprotection, the complement pathway and stem cell therapy are the most promising targets currently under investigation." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La degeneración macular asociada a la edad (DMAE) y en especial su forma neovascular, supone la principal causa de baja visión en países desarrollados. Aunque en años recientes la introducción de los fármacos conocidos como anti-VEGF ha supuesto una revolución en el manejo de esta enfermedad, su precio, la necesidad de inyecciones intravítreas repetidas, y la pérdida de efectividad a largo plazo en una importante proporción de pacientes son problemas aún por resolver. En la actualidad existen en desarrollo una serie de nuevas estrategias que tratan de ofrecer soluciones a las limitaciones que presentan los fármacos intravítreos actuales. Entre ellos destacan nuevos anti-VEGF como brolucizumab o abicipar, fármacos contra el receptor de angiopoyetina-2 como faricimab, sistemas de liberación sostenida de macromoléculas o inhibidores de la tirosinkinasa.Respecto a la DMAE seca la neuroprotección, la modulación de la vía del complemento y, en última instancia, la terapia con células madre son las líneas de investigación más prometedores en la actualidad." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Muñoz-Ramón PV, Hernández Martínez P, Muñoz-Negrete FJ. Nuevas dianas terapéuticas en el tratamiento de la degeneración macular asociada a la edad. Arch Soc Esp Oftalmol. 2020;95:75–83." ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "q16s, q12s and q8s: every 16, 12 and 8 weeks, respectively." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Therapy \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Action mechanism \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Differences with available therapies \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Development phase \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Brolucizumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VEGF-A receptor antagonist \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Small size molecule (26 KDs) –> higher molar concentration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase III in progress \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Possibility of q12s regime \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Abicipar-Pegol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ability to join all soluble VEGF-A isoforms, preventing its joining the receptor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Possibility of q8s and q12s regime \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase III in progress \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Issues related to post-administration higher intraocular inflammation rates yet to be resolved \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Conbercept \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VEGF-A, VEGF-B, VEGF-C and PlGF antagonist \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Theoretical pharmacological advantage due to the ability to bind with more VEGF isoforms than existing therapies → to be confirmed with clinic results \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Marketed (China) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Faricimab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Combined Anti-VEGF and Ang-2 action \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Possibility of q12 s and q16 s regime \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase III in progress \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tyrosine kinase inhibitors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Blocking intra-cell transduction of the signal triggered by the bonding of VEGF to its receptor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Possibility of oral administration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase I/IIa \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Discouraging topical formulation trials \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Port Delivery System \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Implant for sustained release of ranibizumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Requires surgical implant. Refilling needed only twice a year \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase III in progress \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Could overcome the gap observed between anti-VEGF results in clinic trials and actual clinic practice \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gene therapy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Induction of autonomous anti-VEGF production by retina cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IndependenE of intravitreal injection \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Preclinic/Phase I \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2226159.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Summary of the main therapies in research for treating neovascular AMD." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:46 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Age-related macular degeneration" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "P. 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New therapeutic targets in the treatment of age-related macular degeneration

Nuevas dianas terapéuticas en el tratamiento de la degeneración macular asociada a la edad

P.V. Muñoz-Ramóna,

Corresponding author

Pablomuram@gmail.com

Corresponding author.

, P. Hernández Martíneza, F.J. Muñoz-Negretea,b

a Servicio de Oftalmología, Hospital Universitario Ramón y Cajal, Madrid, Spain

b Universidad de Alcalá de Henares, Madrid, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Age-related macular degeneration &#40;AMD&#41; is a disease that compromises the macular region of the retina and produces progressive loss of central vision&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> At present&#44; AMD is the main cause of poor vision and blindness in developed countries and it is expected to affect approximately 200 million people worldwide in 2020 and 300 million by 2040&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">AMD is a disease with considerable socioeconomic and individual repercussions due to the quality of life limitations it entails&#46; Patients with AMD exhibit higher levels of stress&#44; lower levels of satisfaction and activity and higher rates of depression compared to controls within the same age&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> In addition&#44; several studies have found an association between AMD and increased number of falls&#44;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> higher cognitive deficit risk &#40;including Alzheimer&#8217;s disease&#41;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> as well as a 20 &#37; increase