Visual Outcomes in Wet AMD: Can We do Better?

A therapeutic approach that targets broader VEGF-family signalling pathways, not only VEGF-A, could be one solution.

By David Eichenbaum, MD

Better visual outcomes remain a significant unmet need in the treatment of patients with neovascular or wet age-related macular degeneration (wet AMD). Despite the availability of approved anti-vascular growth factor (VEGF)-A drugs, new biosimilar agents, the first bi-specific drug for wet AMD, and emerging approaches to extend dosing intervals, many patients in the real world have sub-optimal visual gains with these standard-of-care drugs that fall short of those observed in clinical trials.

Why Do Visual Gains with Anti-VEGF-A Therapy Fall Short?
Although most patients in the real world have visual acuity increases with anti-VEGF-A standard of care, there is a ceiling effect and often a subsequent decline despite frequent injections. More than half of patients treated with approved VEGF-A inhibitors fail to achieve 20/40 vision after 12 months of standard-of-care treatment, impeding the resumption of routine daily activities such as driving and reading, functions key to their independence.^1-5  Up to a quarter of patients suffer further vision loss despite VEGF-A monotherapy.⁶

Suboptimal improvements with anti-VEGF-A therapy can partially be attributed to undertreatment due to reduced adherence to treatment protocols specified in clinical trials.⁷

Patients Prioritize Visual Outcomes
A primary driver for the lack of treatment adherence by many patients is unrealized visual acuity gains. In one study,⁸ approximately 35% of patients cited dissatisfaction with ranibizumab’s benefit as the main reason for their stopping treatment. If patients can expect better visual outcomes, however, they may be more likely to tolerate recommended injection regimens.

In a survey of 284 patients, almost three-quarters cited change in visual acuity as the most important factor influencing treatment options and most were willing to accept the time burden associated with ongoing injections in exchange for better vision.⁹ Another recent survey of 466 wet AMD patients across 10 countries showed vision improvement was the key desired treatment outcome, with durability or extended dosing intervals ranked lower.¹⁰

Yet, beyond anti-VEGF-A inhibition, treatment choices are limited. Strategies such as switching among approved anti-VEGF-A therapies have been shown in a meta-analysis to be associated with limited or no improvement in visual acuity.¹¹ At the same time, newer agents that continue to potently target the VEGF-A pathway or target VEGF-A and angiopoietin 2 have prioritized and demonstrated extending treatment intervals with non-inferiority in visual function outcomes compared to approved anti-VEGF-A monotherapy.¹²

We Need to Consider the Role of VEGF-C and -D
Within the wider VEGF family of ligand-receptor signaling, VEGF-C and -D join VEGF-A as drivers of the angiogenic process.^13,14 In addition, VEGF-A suppression has been shown to increase the upregulation of the release of VEGF-C and -D.^15-19  Therefore, suboptimal outcomes with standard-of-care VEGF-A blockers are possibly due to these therapies not targeting the multi-factorial pathogenesis of choroidal neovascularization (CNV).

Various therapeutic approaches including high-molarity VEGF-A inhibition, targeting platelet-derived growth factor, and simultaneously blocking angiopoietin-2 have improved durability over standard of care, but none have succeeded to improve vision over standard of care.⁹ Furthermore, none of the currently registered treatments provide a more broad blockade of the VEGF pathway implicated in CNV development, including VEGF-C and VEGF-D (Figure). Hence, there is a need for therapeutic options that better address the complex molecular and multi-factorial pathogenesis of neovascular AMD.

New Strategy: OPT-302 Trap Molecule Targeting VEG-C and -D
A first-in-class biologic specifically designed to “trap” and sequester VEGF-C and -D, OPT-302 (Opthea), has shown promise in a recent 366-patient Phase 2b study in wet AMD.^20,21 Patients assigned to combination treatment with 2 mg OPT-302 plus 0.5 mg ranibizumab (n = 123) achieved the primary endpoint of a statistically significant mean change in BCVA at 24 weeks, with an additional gain of +3.4 letters (P = 0.0107) over the ranibizumab plus sham control group in the total population, together with a similar safety and tolerability profile. The trial also showed improvements in secondary anatomic endpoints for OPT-302 combination therapy versus ranibizumab monotherapy, with reductions in retinal thickness, subretinal fluid, intraretinal fluid, lesion size, and neovascular area versus the control group. A prespecified subgroup of participants with minimally classic and occult lesions who received the 2-mg OPT-302 combination (n = 88) were found to have an addi­tional mean improvement in BCVA of +5.7 letters (P = 0.0002) at 24 weeks over the sham-plus-ranibizumab group (n = 87).

Based on these promising data, Opthea is currently investigating OPT-302 combination therapy in 2 concurrent, randomized, controlled, pivotal Phase 3 studies, ShORe (OPT-302 2 mg plus ranibizumab 0.5 mg, NCT04757610) and COAST (OPT-302 2 mg plus aflibercept 2 mg, NCT04757636).^22,23 The study drug will be administered every 4 or 8 weeks following 3 monthly loading doses in combination with standard-of-care anti-VEGF-A therapy. Control subjects in ShORe will receive ranibizumab 0.5 mg plus sham every 4 weeks and COAST control subjects will receive aflibercept 2 mg plus sham for 3 loading doses every 4 weeks and then every 8 weeks thereafter. The primary endpoint for both studies is superiority in visual acuity gains at 12 months for the combination therapy compared with standard-of-care monotherapy. Participants will also receive continued dosing through year 2 to assess longer-term safety. Opthea plans to submit regulatory filings for a biologics license and marketing authorization to the U.S. Food and Drug Administration and European Medicines Agency, respectively, after completion of the 12-month primary efficacy phase.

Conclusion
We know from a number of studies that wet AMD patients with better vision at the beginning of treatment often have better longer-term outcomes.²⁴ Unfortunately, those who start with poor vision may struggle to achieve sustained meaningful visual gains. This is where OPT-302 combination therapy has the potential to shine as it is the only investigational therapeutic approach in late-stage phase 3 trials that is focused on improving visual function outcomes for all patients, in contrast to other approaches aiming to extend treatment intervals.

It has become clear that there is more going on in neovascular AMD than just dysregulation or overproduction of VEGF-A. Patients and retinal specialists strongly desire improved visual outcomes for wet AMD treatment. Combination therapy with OPT-302 and its mechanism of action targeting VEGF-C and -D, together with a VEGF-A inhibitor, appears to be an exciting approach to potentially deliver better vision for our patients. I strongly encourage ophthalmologists to consider enrolling appropriate patients in these Phase 3 ShORe and COAST clinical trials investigating OPT-302 combination therapy for wet AMD.

David Eichenbaum, MD is director of research for Retina Vitreous Associates in St. Petersburg, Florida, and Collaborative Associate Professor at the Morsani College of Medicine at the University of South Florida. He is an investigator and consultant for Opthea, Genentech, Regeneron, and Bayer, and is a speaker for Genentech. Dr. Eichenbaum may be reached at [email protected].

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