It has been nearly 2 decades since the treatment of neovascular age-related macular degeneration (nAMD) was revolutionized with now standard-of-care anti-VEGF-A therapies. In real-world practice, these agents have limitations and patients do not always enjoy the same visual acuity results as those that were shown in pivotal clinical trials. 

Up to 45% of nAMD patients either fail to respond optimally to current anti-VEGF therapies, exhibit late failure to therapy, or require intensive, frequent injections.^1,2 Of the 35% who fail to respond optimally to therapy, more than 10% worsen despite treatment, and another 25% show no improvement.^3,4 Despite maximal intensive anti-VEGF-A therapy, more than 60% of eyes have persistently active disease, which can result in poor long-term outcomes.^4,5 Thus, standard-of-care anti-VEGF-A therapy has some limitations.^6-8

The VEGF Family

The vascular endothelial growth factor (VEGF) family of 5 secreted glycoproteins — VEGF-A, VEGF-B, VEGF-C and VEGF-D, and placental growth factor (PlGF) — are critical inducers of angiogenesis as well as lymphangiogenesis. They each exhibit binding specificities for the VEGF receptors (VEGFR) VEGFR-1, VEGFR-2, and VEGFR-3, which are typically expressed on vascular endothelial cells.⁹ The ligands VEGF-A, VEGF-C, and VEGF-D bind and activate VEGFR-2, which is known as the main receptor signaling for angiogenesis and vascular permeability. VEGF-C and VEGF-D are the only known ligands for VEGFR-3, which is also an important driver of angiogenesis and lymphangiogenesis.^10-12 Both VEGF-C and VEGF-D and their related receptors have been detected in human vitreous, and the retinal pigment epithelium of AMD patients shows a higher expression of VEGF-C and VEGF-D.¹³ VEGF-C levels are also higher in the circulation and retinal tissue of nAMD patients compared to those without disease (Figure 1).^14,15 

Critical mediators of angiogenesis, VEGF-C and VEGF-D, are increased in response to VEGF-A inhibition,^16-19 likely contributing to a less-than-optimal responsiveness with standard-of-care anti-VEGF-A therapies.¹⁸ Research reveals that VEGF-C can induce the formation of endothelial cell fenestrations, which subsequently increase vessel permeability, vascular leakage, and edema formation.^10,12 Similarly to VEGF-A, VEGF-C is also upregulated by inflammatory mediators that are implicated in the pathogenesis of retinal diseases.¹⁹ 

Sozinibercept

Sozinibercept (OPT-302; Opthea) is a first-in-class recombinant fusion protein “trap” molecule composed of the first 3 extracellular ligand binding domains of human VEGFR-3, fused to human immunoglobin G1 constant domain (hIgG1 Fc). It binds to and neutralizes the activity of VEGF-C and VEGF-D by preventing ligand binding to the endogenous receptors VEGFR-2 and VEGFR-3. It is highly specific for VEGF-C and VEGF-D and does not bind VEGF-A.

The novel agent was studied in a 366-patient phase 2b randomized controlled trial, in which sozinibercept in combination with ranibizumab demonstrated superior visual outcomes compared with ranibizumab alone. Patients assigned combination treatment with 2 mg sozinibercept plus 0.5 mg ranibizumab (n=123) achieved the primary endpoint of a mean change in best-corrected visual acuity (BCVA) from baseline to week 24 of +14.2 letters, representing a significant additional gain of +3.4 letters (P=.0107) over the ranibizumab monotherapy control group.²⁰ Even greater visual acuity (VA) gains were achieved over the control group in prespecified analyses of patients with certain lesion subtypes. 

Opthea is now conducting 2 concurrent, randomized, controlled, pivotal phase 3 studies, ShORe (2 mg sozinibercept plus 0.5 mg ranibizumab) and COAST (2 mg sozinibercept plus 2 mg aflibercept).^21,22 COAST has completed enrollment and ShORe is expected to complete enrollment over the coming months. Sozinibercept is administered every 4 or 8 weeks following 3 monthly loading doses in combination with standard-of-care anti-VEGF-A therapy. Control subjects receive ranibizumab 0.5 mg plus sham every 4 weeks in ShORe and aflibercept 2 mg plus sham for 3 loading doses every 4 weeks and then every 8 weeks thereafter in COAST. The primary endpoint for both studies is superiority in BCVA gains from baseline at 12 months for the sozinibercept combination therapy compared with standard-of-care anti-VEGF-A monotherapy. Unlike many recent trials with noninferiority designs, these are the only late-stage trials in nAMD with a primary endpoint of superiority of BCVA outcomes over standard of care monotherapy. Participants also receive continued dosing through year 2 to assess longer-term safety. Opthea plans to submit registrational regulatory filings after completion of the 12-month primary efficacy phase.