in mortality for any cause&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Despite the fact that the etiopathogeny of AMD is not yet well known&#44; the consensus is that AMD is a multifactorial disease involving genetic predisposition&#44; the complement pathway&#44; neoangiogenesis processes&#44; an inflammatory component and retinal extracellular matrix remodeling processes&#46; As the name indicates&#44; the main risk factor in AMD is age while the main modifiable risk factor is tobacco smoking&#46; In addition&#44; the existence of other risk factors with less evidence has been proposed&#44; including aggregate solar exposure&#44; the color of the iris or the consumption of alcohol&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The best know classification of AMD divides the disease in 2 forms according to the nature of each&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1</span><p id="par0025" class="elsevierStylePara elsevierViewall">Dry AMD&#44; characterized by degeneration of the retina pigment epithelium &#40;RPE&#41; cells&#44; without involving choroidal neovascularization&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2</span><p id="par0030" class="elsevierStylePara elsevierViewall">Neovascular AMD&#44; the defining characteristic of which is the development of neovessels at the level of the choroids&#46;</p></li></ul></p><p id="par0035" class="elsevierStylePara elsevierViewall">At present&#44; the only available pharmacological therapy is vascular endothelial growth factor &#40;VEGF&#41; inhibitors&#44; indicated only for the neovascular form&#46; As will be discussed below&#44; VEGF inhibitors are expensive drugs<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> with uncomfortable posology&#44; prone to complications&#44; only partially efficient and in addition do not provide benefits for the dry form of the disease&#46; The present review aims at discussing the most promising therapeutic targets identified to date for AMD and the breakthroughs achieved by new drugs being researched in ongoing clinic trials &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Limitations of current treatment for age-related macular degeneration</span><p id="par0040" class="elsevierStylePara elsevierViewall">At present&#44; the majority of patients with AMD are not candidates for any pharmacological treatment capable of modifying the course of the disease or reverting its damages&#46; This is because in dry AMD&#44; the most prevalent form of the disease&#44; none of the drugs have demonstrated benefits&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> The only interventions that can be carried out in dry AMD involve controlling modifiable risk factors&#44; predominantly giving up smoking&#44; recommending nutritional supplements based on fatty acids&#44; lutein&#44; zeaxanthin&#44; copper and zinc&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In what concerns the neovascular form of AMD&#44; the treatment paradigm changed radically in the first years of the current century with the introduction of the first anti-VEGF drugs&#44; 2 of which are approved for treating neovascular AMD &#40;aflibercept &#91;Bayer&#44; Leverkusen&#44; Germany&#93; and ranibizumab &#91;Novartis&#44; Basel&#44; Switzerland&#93;&#41; and a third drug &#40;bevacizumab &#91;Roche Pharma&#44; Basel&#44; Switzerland&#93;&#41; the off-label use of which is common due to its good results&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Even though said drugs are able to stop the progression of the disease and improve visual acuity in a high percentage of patients&#44; there is a significant proportion of cases in which they are not effective&#46; In addition&#44; we must add a number of drawbacks including the following<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">1</span><p id="par0050" class="elsevierStylePara elsevierViewall">Uncomfortable administration for the patient as well as for the doctor &#40;the need to puncture the eye&#44; requirement of surgical theater or a room specially adapted for administration&#44; etc&#46;&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">2</span><p id="par0055" class="elsevierStylePara elsevierViewall">Administration pathway comprising risks&#46; Even though anti-VEGF drugs are very safe&#44; the necessity of administering them on a regular basis increases the probability of some of the complications associated to administration&#44; the most feared of which is endophthalmitis<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> which has an incidence per patient ranging between 0&#46;019 and 1&#46;6 &#37;&#59; and the most common complication being conjunctival hemorrhage which arises in approximately 10 &#37; of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">3</span><p id="par0060" class="elsevierStylePara elsevierViewall">Partial efficacy&#46; As described above&#44; some patients do not respond positively to anti-VEGF drugs&#44; while others initially exhibit a positive response but subsequently develop tachyphylaxis or resistance to treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">4</span><p id="par0065" class="elsevierStylePara elsevierViewall">There is a gap between the efficacy demonstrated in clinic trials and the actual effectiveness in daily clinic practice&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> This could be due to factors such as careful selection of patients included in clinic trials and the difficulties in daily clinic practice to administer injections at exact intervals of 4 or 8 weeks as occurs in research studies&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">5</span><p id="par0070" class="elsevierStylePara elsevierViewall">High cost of treatment&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> involving a significant burden for publicly funded health systems such as that of Spain&#44; in addition to limiting access to treatment in countries with a scarcity of resources or based on private health systems&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">6</span><p id="par0075" class="elsevierStylePara elsevierViewall">From the pharmacodynamics viewpoint&#44; anti-VEGF act as VEGF action suppressants&#46; Even though this molecule is crucial in the pathogeny of choroidal neovascularization&#44; it also exhibits beneficial trophic effects on the choriocapillaries that participate in maintaining the adequate function of the retina&#46; Increased choriocapillary atrophy has been found in patients treated with anti-VEGF&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> In this regard&#44; efforts should be focused on the modulation of the VEGF pathway &#40;enhancing its beneficial effects and inhibiting the negative ones&#41; instead of the indiscriminate suppression thereof as is the case with the currently available therapeutic armamentarium&#46;</p></li></ul></p><p