**Abstract**

Anti-vascular endothelial growth factor (anti-VEGF) therapies have revolutionized the care of patients with retinal diseases. In the 1990s, it was observed that anti-VEGF antibodies reduced tumor angiogenesis, and consequently, these antibodies started to be used off-label in the exudative form of age-related macular degeneration (AMD). In the 2000s, research was directed towards the development of anti-VEGF therapies for retinal disease management. Several anti-VEGF therapies were approved: pegaptanib, an RNA aptamer, in 2004; ranibizumab, an anti-VEGF Fab, in 2008; aflibercept, a humanized IgG Fc, in 2011; and brolucizumab, an scFv, in 2019. Currently, new therapeutic options are emerging, and approval is expected soon. These new therapies aim to increase treatment durability and thus reduce treatment burden and improve real-world outcomes. In this chapter, the mechanisms of action and the preliminary trial results of these potential new therapies will be described.

**Keywords:** AMD, drug therapy, intravitreal injections, clinical trials, pipeline

## **1. Introduction**

Global prevalence estimates suggest that approximately 196 million people lived with age-related macular degeneration (AMD) in 2020. Of these, 10.4 million people were living with moderate to severe vision impairment. In 2030, AMD is estimated to affect 243 million people due to aging [1]. The pathogenesis of AMD results from complex multifactorial interactions, including metabolic, genetic, and environmental [2]. AMD has been classified into two major subtypes: non-exudative or dry AMD and exudative or wet AMD. Although dry AMD represents 90% of patients, exudative AMD causes more severe loss of vision, being the target of most investigations [3]. These patients require very regular clinic visits, and the chronicity of anti-vascular endothelial growth factor (anti-VEGF) therapy can substantially impact the quality of life of the patient and the caregivers [4, 5]. This decrease can compromise anti-VEGF therapy compliance and explain the undertreatment of patients observed in real-world studies and the waiver of patients involved in clinical trials [6, 7]. New trials are focusing on improving the therapeutic options, particularly on the decrease of the associated burden. This chapter describes the current research on therapeutical approaches to treat the dry and exudative forms of AMD. **Figure 1** summarizes the drugs and stages of development.

The information was gathered from a medical literature review and ongoing clinical trials and their results in the area of AMD treatment using PubMed database (https://www.ncbi.nlm.nih.gov/pubmed). The words or medical head subjects

#### **Figure 1.**

*Summary of new drugs in the pipeline for the management of age-related macular degeneration (AMD).*

used were: AMD and clinical trials. All relevant articles were imported into Zotero (Version 5.0, Center for History and New Media at Universidade George Mason, USA), and duplicate articles were deleted. We selected the promising therapies according to action mechanisms and excluded all therapies that had failed in clinical trials. Comments, editorials, and articles not written in English were not analyzed.

### **2. For dry AMD**

#### **2.1 Complement inhibition**

Although lampalizumab (anti-factor D Fab) and eculizumab (inhibitor of the activation of terminal complement) failed to slow geographic atrophy progression, the complement system has been implicated in the pathogenesis of geographic atrophy, and so, research on how to inhibit the complement system did not stop [8, 9].

Pegcetacoplan (APL-2; Apellis Pharmaceuticals, Waltham, Massachusetts, USA) is a synthetic molecule that selectively inhibits C3, effectively downregulating all three complement pathways. Phase 2 of the FILLY clinical trial compared patients receiving intravitreal injection (monthly and bi-monthly) with a control group. The results showed a 29% reduction in the rate of geographic atrophy and a better outcome in the monthly injection group. Moreover, it was observed that the risk of neovascular AMD was higher (18%) in the group subjected to monthly injections when comparing with the group subjected to bi-monthly injections (8%) and with the control group (1%) [10]. A phase 3 trial is currently in the recruitment phase (NCT03525600) [11].

Avacincaptad pegol (Zimura; Iveric Bio, New York, New York, USA) is a C5 inhibitor. Phase 2/3 GATHER1 clinical trial showed a significant reduction of geographic atrophy growth over 12 months, probably due to C3 activity preservation. A second confirmatory trial (GATHER2) is underway [12].

