**4.1 Failed therapeutics for non-exudative AMD**

Lampalizumab, a fragment antigen binding portion of a humanized monoclonal antibody that selectively binds and inhibits complement factor D [57], showed success early on as it passed both Phase I and II clinical trials. Unfortunately, it failed to show superior effects to sham treatment in treating non-exudative AMD with GA in Phase III trials [58]. Eculizumab is another antibody, which targets complement component C5. It was investigated in the COMPLETE trial to assess the progression of GA in patients with non-exudative AMD. While it demonstrated safety, it did not prove to be efficacious in slowing the rate of GA progression [59]. Much like eculizumab, LFG316, another C5 inhibitor, failed to progress past Phase II when it did not show success in stunting the growth of GA [60].

A study evaluating the safety of transplanting subretinal RPE cells derived from human umbilical tissue showed complications associated with the method of delivery. This study reported high rates of retinal perforations and detachments [61].

A unique technique of delivering cell therapy to a tissue of interest is through encapsulated cell technology (ECT). A study utilizing this technology with the NT-501 ECT implant showed promising results. A capsule containing a mass of RPE cells engineered to produce and release ciliary neurotrophic factor (CNTF) was implanted into the eye. CNTF can diffuse across the capsule and act on retinal cells to induce differentiation and promote survival of retinal cells. The exact mechanism of CNTF remains to be elucidated [62]. Studies proved this method is safe, but visual acuity (VA) did not show significant improvement. There was, however, significant improvement in the thickness of the macular region, which has been shown to be associated with increased stabilization of VA regardless of baseline best corrected visual acuity (BCVA) [63, 64]. Despite a lack of significant improvement in VA in AMD patients, this technology has since been repurposed for use in macular telangiectasia type 2 and is effective at improving BCVA and slowing progression of retinal degeneration [65].

#### **4.2 Therapeutics in development**

## *4.2.1 Non-exudative AMD therapies in development*

There is hope that an IVT formulation of Zimura, a C5 inhibiting RNA aptamer, will show more promising results than eculizumab and LFG316 [66]. A C3 inhibitor called APL-2 passed Phase II clinical trials in the FILLY study when it demonstrated the ability to impede progression of GA [67]. Two Phase III trials of this drug are underway with the Oaks and Derby trials (Apellis). These are multicenter, randomized, double blind, sham-controlled studies that are estimated to complete around December 2022 [68].

There are studies evaluating the utility of combination antibody therapy. This concept involves inhibition of two separate pathogenic mechanisms contributing to disease progression to elicit compounding effects. A Phase I trial evaluating the combination of LFG316 and CLG561, an inhibitor of complement regulator properdin, is underway for GA [69].

Bone marrow stem cells (BMSCs) have shown safety and efficacy in patients affected by non-exudative AMD. The Stem Cell Ophthalmology Treatment Study (SCOTS) trial showed improvement in BCVA and demonstrated both safety and tolerability [70]. The trial consisted of 32 eyes affected by non-exudative AMD that were treated with autologous BMSC transplant by a variety of methods. Over a one-year period, 63% of eyes showed improvement in VA while 34% maintained a

#### *An Overview of Age-Related Macular Degeneration: Clinical, Pre-Clinical Animal Models… DOI: http://dx.doi.org/10.5772/intechopen.96601*

stable VA. There were no complications, and as these were autologous transplants, no immunosuppression was required.

Current gene therapy in development for non-exudative AMD works to target the complement pathway. Gene supplementation of CD59 inhibits formation of the membrane attack complex (MAC) and is being investigated with the drug AAVCAGsCD59 [71]. By preventing formation of the MAC, inhibition of complement-mediated cell lysis reduces retinal cell death, thus slowing progression of GA. Results from the recently finished Phase 1 clinical trials for AAVCAGsCD59 are being evaluated. Another promising drug, GT005, holds genetic information coding for complement factor I. It will be delivered using a recombinant, non-replicating adeno-associated viral vector. Phase I/IIa clinical trials are underway [72].

#### *4.2.2 Exudative AMD therapies in development*

The use of a port delivery system involves implanting a device into the eye that slowly releases drug over an extended period. With this device in place, the patient can have fewer office appointments and less injections. The Phase 2 Ladder study has already shown promise with this type of drug administration [73]. Bifunctional antibodies, antibodies that can bind two or more targets, are being investigated for use in exudative AMD. By targeting both the VEGF and the complement pathway it is hypothesized that patients may require fewer injections and/or show improved outcomes, similarly to the non-exudative AMD combined therapy. IBI302 is an antibody with domains for both VEGF and complement. It is undergoing dose escalation Phase I clinical trials [74]. Another drug being developed for exudative AMD is abicipar pegols, a designed ankyrin repeat protein that is part of the designed ankyrin repeat proteins (DARPin) class that inhibits all isoforms of VEGF-A. While it showed similar efficacy to ranibizumab, the FDA currently denied its approval because of reports of associated intraocular inflammation [75].

A Phase I clinical trial involving only two patients with severe exudative AMD and no control group showed successful implantation of fully differentiated human ESC-derived RPE cells that were grown on a synthetic basement membrane. VA at 12 months showed improvement in 29 and 21 letters. The patch of RPE cells appeared intact and healthy when visualized through biomicroscopy and optical coherence tomography (OCT) [76].

There are documented cases of successful autologous and allogenic transplants of induced pluripotent stem cells. However, the cost of these studies and unexpected genetic changes have been discouraging [78, 79]. Further endeavors in cell-based treatment of AMD are aimed at generating a layer of multipotent stem cells from RPE cells. Proliferation and differentiation of these stem cells may restore function to diseased retina [77].

Exudative AMD gene therapy mainly targets the VEGF pathway, but other areas of intervention include PEDF, angiostatin, and endostatin. Phase II clinical trials of rAAV.sFLT-1, which codes for a soluble, full length version of the VEGFR-1 protein, are currently underway [78]. A Phase I clinical trial evaluating safety and tolerability is currently underway for a recombinant, replication-deficient adeno-associated virus (AAV.7 m8-aflibercept) IVT injection gene therapy carrying an aflibercept coding sequence [79]. A Phase I clinical trial demonstrated safety for using an adeno-associated virus vector carrying genetic information for human PEDF (AdPEDF.11) [80]. Endostatin and angiostatin, are proteins that inhibits angiogenesis. A combination drug of endostatin and angiostatin (RetinoStat) demonstrated safety and tolerability [81]. There are many promising therapies in different stages of clinical trials for the treatment of AMD.