id="par0080" class="elsevierStylePara elsevierViewall">Considering the above&#44; an ideal treatment for AMD should be easy and comfortable to administrate for the patient as well as for the doctor&#46; It should also exhibit high tolerance and safety &#40;i&#46;e&#46;&#44; low adverse effects rates&#41; and it should be able to develop long-lasting action and low resistance rates&#46; In addition it should be readily available&#44; economically sustainable and able to be administered on an outpatient basis&#46; The following sections of this review describe some of the drugs in development that aspire to fulfill one or more of said conditions&#46;</p></span></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Physiopathology of neovascularization in age-related macular degeneration</span><p id="par0085" class="elsevierStylePara elsevierViewall">Even though in its final stages&#44; the RPE atrophy that characterizes dry AMD could culminate in loss of vision due to the degeneration of overlying photoreceptors&#44; with increased visual morbidity of the disease being the consequence of the development of choroidal neovascularization&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The neoangiogenic stimulus is regulated by a number of molecules that are released in response to the RPE lesion&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> The best-known of these are the molecules comprising the VEGF sub-family&#44; which in addition are the targets of the drugs being applied at present&#46; However&#44; an entire series of new molecules has been recently identified as joint participants with VEGF in the development of choroidal neovascularization&#46; Accordingly&#44; these new molecules are becoming new potential therapeutic targets for the development of drugs to enable improved management of AMD&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">The VEGF sub-family</span><p id="par0095" class="elsevierStylePara elsevierViewall">The VEGF sub-family is a member of the platelet-derived growth factor &#40;PDGF&#41; family and comprises VEGF isoforms A&#44; B&#44; C and D as well as the placenta growth factor &#40;PlGF&#41;&#46; The best characterized molecule of this subfamily is VEGF-A&#44; which seems to regulate the primary pathogenic stimulus in the development of choroidal neovascularization&#46; Even though the role of the rest of isoforms is not entirely defined&#44; experimental evidence indicates that the VEGF-C isoform could be as powerful as VEGF-A&#46; in addition&#44; the finding that blocking VEFG-A with anti-VEGF associates increased levels of the rest of sub-family isoforms in the vitreous has led the group of Cabral et al&#46; to propose that VEGF-B&#44; VEGF-C&#44; VEGF-D and PlGF could be involved in the tachyphylaxis and resistance processes exhibited by some patients in treatment with anti-VEGF&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">The drugs utilized at present that belong to this family include bevacizumab &#40;Roche Pharma&#44; Basel&#44; Switzerland&#41;&#44; ranibizumab &#40;Novartis&#44; Basel&#44; Switzerland&#41; and aflibercept &#40;Bayer&#44; Leverkusen&#44; Germany&#41;&#46; The first 2 only block the VEGF-A isoform while the latter has the property of blocking VEGF-B and PlGF as well&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The new drugs in development that exhibit action on said molecules include conbercept &#40;Chengdu Kanghong biotech Co&#46; Ltd&#44; Chengdu&#44; China&#41;&#44; brolucizumab &#40;Novartis&#44; Basel&#44; Switzerland&#41; and abicipar-Pegol &#40;Allergan&#44; Dublin&#44; Ireland&#41;&#46; In addition&#44; the upstream inhibition of VEGF by means of silencing RNA &#40;siRNA&#41; or the downstream inhibition by means of oral tyrosine kinase inhibitors are also the subjects of research&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">The PDGF family</span><p id="par0110" class="elsevierStylePara elsevierViewall">PDGF is a molecule with a powerful mitogen activity which also plays a crucial role in pericyte survival and adequate function&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a><span class="elsevierStyleItalic">In vitro</span> experiments found that combined blockage of VEGF and PDGF was more efficient than the blockage of VEGF only in the prevention of angiogenesis of endothelial cells&#46; This finding raised great expectations about the potential usefulness of said drugs for treating neovascular AMD&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Pegpleranib &#40;Ophthotech&#44; Nueva York&#44; USA&#41; and rinucumab &#40;Regeneron ltd&#44; New York&#44; USA&#41; were developed with the intention of acting jointly on the VEGF and PDGF pathways&#46; However&#44; the results of phase III studies did not reveal additional benefits to those provided by VEGF in isolated therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> This failure can be partly explained by the fact that the action of PDGF on angiogenesis is complex as it operates at various levels&#46; Accordingly&#44; even though it is true that its action on endothelial cells triggers a powerful proliferative stimulus&#44; it is also true that its action on pericytes is necessary for the survival and migration thereof along avascular axis in development&#46; By blocking PDGF action&#44; the new developing vessels are deprived of the stabilizing function carried out by pericytes&#44; leading to capillary dilatation with worsened exudation and progression of choroidal neovascularization&#46; Therefore&#44; greater knowledge is needed about the involvement of PDGF in its various levels of action before designing new molecules targeting this pathway&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Pigment epithelium-derived growth factor</span><p id="par0120" class="elsevierStylePara elsevierViewall">The pigment epithelium-derived growth factor &#40;PEDF&#41; is a molecule released by the RPE cells that is able to inhibit the angiogenic stimulus of the hypoxia induced factor 1 &#40;HIF-1&#41; as well as diminishing VEGF levels and regulating the action of specific matrix metalloproteinases&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Even though there are no trials with drugs acting on said pathway in humans&#44; choroidal neovascularization regression has been observed in animal models treated with virus-mediated PEDF gene transfer&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Angiopoietin family</span><p id="par0130" class="elsevierStylePara elsevierViewall">The action of angiopoietin on choroidal neovascularization is complicated and depends on the inflammatory environment in the eye at a given point in time&#46; Accordingly&#44; angiopoietin-1 is abundant in healthy vascular environments and exerts a positive action for maintaining homeostasis by inhibiting angiogenesis&#44; diminishing vascular permeability and exudation as well as an attenuating fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">In turn&#44; the action of angiopoietin-2 is more difficult to understand&#46; This molecule can perform as an agonist or antagonist of the Tie-2 receptor depending on the environment on which it acts&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> In a healthy environment&#44; angiopoietin -2 facilitates vascular stability&#46; It has been demonstrated that an environment with a high ANG-2&#47;VEGF ratio is able to promote the regression of new vessels&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> However&#44; in an environment in which inflammatory cytokins and other proangiogenic have already acted&#44; angiopoietin-2 performs as an antagonist of the Tie-2 receptor&#44; developing synergetic action with VEGF in stimulating choroidal neovascularization&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Other involved molecules</span><p id="par0140" class="elsevierStylePara elsevierViewall">In addition to the molecules discussed above&#44; other substances can actively participate in choroidal angiogenesis even though the exact mechanisms of action are unknown at this date&#46; For instance&#44; it is known that a member of the epidemic growth factor &#40;EGF&#41; family&#44; specifically the EGF-like growth factor which is capable to join heparin &#40;HB-EGF&#41;&#44; increases its levels in the vitreous in response to treatment with bevacizumab&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> This could point to its participation in the development of resistance to treatment with anti-VEGF&#46; The same occurs with other markers such as endothelin-1&#44; folistatin&#44; hepatocyte-derived growth factor &#40;HGF&#41; or interleukin 8 &#40;IL-8&#41;&#46; Among these&#44; the role of endothelin-1 is well-known as vasoconstrictor and therefore flow regulator in smaller gauge vessels as those of the retina&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Another molecule worthy of note is the hypoxia inducible growth factor 1 &#40;HIF-1&#41;&#44; a transcription factor that increases in response to oxygen deprivation in several tissue types including the retina&#44; stimulating the transcription of multiple pro-angiogenic molecules including VEGF&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Finally&#44; it is worth pointing out that a considerable part of receptors on which pro-angiogenic molecules act have an intrinsic tyrosine kinase activity&#46; Accordingly&#44; tyrosine kinase inhibitors which are already approved for non-ophthalmological indications are becoming an additional therapeutic option for neovascular AMD&#44; as explained below&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">New drugs for treating neovascular age-related macular degeneration</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Brolucizumab</span><p id="par0155" class="elsevierStylePara elsevierViewall">Brolucizumab &#40;Novartis&#44; Basel&#44; Switzerland&#41; is a new monoclonal antibody in advanced development that targets the VEGF isoform A &#40;VEGF-A&#41;&#46; From the pharmacological viewpoint&#44; its main advantage in relation to existing drugs is its small size&#58; 26&#8239;kDA against 115&#8239;kDA for aflibercept and 48&#8239;kDa for ranibizumab&#46; This feature enables the concentration of brolucizumab up to 120&#8239;mg&#47;ml so that an intravitreal 0&#46;05&#8239;ml injection would supply 6&#8239;mg of brolucizumab&#46; At the molar level&#44; i&#46;e&#46;&#44; in what concerns the number of molecules&#44; this is equivalent to 12 times the dose of the standard 2&#8239;mg of aflibercept and 22 times the 0&#46;5&#8239;mg dose of ranibizumab&#46; Theoretically&#44; higher anti-VEGF molecule concentrations in the vitreous could involve longer clearing time of the drug and therefore extended duration of action&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">In what concerns clinic evidence&#44; the preliminary results of 2 phase III clinical trials &#40;HAWK and HARRIER&#41;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> have been published&#46; These studies compared brolucizumab 3 or 6&#8239;mg every 8 or 12 weeks after the loading phase with aflibercept every 8 weeks&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Said studies included 1818 patients who were randomized for receiving brolucizumab every 4 weeks during 12 weeks &#40;loading phase&#41; followed by brolucizumab every 12 weeks or aflibercept every 4 weeks during 12 weeks &#40;loading phase&#41; followed by aflibercept every 8 weeks&#44; as indicated in the technical specifications&#46; The patients in the brolucizumab branch of the study could initiate an administration pattern every 8 weeks in case the response was regarded as insufficient&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">The study completed the main objective of no inferiority as regards best corrected visual acuity in the group treated with brolucizumab against the aflibercept group in the protocol analysis&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">In the Kaplan-Meier analysis&#44; 49&#46;4 &#37; of patients randomized to brolucizumab 3&#8239;mg in HAWK&#44; 55&#46;6 &#37; of those randomized to brolucizumab 6&#8239;mg in HAWK and 51&#46;0 &#37; of those allocated to brolucizumab 6&#8239;mg in HARRIER maintained the administration regime of every 2 weeks at follow-up week 48&#46; In addition&#44; over 80 &#37; of patients without activity during the first 2 weeks of treatment maintained the administration frequency of 12 weeks at follow-up week 48&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">In what concerns safety data&#44; the side effects profile was similar in all treatment branches&#44; with conjunctival hemorrhage being the most frequent adverse effect in line with the experience from years of treatment with intravitreal drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Taking into account the above data&#44; brolucizumab could provide an efficacy and safety profile similar to that of aflibercept but with a more comfortable administration both for doctors and patients&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">According to the data of the pharmaceutical company developing the drug&#44; brolucizumab is up for approval by the US <span class="elsevierStyleItalic">Food and Drug Administration</span> &#40;FDA&#41; presumably by late 2019&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Abicipar-Pegol</span><p id="par0195" class="elsevierStylePara elsevierViewall">Abicipar &#40;Allergan&#44; Dublin&#44; Ireland&#41; is one of a new class of drugs known as DARPin &#40;designed ankyrin repeat protein&#41; characterized by proteins with a design similar to that of ankyrin having a great capacity to bond to a given molecule&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Abicipar is able to join all the soluble forms of VEGF-A