**3. For wet AMD**

#### **3.1 Potentially more durable anti-VEGF agents**

Potentially more durable anti-VEGF agents may reduce the burden of intravitreal injections, help stabilize the disease and improve compliance with treatment.

Brolucizumab (Beovu; Novartis, Basel, Switzerland) is the most recent intravitreal anti-VEGF agent to receive FDA approval. It is a humanized single-chain antibody fragment with a molecular weight of 26 kDa. Phase 3 of the HAWK and HARRIER clinical trials showed that brolucizumab was non-inferior to aflibercept regarding visual function as at week 48, more than 50% of the eyes treated with 6 mg of brolucizumab were maintained on q12w dosing intervals. Moreover, anatomic outcomes favored brolucizumab over aflibercept, and the overall safety results were similar between the two drugs [30].

Abicipar pegol (Allergan) is a novel class of molecules referred to as designed ankyrin repeat proteins (DARPin) that bind VEGF-A. DARPin is smaller and has a high affinity to VEGF, leading to greater stability and a longer-acting effect. The results of phase 3 of the SEQUOIA and CEDAR clinical trials showed that the eight and 12-week abicipar regimens were non-inferior to the ranibizumab's monthly regimen, but patients had a much higher risk of developing intraocular inflammation (15% and 15.4% vs. 0%) [31–33]. The company modified the manufacturing process after finding impurities in the formulation, and subsequently, the MAPLE study showed a decrease in the incidence of intraocular inflammation to 8.9% [34]. A license for abicipar pegol was already submitted to the *Food and Drug Administration* and the European Medicines Agency.

Conbercept (Chengdu Kanghong Biotech Co., Ltd.) is an antibody that targets VEGF-A, VEGFB, VEGF-C, and placental growth factors. It was approved to treat exudative AMD in China in 2013. Phase 2 of the AURORA and phase 3 of the PHOENIX clinical trials showed the safety and efficacy of conbercept with three initial monthly treatments followed by quarterly treatments compared with the sham group [35, 36]. Phase 3 of the PANDA-1 and PANDA-2 global clinical trials compare maintenance doses of conbercept every 8 or 12 weeks with doses of aflibercept every eight weeks; results are expected in 2022 [37, 38].

OPT-302 (Opthea Limited) is a soluble form of the human VEGF receptor-3 (VEGFR-3), expressed as an Fc-fusion protein molecule design to inhibit VEGF-C and VEGF-D. Results from phases 1 and 2 of the ShORe and COAST clinical trials showed that this molecule was safer and had better visual outcomes than ranibizumab alone [39, 40]. Phase 3 of the ShORe and COAST clinical trials will be double-masked and sham-controlled. Treatment-naïve patients will be enrolled to assess the efficacy and safety of 2.0 mg OPT-302 combined with anti-VEGF-A therapy by comparison with anti-VEGF-A monotherapy (standard of care). Opthea expects to initiate patient recruitment in the first half of 2021 [41].

Faricimab (Roche, Genentech) is a novel bispecific antibody that targets both angiopoietin-2 (Ang-2) and VEGF-A. Phase 2 of the STAIRWAY clinical trial

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

suggests that faricimab can be an effective maintenance therapy for exudative AMD with a dosing interval of 16 weeks [42, 43]. Phase 3 of the TANAYA and LUCERNE clinical trials will compare faricimab given every 16 weeks with aflibercept given every eight weeks [44, 45]. FDA requests for faricimab are expected to occur in 2021 for diabetic macular edema and in 2022 for exudative AMD.

KSI-301 (Kodiak Sciences) is a novel intravitreal, anti-VEGF antibody biopolymer conjugate designed to block all VEGF-A isoforms. Phase 1 of the DAZZLE clinical trial showed excellent safety, strong efficacy, and considerable durability in most patients for three or more months [46]. Phase 2 of the DAZZLE clinical trial is a prospective, randomized controlled clinical trial designed to evaluate the safety and efficacy of KSI-301 [47].

#### **3.2 ONS-5010 and biosimilars**

ONS-5010 (Outlook Therapeutics, Inc) is an ophthalmic formulation of bevacizumab. Phase 3 clinical trials compare monthly doses of ONS-5010 with a ranibizumab regimen of 3 monthly doses followed by quarterly doses [48]. FDA approval is expected in 2021 or 2022, and 12 years of exclusivity, protecting against bevacizumab biosimilars, are expected.

FYB201 (Formycon and Bioeq), SB11 (Samsung Bioepis), and Xlucane (Xbrane Biopharma) are biosimilars for ranibizumab under development that are expected to reach the market in less than one year when the patent for ranibizumab expires [49–51].

Aflibercept biosimilars are in phase 3 of clinical trials and are expected to reach the market between two and three years when the patent for aflibercept expires.

#### **3.3 Topical anti-VEGF ± anti-PDGF**

Although regorafenib, pazopanib, and LHA510 failed, other therapies showed promising results [52–54]. These formulations have the great advantage of being less invasive, but they can decrease the possibility of monitoring treatment compliance, as it happens with glaucoma patients medicated with lowering ocular hypertension drops.

PAN-90806 (PanOptica) is a topical formulation of a small molecule, a tyrosine kinase inhibitor (TKI), to treat wet AMD. In phase 1/2 of a dose-ranging clinical trial, more than half of patients receiving PAN-90806 once a day for 12 weeks completed the study without needing anti-VEGF rescue therapy. Fourteen of the 51 patients in the study, 88% experienced clinical improvement of their condition or their disease's stability [55].