Clinical Practice

Over the past few years, some of the shortcomings of intravitreal anti-VEGF-A monotherapy have become a bit clearer. To that end, a variety of agents are in clinical development. In a perfect world, we are looking for a drug that remains safe, dries better, lasts longer, and most importantly, provides better visual outcomes. Currently, there are many promising agents in the pipeline, such as tyrosine kinase inhibitors and anti-VEGF-A gene therapies, with the goal of improved durability (thus reduced treatment frequency) and maintenance of the same visual outcomes as seen with standard of care. Yet, with chronic VEGF-A blockade leading to VEGF-C and VEGF-D upregulation and potentially less treatment efficacy over time, there is an unmet need for novel agents that can safely and directly suppress other proangiogenic factors involved in nAMD. Toward that end, early-stage gene therapies are being developed. These include 4D-150 (4D Molecular Therapeutics), which inhibits VEGF-A, VEGF-B, VEGF-C, and PlGF, and EXG102-031 (Exogenesis), which inhibits all known subtypes of VEGF plus Ang-2, according to the companies. 

The phase 2b data on sozinibercept, which is highly specific for VEGF-C and VEGF-D, show potential, with better visual outcomes when used in combination over standard of care alone. The phase 2b data indicate that broader targeting of VEGF/VEGFR pathways may be more helpful in suppressing exudation rather than simply focusing on VEGF-A inhibition. 

Although greater durability of current treatment effects is an admirable goal, it should not supplant the pursuit of further visual gains. How would this potentially novel therapy translate to a busy retina practice? Treatment burden is a very real issue in today’s clinic and presents a potential hurdle with the adoption of any new therapy, particularly with a combination therapy; however, patients will likely prioritize their vision. Fortunately, the retina community has a strong tradition of embracing change to offer the most robust treatment options to our patients. If and when additional therapeutic options become available for nAMD patients, retina specialists will learn how to adapt them to their clinics. 

Conclusion

In nAMD, focusing only on VEGF-A is an oversimplification of a very complex process. VEGF-C and VEGF-D are innately involved in the neovascular etiology, so treating that component, in addition to traditional anti-VEGF-A treatment, may have the potential for improved VA. The ongoing investigation into pan-VEGF blockade thus represents an exciting, potentially revolutionary idea: to challenge the status quo of anti-VEGF-A monotherapy, to push the boundaries of visual acuity gains, and to strive for measurable improvements in the treatment of patients suffering with nAMD. RP

Hear discussion of this article on the Retina Podcast at www.retinapodcast.com. 

Mark R. Barakat, MD, is director of research at the Retina Macula Institute of Arizona, medical director of Spectra Eye Institute, and clinical assistant professor at the University of Arizona College of Medicine in Phoenix, Arizona. Dr. Barakat is a consultant to AbbVie Inc, Adverum Biotechnologies, Alcon, Alimera Sciences, Allegro, Allergan, AmerisourceBergen, Annexon, Apellis Pharmaceuticals, Arctic Vision, Bausch + Lomb, Biogen, CalciMedica, Clearside Biomedical, Coherus Biosciences, EyePoint Pharma, Genentech, Kodiak Sciences, Iveric Bio, Janssen, Neurotech, Novartis, Ocular Therapeutix, Opthea, Outlook Therapeutics, Palatin Technologies, Regeneron, RegenxBio, RevOpsis Therapeutics, Roche, and Stealth Biotherapeutics. He receives research funding from Adverum Biotechnologies, Annexon Biosciences, CalciMedica, Clearside Biomedical, EyeBio, EyePoint Pharma, Gemini Therapeutics, Genentech, Gyroscope Therapeutics, Kanghong/Vanotech, Kodiak Sciences, Novartis, Ocular Therapeutix, Oculis, Opthea, Oxular, Oxurion, Perfuse, RegenxBio, ReNeuron, Ribomic, Roche, Stealth Biotherapeutics, and Unity Biotechnology. He is a speaker for Apellis, Bausch + Lomb, Genentech, Iveric Bio, Novartis, and Regeneron; and has equity in NeuBase, Oxurion, and RevOpsis Therapeutics. Reach him at mark.barakat@gmail.com.

Mark P. Breazzano, MD, is a retina specialist with Retina-Vitreous Surgeons of Central New York, and clinical assistant professor at SUNY Upstate Medical University in Syracuse, New York. Dr. Breazzano is a consultant/speaker for Iveric Bio. He receives research funding from Roche, Iveric Bio, DRCR retina network/NEI, Opthea, Janssen, Lexitas, Kyowa, Oculis, Aviceda, Eyebiotech, Ocugen, RegenxBio, Ocular Therapeutix, Oxurion, Ocuterra, and Regeneron. Reach him at mark.breazzano@gmail.com.

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