to block their action&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Recently the results of a phase II clinical trial &#40;REACH&#41;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> have been published&#46; This study included 64 patients with the objective of comparing the efficacy and safety of abicipar compared to ranibizumab with a 20-week follow-up&#46; The study concluded that abicipar is not inferior to ranibizumab in visual acuity gain at 12 weeks and exhibits increased capacity to resolve the accumulation of intra- and subretinal fluid in a shorter period of time &#40;a higher percentage of patients treated with abicipar exhibited dry retina at 4 and 8 weeks in comparison with ranibizumab&#41;&#46; In addition&#44; the results of said studies suggest that an abicipar administration regime of 8&#8211;12 weeks could be as effective as ranibizumab every 4 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> However&#44; abicipar exhibited higher post-administration intraocular inflammation incidence than ranibizumab&#46; Two phase III studies comparing abicipar every 8 or 12 weeks after a loading dose with ranibizumab every 4 weeks are in progress &#40;NCT02462928 and NCT02462486&#41;&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conbercept</span><p id="par0205" class="elsevierStylePara elsevierViewall">Conbercept &#40;Chengdu Kanghong biotech Co&#46; Ltd&#44; Chengdu&#44; China&#41; is a monoclonal antibody distributed in China that has the theoretical advantage of acting against VEGF-A&#44; VEGF-B and VEGF-C forms in addition to PlGF&#46; However&#44; there are no clinic studies with sufficient quality to compare the efficacy of conbercept against the anti-VEGF drugs marketed in the Western world&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Tyrosine kinase inhibitors</span><p id="par0210" class="elsevierStylePara elsevierViewall">Tyrosine kinase inhibitors are well-known drugs due to their indications in oncology&#46; An important advantage of these inhibitors is oral administration&#46; As many pro-angiogenic molecule receptors that participate in the development of choroidal neovascularization have an intrinsic tyrosine kinase activity &#40;including VEGF and PDGF receptors or the angiopoietin Tie-2 receptor&#41;&#44; it has been proposed that these drugs could be efficient for treating neovascular AMD&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">At present there is only one published Phase 1 study that concludes that X-82 &#40;Tyrogenex&#44; Rockville&#44; USA&#41; is safe for oral administration in patients with AMD&#46; Phase II trials to assess the efficacy of these drugs as intravitreal monotherapy or anti-VEGF co-adjuvants for AMD have not started yet&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">Axitinib &#40;Pfizer&#44; New York&#44; USA&#41; is another medicament in this category that is being researched for treating neovascular AMD&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Faricimab</span><p id="par0225" class="elsevierStylePara elsevierViewall">As discussed above&#44; the action of angiopoietin on the induction of neovessels is complex&#46; The ANG-1 isoform contributes to the stability of vessels while the ANG-2 isoform is involved in aberrant angiogenesis&#46; Faricimab is a new monoclonal antibody that combines anti-VEGF and anti-ANG-2 action and which has demonstrated in a phase II trial &#40;STAIRWAY&#41; in a 12&#8211;16 week administration regime after a loading dose to be not inferior to ranibizumab &#40;Novartis&#44; Basel&#46; Switzerland&#41; every 4 weeks&#46; At present there are 2 phase III studies in progress &#40;TENAYA-NTC03823287 and LUCERNE-NTC03823300&#41; aiming at the confirmation of these results&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">Nesvacumab is another monoclonal antibody with selective action against ANG-2 that was researched in the past in combination with ranibizumab&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> However&#44; the phase II trial that was studying this drug was suspended due to lack of efficacy&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Topical formulations</span><p id="par0235" class="elsevierStylePara elsevierViewall">Due to the ease of topical pathway administration&#44; a significant effort has been made in recent years to develop drugs for neovascular AMD treatment&#46; The most relevant are&#58;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#8226;</span><p id="par0240" class="elsevierStylePara elsevierViewall">Pazopanib &#40;GlaxoSmithKline&#44; Brentford&#44; United Kingdom&#41; and regorafenib &#40;Bayer Healthcare&#44; Leverkussen&#44; Germany&#41;&#44; multikinase inhibitors approved for treating a range of solids tumors&#46; The targets include the downstream inhibition of VEGF and PDGF receptors&#46; This led to researching these drugs in combination with anti-VEGF &#40;in the case of pazopanib&#41; or in monotherapy &#40;regorafenib&#41; in patients with neovascular AMD&#46; However&#44; the primary endpoint of the study was not reached and at the time of writing there are no new studies in progress&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;36</span></a></p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">&#8226;</span><p id="par0245" class="elsevierStylePara elsevierViewall">Squalamine &#40;Ohr pharmaceuticals&#44; New York&#44; USA&#41; is a molecule that was first isolated from sharks that aroused great interest for treating a range of diseases including AMD due to its ability to modulate a large amount of intracellular signaling pathways&#46; However&#44; a phase III study &#40;Mako study - NTC 02727881&#41; on squalamine in combination with ranibizumab was unable to demonstrate additional benefits to monotherapy ranibizumab treatment&#44; for which reason its development is on hold at present&#46;</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">&#8226;</span><p id="par0250" class="elsevierStylePara elsevierViewall">LHA-510 &#40;Alcon&#44; Geneva&#44; Switzerland&#41; and PAN-90806 &#40;PanOptica&#44; Bernardsville&#44; USA&#41; are topical drugs in early clinic research phase for monotherapy treatment of neovascular AMD&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a></p></li></ul></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Other drugs</span><p id="par0255" class="elsevierStylePara elsevierViewall">Even though the medicaments discussed above are the most promising drugs with the highest possibilities of reaching the market in the near future&#44; other drugs are also worthy of note&#44; including&#58;<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">&#8226;</span><p id="par0260" class="elsevierStylePara elsevierViewall">Bevasinarib &#40;Opko Health&#44; Miami&#44; USA&#41; is a member of the class known as silencing RNA molecules &#40;siRNA&#41;&#46; This is a dual RNA strand designed to join