Beyond Treat-and-Extend: How Future Treatment Approaches May Transform Management of Wet AMD

Anti-VEGF therapy has transformed how we treat and manage wet age-related macular degeneration (AMD).^1,2 However, the reliance on frequent injections over the years places a significant burden on patients.3,4 In general, very few physicians follow clinical trial treatment protocols, especially for anti-VEGFs, which utilized fixed dosing intervals in the pivotal studies of ranibizumab and aflibercept. This has led to undertreatment in many real-world studies, and consequently worse visual gains than seen in the clinical trial setting.⁵

In real-world practice, this effort to extend the durability of injections has led to a “treat-and-extend" (T&E) approach that has been widely implemented.^6,7

Current T&E practices often rely on short-term assessments to help mitigate retinal fluid. However, this approach can lead to suboptimal disease control, which may result in fibrosis and poor long-term visual outcomes.^6,8,9

An important question emerges: does T&E result in durable, sustained disease control over time, or is it a strategy of simply treating the recurrence of fluid from visit to visit? Addressing this question underscores a broader goal for future treatments in wet AMD and how to achieve sustained disease control without sacrificing treatment durability.

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Treat-and-Extend in Practice

In clinical practice, T&E extension decisions are not uniform. They reflect varying thresholds for fluid and differing comfort levels with extending intervals.¹⁰ As a result, fluid may begin to accumulate while intervals lengthen. Retinal thickness and fluid fluctuations have been associated with worse visual and anatomic outcomes, suggesting that this pattern may contribute to irreversible retinal atrophy and fibrosis over time.^8,9 In practice, T&E can become a cycle of treating the recurrence of fluid rather than maintaining durable, sustained disease control.

Durability Is More Than Extending Intervals

Durability is often interpreted as the ability to reach longer treatment intervals. Clinically, however, it is better defined as the ability to maintain consistent disease control over time without recurrence, as interval length alone does not necessarily reflect effectiveness.

While extending dosing schedules can reduce treatment burden, these decisions must be balanced against the risk of poor long-term outcomes that occur when patients are not adherent to the injection regimen.

This raises a critical question: are we extending treatment intervals, or extending periods where disease control may not be durably sustained?

Consequences of Recurrence

Recurrent disease activity is common in real-world wet AMD management and may occur even when disease appears clinically stable (e.g., based on OCT).8,11 One study found that more than half of patients who discontinued treatment following stable disease experienced recurrence within one year.¹²

Adherence remains a significant challenge in long-term management of wet AMD.¹³ Real-world evidence suggests that almost half of patients discontinue treatment within the first year after diagnosis, while longer-term data show that approximately 66% of patients eventually discontinue therapy after 8 years, with a median time of 1.5 years after the initial injection.^14,15

Perhaps even more troubling, a study found that over time, almost 40% of recurrences were asymptomatic.¹⁶ This means that patients experienced reactivation of their wet AMD without noticing blurring or vision changes.¹⁶

For these patients, repeated fluid recurrence and fluctuation may serve as early biomarkers of ongoing disease activity, even in the absence of significant visual acuity loss initially.^6,16

Without stable disease control, the retina may be exposed to repeated peaks and troughs of fluid, reflecting the underlying biological instability.8 This pattern may be associated with cumulative damage to the retina over time, often leading to irreversible retinal atrophy and fibrosis, resulting in permanent vision loss.^6,9,11

These risks may be amplified by missed or delayed visits, the cycle of instability, and increasing the likelihood of long-term damage.^6,9

Reframing the Goal of Treatment

Rather than defining durability solely by dosing interval, another clinically meaningful goal could be sustained disease control that translates into improved adherence, long-term durability, and outcomes. This reframing shifts the focus from maximizing interval length alone to defining durability as sustained disease control over time in support of long-term outcomes.

The goal is not simply “how far can we extend,” but “how well can we preserve” a patient’s long-term vision – both anatomically and functionally. This requires recognizing the importance of consistent fluid control – because even intermittent disease activity is not benign, and may signal future atrophy, fibrosis, and permanent vision loss.¹⁷

The evolving definition of durability is also reflected in the design of new investigational therapies. Ocular Therapeutix is aiming to redefine the retina experience for patients, with the hope of preserving vision for the long term.

Redefining Durability in Wet AMD

As the field continues to advance, we believe the goal of durability should evolve toward continuous, consistent disease control that supports improved long-term anatomical and visual outcomes. Sustaining that level of control is critical to achieving meaningful durability and long-term outcomes.

Momentum across the field is focused on rethinking how therapies are designed and delivered, with the goal of improving long-term adherence and stability. As innovation accelerates, the work of companies like Ocular Therapeutix reflects a broader commitment to redefining what long-term outcomes can look like for patients.