Squalamine lactate (Genaera Corporation) is an amino sterol derived from the dogfish shark's cartilage that blocks VEGF, PDGF basic fibroblast growth binding calmodulin and its chaperones. A phase 2 clinical trial showed improved vision when squalamine lactate was used in combination with anti-VEGF treatments [56, 57].

#### **3.4 Extended-release options**

The extended-release options may also reduce the burden of intravitreal injections.

The port delivery system (PDS; Hoffmann-La Roche) is a permanent, refillable implant, which is surgically placed at the pars plana through an incision in the sclera. PDS continuously releases concentrated ranibizumab by passive diffusion into the vitreous cavity.

Phase 2 of the LADDER clinical trial showed similar functional and anatomical outcomes after nine months of treatment with ranibizumab delivered through PDS or monthly intravitreal injections of ranibizumab [58, 59]. The mean time for the first PDS refill was 15 months, with 80% of patients not requiring a PDS refill for six or more months. Phase 3 of the ARCHWAY clinical trial is ongoing [60].

GB-102 (Graybug Vision) is a depot formulation of sunitinib malate that might need only 2 or 3 treatments per year [61]. Phase 2 of the ALTISSIMO clinical trial evaluated the safety and effect duration of GB-102 intravitreal injections administered every six months compared to aflibercept intravitreal injections administered every two months [62]. The results are currently pending.

NT-503 (Neurotech Pharmaceuticals) is a biological sustained drug delivery device that can provide anti-VEGF therapy's continuous delivery. Preliminary studies show that the device can be implanted safely in humans [63]. The results of phases 1 and 2 of clinical trials are pending [64].

Aflibercept Hydrogel Depot (Regeneron Pharmaceuticals and Ocular Therapeutix™) is a delivery system based on a PolyActive hydrogel copolymer's microparticles. In studies with animals intravitreally injected with aflibercept hydrogel depot a, sustained and controlled release of aflibercept was achieved. No adverse effects in the eyes of healthy rhesus macaques were observed for up to 6 months [65].

pSivida Durasert Technology (EyePoint Pharmaceuticals, Inc.) can be used to deliver different drugs for extended periods (months or even years) with a single application. Delivery of a tyrosine kinase inhibitor in animals provided promising results [66].

#### **3.5 Gene therapy**

Gene therapy is based on the insertion of an anti-VEGF coding sequence into retinal cells' DNA through a viral vector.

ADVM-022 (Adverum) produces an anti-VEGF-A fusion protein delivered through intravitreal injection via the AAV.7 m8 viral vector. Phase 1 of the OPTIC clinical trial showed that treatment with a single injection prevented additional anti-VEGF treatment over six months [67, 68].

RGX-314 (RegenexBio) (Rockville, MA, USA) produces an anti-VEGF A fab delivered through a subretinal treatment via an AAV8 viral vector. Phases 1/2a of the AAVIATE clinical trial showed a decrease in injection burden without significant inflammation or adverse effects [69]. Phase 2b of the AAVIATE clinical trial will explore a suprachoroidal injection [70].

Retinostat (Oxford BioMedica) is a lentiviral vector expressing endostatin and angiostatin to inhibit angiogenesis potentially. Phase 1 clinical trial showed that the LentiVector® gene therapy platform safely and efficiently delivered genes to the retina resulting in stable, long-term expression [71].

AAV2-sFLT01 (Genzyme, a Sanofi Company) is a vector that expresses a modified soluble Flt1 receptor designed to neutralize the proangiogenic activities of VEGF via an intravitreal injection. Phase 1 clinical trial showed that AAV2-sFLT01 was safe and that there was good tolerance to this vector [72]. After three years of follow-up, AAV2-sFLT01 appears to be generally safe, well-tolerated and does not appear to raise any new safety concerns [73].

AAVCAGsCD59 (Hemera Biosciences) is a molecule that targets the terminal step of complement activation that leads to the formation of the membrane attack complex. Two-phase 1 clinical trials for both exudative and dry AMD showed that subretinal injection of AAV-CD59 attenuated the formation of laser-induced choroidal neovascularization by around 60% in mice, even when the site of delivery was distal to the laser-induced choroidal neovascularization site [74].

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

An alternative for genetic interference is small interfering RNA (siRNA) that inhibits the protein-coding genes and prevent protein synthesis. Delivery can be by the topical installation or intravitreal injection. Bevasiranib (Opko) was the first siRNA used, but it did not show efficacy in phase 3 of the COBALT clinical trial [75]. AGN211745 (Alergan) was designed to reduce pathologic angiogenesis mediated by both VEGF *and* PIG. The study was terminated early due to a company decision (non-safety-related), and for this reason, certain outcome measures were not analyzed [76].

PF-655 (Pfizer) is a siRNA that inhibits expression of the hypoxia-inducible gene RTP801, which inhibits the mammalian target of the rapamycin (mTOR) signaling pathway and reduces VEGF-A production. Results from phase 2 of the MONET clinical trial showed that the combination of PF-655 with ranibizumab led to an average gain in visual acuity superior to the one observed for patients under ranibizumab monotherapy [77].