the VEGF messenger RNA molecule with intravitreal administration in order to block its translation&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> This would achieve a lower VEGF expression&#46; Even though the siRNA technology holds a lot of promise for the future of pharmacology&#44; clinic studies with bevasinarib was suspended and at present there are no additional molecules under research&#46;</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">&#8226;</span><p id="par0265" class="elsevierStylePara elsevierViewall">Another example of interrupted trials due to lack of efficacy are those related to pegpleranib and rinucumab&#44; PGDF inhibitors&#46; As discussed above&#44; the action of PDGF on choroidal neovascularization is complex and the action of this molecule would be focused on modulation instead of induction of angiogenesis&#46; Accordingly&#44; a more selective approach than simple inhibition would be required to act on this pathway&#46;</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">&#8226;</span><p id="par0270" class="elsevierStylePara elsevierViewall">OPT-302 &#40;Opthea&#44; Victoria&#44; Australia&#41; is a soluble form of the VEGFR-3 receptor that is capable of sequestering the VEGF-3 isoform which is increased in the vitreous of patients treated with VEGF-A inhibitors&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> This drug could help overcome the resistance experienced by some patients against anti-VEGF treatments because it depends at least partially on an offsetting increase of VEGF isoforms that are different to VEGF-A&#46;</p></li></ul></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Gene therapy</span><p id="par0275" class="elsevierStylePara elsevierViewall">Gene therapy could also find applications for the treatment of choroidal neovascularization through the induction of the expression in the patient retina of a micro-environment that is able to restore the homeostasis altered by the disease&#46; At present the transfer of genes encoding VEGF inhibiting molecules and other pro-angiogenic factors to retina cells compromised by neovascular membranes is in pre-clinic research&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p><p id="par0280" class="elsevierStylePara elsevierViewall">In this line of research&#44; the most promising therapies are&#58;<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">&#8226;</span><p id="par0285" class="elsevierStylePara elsevierViewall">ADVM-022&#8239;&#47;&#8239;ADVM-032 &#40;Adverum biotechnologies&#44; Menlo Park&#44; USA&#41;&#58; this is a vector that encodes DNA necessary for the production of aflibercept and ranibizumab&#44; respectively&#46; At the time of writing&#44; there is a phase 1 trial in progress &#40;NTC 0374884&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a></p></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">&#8226;</span><p id="par0290" class="elsevierStylePara elsevierViewall">RGX-314 &#40;Regenxbio&#44; Rockville&#44; USA&#41; is a vector that is able to induce the expression of a molecule with anti-VEGF capacity similar to ranibizumab in retinal cells subject to gene transfer&#46; The administration of this drug requires vitrectomy to enable subretinal inoculation of the drug&#46; The safety and tolerability of the drug shall be studied in a phase I&#47;IIa trial &#40;NTC 03066258&#41; that is in the recruitment stage at the time of writing&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a></p></li></ul></p></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Sustained-release devices</span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Port delivery system</span><p id="par0295" class="elsevierStylePara elsevierViewall">Port Delivery System &#40;Genentech&#44; San Francisco&#44; USA&#41; is an implantable device that provides sustained release of ranibizumab&#46; It is inserted at the subconjunctival level at the height of pars plana and can be filled in with ambulatory treatment every 24 weeks&#46; In a recent phase II clinical trial<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> the sustained administration of ranibizumab 100&#8239;mg&#47;ml by means of the Port Delivery System demonstrated to be not inferior to monthly ranibizumab&#46; At present 2 phase III trials are in progress &#40;PORTAL and ARCHWAY&#41;&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Others</span><p id="par0300" class="elsevierStylePara elsevierViewall">Additional sustained-release devices in early development include GB-102 &#40;GrayBug Vision&#44; Redwood city&#44; USA&#41;&#44; an sunitinib maleate implant &#40;a tyrosine kinase inhibitor&#41;&#59; NT-503 &#40;Neurotech&#44; Waukesha&#44; USA&#41;&#44; an intravitreous implant containing a genetically modified pigment epithelium cell line that produces a molecule with the ability of inhibiting VEGF-A&#59; Hydrogel anti-VEGF depot &#40;Ocular Therapeutix&#44; Bedford&#44; USA&#41;&#59; Durasert &#40;EyePoint Pharmaceuticals&#44; Watertown&#44; USA&#41; or ENV-1305 &#40;Envisia Therapeutics&#44; Morrisville&#44; USA&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a></p></span></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">New drugs for treating dry age-related macular degeneration</span><p id="par0305" class="elsevierStylePara elsevierViewall">Dry macular degeneration is characterized by RPE alterations that involve progressively towards the final stage known as geographic atrophy&#46; As a consequence of said alteration&#44; overlying photoreceptors are deprived of the atrophic actions of the RPE cells and suffer degeneration which is ultimately responsible for the loss of vision found in these patients&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall">RPE damage is due to a range of not entirely known factors&#44; notably alterations in the mitochondrial function of RPE cells leading to oxidative stress&#44; complement activation that establishes a chronic inflammation environment&#44; lipofuscin deposits or insufficient blood supply for the choroids&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0315" class="elsevierStylePara elsevierViewall">Taking the above into account&#44; only 2 strategies can be considered for treating said pathology&#46; On the one hand&#44; actions aimed at slowing down genetic atrophy as much as possible and confining it to areas as removed as possible from the macula&#44; and on the other hand treatments focused on regeneration of the RPE and degraded photoreceptors in the case of advanced stages of the disease&#46;</p><p id="par0320" class="elsevierStylePara elsevierViewall">The drugs that have been tested to counteract geographic atrophy by controlling inflammation in dry AMD include those acting on complement cascade&#44; the best-known of which is lampalizumab &#40;Roche&#44; Basel&#44; Switzerland&#41;&#44; a complement <span class="elsevierStyleSmallCaps">d</span>-factor