#### **2.2 Neuroprotection**

Retinal neuroprotection strategies have been studied for dry AMD, including apoptosis and necrosis prevention, and oxidative injury reduction [13].

*New Drugs in the Pipeline for the Management of AMD DOI: http://dx.doi.org/10.5772/intechopen.97665*

Elamipretide (Stealth Biotherapeutics) is a mitochondria-targeted drug thought to reduce mitochondrial dysfunction. Phase 1 of the ReCLAIM clinical trial showed that elamipretide was safe, well-tolerated and that this drug may improve vision in patients with intermediate AMD, manifested as high-risk drusen [14]. Phase 2 ReCLAIM-2 clinical trial is underway [15].

Brimonidine tartrate (Allergan) is best known in glaucoma as the intraocular pressure (IOP) lowering agent. Phase 2A of the BEACON clinical trial assessed the intravitreally delivery of brimonidine through a delayed delivery system. Results showed a lower rate of geographic atrophy progression, although not statistically significant [16]. Phase 2B of the BEACON clinical trial demonstrated a reduction in geographic atrophy progression using higher doses of brimonidine [17]. Phase 3 of IMAGINE and ENVISION clinical trials are being designed [16].

#### **2.3 Visual cycle modulators**

One of the earliest changes in the retina that precede AMD symptoms is the formation of toxic vitamin A dimers.

ALK-001 (Alkeus Pharmaceuticals) is a chemically modified form of vitamin A that replaces the vitamin A in the body to prevent toxic vitamin A dimers. Studies demonstrated functional preservation of visual function in animal models [18]. Phase 3 of the SAGA clinical trial will measure the extent to which treatment with the oral capsule of ALK-001 slows geographic atrophy progression [19].

#### **2.4 Cell-based therapies**

Cell therapy is an alternative strategy when the naturally existing cells are already too damaged to be preserved using neuroprotective agents. Human pluripotent stem cells (hPSCs) comprise human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs). There are two subtypes of cellbased treatments: stem cell therapies that involve delivering new retinal pigment epithelial (RPE) cells to the subretinal space, and non-stem cell therapies based on cell implantation, which generates protective factors [20].

MA09-hRPE (Astellas Pharma) is hESC-derived Retinal Pigment Epithelium (hESC-RPE). The phases 1/2 clinical trial results confirmed that hESC-derived cells could serve as a potentially safe new source for regenerative medicine [21–23].

CPCB-RPE1 (The California Project to Cure Blindness-Retinal Pigment Epithelium1) is a polarized monolayer of hESC-RPE ultrathin, synthetic parylene substrate designed to mimic Bruch's membrane. This therapy involves a subretinal implant. It was demonstrated the feasibility and safety of CPCB-RPE1 subretinal implantation in a comparable animal model [24]. Phase 1/2A of the clinical trial suggests that CPCB-RPE1 may improve visual function [25, 26].

#### **2.5 Anti-inflammatory agents**

Inflammation has been implicated in AMD pathogenesis and progression, even though it is no classical inflammatory disease like uveitis [27].

Doxycycline (Oracea; Galderma Laboratories, Fort Worth, Texas, USA) is an antibiotic that belongs to the tetracycline class of antibiotics and plays a role in immunomodulation, cell proliferation, angiogenesis, and the regulation of inflammation. Phase 3 of the TOGA clinical trial includes patients with geographic atrophy randomized in groups treated with Oracea® or placebo. The results are pending [28].

FHTR2163 (Genentech/Roche) is a new antibody delivered by intravitreal injection that inhibits the HTRA1 gene associated with geographic atrophy. Phase 2 of the GALLEGO clinical trial will evaluate the safety, tolerability, and efficacy of intravitreal injections of RG6147, administered every four or every eight weeks for a total of approximately 76 weeks, in participants with geographic atrophy secondary to AMD (when compared with the sham control) [29].
