This review summarizes the latest findings in the literature of Angiopoietin-2 (Ang-2), Tyrosine-protein kinase receptor (Tie-2) complex, and faricimab along with their involvement for the treatment of retinal vascular diseases in various clinical trials. In ischemic diseases, such as diabetic retinopathy, Ang-2 is upregulated, deactivating Tie-2, resulting in vascular leakage, pericyte loss, and inflammation. Recombinant Angiopeotin-1 (Ang-1), Ang-2-blocking molecules, and inhibitors of vascular endothelial protein tyrosine phosphatase (VE-PTP) decrease inflammation-associated vascular leakage, showing therapeutic effects in diabetes, atherosclerosis, and ocular neovascular diseases. In addition, novel studies show that angiopoietin-like proteins may play an important role in cellular metabolism leading to retinal vascular diseases. Current therapeutic focus combines Ang-Tie targeted drugs with other anti-angiogenic or immune therapies. Clinical studies have identified faricimab, a novel bispecific antibody designed for intravitreal use, to simultaneously bind and neutralize Ang-2 and VEGF-A for treatment of diabetic eye disease. By targeting both Ang-2 and vascular endothelial growth factor-A (VEGF-A), faricimab displays an improved and sustained efficacy over longer treatment intervals, delivering superior vision outcomes for patients with diabetic macular edema and reducing the treatment burden for patients with neovascular age-related macular degeneration and diabetic macular edema. Phase 2 results have produced promising outcomes with regard to efficacy and durability. Faricimab is currently being evaluated in global Phase 3 studies.

Group A rotaviruses (RVAs) are the leading cause of gastroenteritis, causing 0.2 million deaths and several million hospitalisations globally each year. Four rotavirus vaccines (Rotarix TM , RotaTeq TM , Rotavac ® and ROTASIIL ® ) have been pre-qualified by the World Health Organization (WHO), but the two newly pre-qualified vaccines (Rotavac ® and ROTASIIL ® ) are currently only in use in Palestine and India, respectively. In 2009, WHO strongly proposed that rotavirus vaccines be included in the routine vaccination schedule of all countries around the world. By the end of 2019, a total of 108 countries had administered rotavirus vaccines, and 10 countries have currently been approved by Gavi for the introduction of rotavirus vaccine in the near future. With 39% of global coverage, rotavirus vaccines have had a substantial effect on diarrhoeal morbidity and mortality in different geographical areas, although efficacy appears to be higher in high income settings. Due to the segmented RNA genome, the pattern of RVA genotypes in the human population is evolving through interspecies transmission and/or reassortment events for which the vaccine might be less effective in the future. However, despite the relative increase in some particular genotypes after rotavirus vaccine use, the overall efficacy of rotavirus mass vaccination worldwide has not been affected. Some of the challenges to improve the effect of current rotavirus vaccines can be solved in the future by new rotavirus vaccines and by vaccines currently in progress.

Age-related macular degeneration (AMD) is one of the most common causes of vision loss. Advanced forms of AMD are seen in primarily 2 types—neovascular AMD (nAMD) with the presence of choroid neovascularization and nonneovascular AMD (nnAMD) with geographic atrophy. Although there are 4 anti-vascular endothelial growth factor drugs either widely used or approved for the former, there are no current treatments for the latter. This review will highlight upcoming treatments for AMD currently in clinical trials. For nAMD: Abicipar pegol, an intravitreal anti-vascular endothelial growth factor based on designed ankyrin repeat proteins (DARPins) is currently pending approval. Conbercept and Faricimab, 2 intravitreal anti-growth factors, are currently in phase 3. Nine other upcoming agents have at least produced results in the 1B/2A phase including intravitreal injections (KSI-301, OPT-302, RGX-314, ICON-1, and DE-122), depot (GB-102), drug reservoir (PDS), topical drops (PAN-90806), and oral formulations (AKST4290). We summarize all the newer molecules.

Gene therapies aim to deliver a therapeutic payload to specified tissues with underlying protein deficiency. Since the 1990s, gene therapies have been explored as potential treatments for chronic conditions requiring lifetime care and medical management. Ocular gene therapies target a range of ocular disorders, but retinal diseases are of particular importance due to the prevalence of retinal disease and the current treatment burden of such diseases on affected patients, as well as the challenge of properly delivering these therapies to the target tissue. The purpose of this review is to provide an update on the most current data available for five different retinal gene therapies currently undergoing clinical trials for use against age-related macular degeneration (AMD) and the development of novel delivery routes for the administration of such therapies. Research has been performed and compiled from PubMed and the select authors of this manuscript on the treatment and effectiveness of five current retinal gene therapies: Luxturna, ADVM-022, RGX-314, GT-005, and HMR59. We present the available data of current clinical trials for the treatment of neovascular and dry age-related macular degeneration with different AAV-based gene therapies. We also present current research on the progress of developing novel routes of administration for ocular gene therapies. Retinal gene therapies offer the potential for life-changing treatment for chronic conditions like age-related macular degeneration with a single administration. In doing so, gene therapies change the landscape of treatment options for these chronic conditions for both patient and provider.

The Ang/Tie2 pathway complements VEGF-mediated activity in retinal vascular diseases such as DME, AMD, and RVO by decreasing vascular integrity, increasing neovascularization, and increasing inflammatory signaling. Faricimab is a bispecific antibody that has been developed as an inhibitor of both VEGF and Ang2 that has shown positive results in phase I, II and III trials. Recent Year 1 data from phase III clinical trials YOSEMITE, RHINE, TENAYA, and LUCERNE have confirmed the efficacy, safety, durability, and superiority of faricimab in patients with DME and nAMD. Faricimab, if approved, may significantly decrease treatment burden in patients with retinal vascular diseases to a greater extent than would current standard of care anti-VEGF injections.

Age-related macular degeneration (AMD) is one of the most common causes of severe vision loss in the developed world. Advanced forms of AMD are seen in primarily 2 types, exudative AMD involving the presence of choroidal neovascularization and nonexudative or dry AMD with geographic atrophy. For the latter, the combination of vitamins and minerals known as the Age-Related Eye Disease Study-2 formulation has been shown to decrease the rate of progression of nonexudative to exudative AMD, as no other treatments are currently approved for nonexudative AMD. This review will highlight upcoming treatments for nonexudative AMD. Six upcoming agents have shown results at least in the 2A phase. This includes intravitreal agents that are inhibitors of integrin (Risuteganib), intravitreal agents that disrupt the complement pathway (Zimura, APL-2), neuroprotective implants (Brimonidine DDS), a subcutaneous injectable (Elamipretide), and photobiomodulation (Valeda Light Delivery System).

No abstract

Age-related macular degeneration (AMD) is characterized as a chronic, multifactorial disease and is the leading cause of irreversible blindness. Advanced AMD is classified as neovascular (wet) AMD and non-neovascular (dry) AMD. Dry AMD can progress to a more advanced form that manifests as geographic atrophy (GA), which significantly threatens vision, leading to progressive and irreversible loss of visual function. There are currently no approved therapeutics commercially available for GA patients. However, data from various clinical trials have demonstrated favorable results with significant reduction in GA lesion growth. This review furthers the understanding of the pathophysiology of GA, as well as current clinical trial data on investigational therapeutics.