inhibitor&#46; After finding contradictory results in phase II trials&#44; phase III Chroma and Spectri studies concluded that there is no difference in atrophy progression compared to placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> Even so&#44; other drugs with similar action mechanisms are at present in research&#46; Perhaps the most promising research is on a C3 inhibitor known as APL-2 &#40;Apellis pharmaceuticals&#44; Kentucky&#44; USA&#41; which in monthly intravitreous administration has demonstrated in a phase II study its ability to diminish the progression rate of geographic atrophy&#46;</p><p id="par0325" class="elsevierStylePara elsevierViewall">Other complement inhibitors such as POT-4 &#40;Apellis pharmaceuticals&#44; Kentucky&#44; USA&#41;&#44; ARC 1905 &#40;Opthotech corporation&#44; Princeton&#44; USA&#41;&#44; eculizumab and immunomodulators such as sirolimus or glatiramer acetate has been researched as possible strategies for diminishing geographic atrophy progression but without demonstrating clear benefits&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a></p><p id="par0330" class="elsevierStylePara elsevierViewall">In what concerns neuroprotection strategies&#44; the most relevant drugs are the ciliary neurotrophic factor &#40;CNTF&#41; and brimonidin&#46; CNTF is being researched in several clinical trials for treating ischemic optic neuropathy&#44; retinitis pigmentosa or glaucoma&#44; and could also play a role in the interruption of atrophic AMD&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> Brimonidin has demonstrated neuroprotective capacity on retinal cells in animal models&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">44&#8211;46</span></a> Recently&#44; an intravitreal sustained release brimonidin device has demonstrated in a randomized prospective and triple blind clinic trial with 310 patients &#40;Beacon study&#41; its ability to diminish geographic atrophy progression in a statistically significant manner&#46; The full results of this study are expected to be published in late 2019&#46;</p><p id="par0335" class="elsevierStylePara elsevierViewall">Finally&#44; in the longer term we may be able to utilize stem cells not only to slow down but also to revert atrophy progression utilizing pluripotential cells to regenerate pigment epithelium and lost photoreceptors&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conclusion</span><p id="par0340" class="elsevierStylePara elsevierViewall">Due to prevalence&#44; morbidity and socioeconomic implications&#44; macular degeneration is one of the biggest challenges facing ophthalmologists in the 21st century&#46; Significant pharmacological developments in the past few years have improved treatments for the neovascular form of the disease which accounts for the highest morbidity&#46; Considering the positive results of pre-market clinic trials&#44; in the next few years we could witness the arrival of a new generation of antiangiogenic drugs including brolucizumab&#44; abicipar or faricimab that could improve the efficacy of currently available therapies or contribute to a more comfortable administration regime by increasing the intervals between intravitreal injections while maintaining efficacy&#46; Sustained release implants of antiangiogenics such as the Port Delivery System are additional novelties that could become available in the coming decade&#46;</p><p id="par0345" class="elsevierStylePara elsevierViewall">In turn&#44; the main challenges for researchers in the next few years involve a full understanding of the reasons for the failure of anti-PDGF drugs as well as the development of oral and topical administration therapies such as tyrosine kinase inhibitors&#44; oral macromolecule administration systems &#40;anti-VEGF&#41; or the formulation of antiangiogenics in the form of gels&#44; drops or the like&#46;</p><p id="par0350" class="elsevierStylePara elsevierViewall">In what concerns dry AMD&#44; a range of drugs have been researched to slow down the development of geographic atrophy with poor results&#46; At present&#44; the most promising drugs are APL-2 and the brimonidin intravitreal implant&#46; Both have demonstrated to slow down in a statistically significant manner the progression of geographic atrophy&#46; Even so&#44; we must await the full publication of research results to determine the extent in which these drugs could be significant in clinic practice&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conflict of interest</span><p id="par0355" class="elsevierStylePara elsevierViewall">No conflict of interests was declared by the authors&#46;</p></span></span>"
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          "titulo" => "Physiopathology of neovascularization in age-related macular degeneration"
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              "titulo" => "The VEGF sub-family"
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              "titulo" => "The PDGF family"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Age-related macular degeneration and specially neovascular age-related macular degeneration is the leading cause of low vision in developed countries&#46; Even though the introduction of anti-VEGF drugs in recent years completely changed the management of this condition&#44; its cost&#44; the need for repeated intravitreal injections and loss of efficacy in the long term are still issues to deal with&#46; Currently&#44; a new generation of novel therapies under development tries to address some of this limitations&#46; Among them some of the most prominent are new anti-VEGFs such as brolucizumab or abicipar&#44; drugs against angiopoyetin-2 receptor such as faricimab&#44; sustained-release systems or tyrosin kinase inhibitors&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Regarding dry age-related macular degeneration&#44; neuroprotection&#44; the complement pathway and stem cell therapy are the most promising targets currently under investigation&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La degeneraci&#243;n macular asociada a la edad &#40;DMAE&#41; y en especial su forma neovascular&#44; supone la principal causa de baja visi&#243;n en pa&#237;ses desarrollados&#46; Aunque en a&#241;os recientes la introducci&#243;n de los f&#225;rmacos conocidos como anti-VEGF ha supuesto una revoluci&#243;n en el manejo de esta enfermedad&#44; su precio&#44; la necesidad de inyecciones intrav&#237;treas repetidas&#44; y la p&#233;rdida de efectividad a largo plazo en una importante proporci&#243;n de pacientes son problemas a&#250;n por resolver&#46; En la actualidad existen en desarrollo una serie de nuevas estrategias que tratan de ofrecer soluciones a las limitaciones que presentan los f&#225;rmacos intrav&#237;treos actuales&#46; Entre ellos destacan nuevos anti-VEGF como brolucizumab o abicipar&#44; f&#225;rmacos contra el receptor de angiopoyetina-2 como faricimab&#44; sistemas de liberaci&#243;n sostenida de macromol&#233;culas o inhibidores de la tirosinkinasa&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Respecto a la DMAE seca la neuroprotecci&#243;n&#44; la modulaci&#243;n de la v&#237;a del complemento y&#44; en &#250;ltima instancia&#44; la terapia con c&#233;lulas madre son las l&#237;neas de investigaci&#243;n m&#225;s prometedores en la actualidad&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Mu&#241;oz-Ram&#243;n PV&#44; Hern&#225;ndez Mart&#237;nez P&#44; Mu&#241;oz-Negrete FJ&#46; Nuevas dianas terap&#233;uticas en el tratamiento de la degeneraci&#243;n macular asociada a la edad&#46; Arch Soc Esp Oftalmol&#46; 2020&#59;95&#58;75&#8211;83&#46;</p>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Therapy&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Action mechanism&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Differences with available therapies&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Development phase&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Brolucizumab&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">VEGF-A receptor antagonist&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Small size molecule &#40;26&#8239;KDs&#41; &#8211;&#62; higher molar concentration&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Phase III in progress&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">Possibility of q12s regime&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t">Abicipar-Pegol&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Ability to join all soluble VEGF-A isoforms&#44; preventing its joining the receptor&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Possibility of q8s and q12s regime&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Phase III in progress&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Issues related to post-administration higher intraocular inflammation rates yet to be resolved&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Conbercept&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">VEGF-A&#44; VEGF-B&#44; VEGF-C and PlGF antagonist&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Theoretical pharmacological advantage due to the ability to bind with more VEGF isoforms than existing therapies &#8594; to be confirmed with clinic results&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Marketed &#40;China&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Faricimab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Combined Anti-VEGF and Ang-2 action&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Possibility of q12&#8239;s and q16&#8239;s regime&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Phase III in progress&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tyrosine kinase inhibitors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Blocking intra-cell transduction of the signal triggered by the bonding of VEGF to its receptor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Possibility of oral administration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Phase I&#47;IIa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Discouraging topical formulation trials&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Port Delivery System&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Implant for sustained release of ranibizumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Requires surgical implant&#46; Refilling needed only twice a year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Phase III in progress&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Could overcome the gap observed between anti-VEGF results in clinic trials and actual clinic practice&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gene therapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Induction of autonomous anti-VEGF production by retina cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IndependenE of intravitreal injection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Preclinic&#47;Phase I&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => "xTab2226159.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Summary of the main therapies in research for treating neovascular AMD&#46;</p>"
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:46 [
            0 => array:3 [
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                            0 => "P&#46; Mitchell"
                            1 => "G&#46; Liew"
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                        ]
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                  ]
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                    0 => array:2 [
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                      "Revista" => array:5 [
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            1 => array:3 [
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "W&#46;L&#46; Wong"
                            1 => "X&#46; Su"
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                        ]
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                      "doi" => "10.1177/1533317513517032"
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                        0 => array:2 [
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                            0 => "M&#46;B&#46; McGuinness"
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                      "titulo" => "Pharmacologic management of neovascular age-related macular degeneration&#58; systematic review of economic evidence and primary economic evaluation"
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                          "etal" => true
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                      "titulo" => "You&#8217;ve got dry macular degeneration&#44; end of story&#8221;&#58; a qualitative study into the experience of living with non-neovascular age-related macular degeneration"
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                          "etal" => false
                          "autores" => array:4 [
                            0 => "D&#46;J&#46; Taylor"
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                          "etal" => true
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                      "titulo" => "Bevacizumab injection in patients with neovascular age-related macular degeneration increases angiogenic biomarkers"
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                          "etal" => true
                          "autores" => array:3 [
                            0 => "T&#46; Cabral"
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                            2 => "L&#46;G&#46;M&#46; Mello"
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