Understanding fluid fluctuation in retinal disorders

Neovascular age-related macular degeneration (nAMD) is a major cause of severe vision loss worldwide despite effective anti-VEGF therapy.¹ Optimal outcomes require regular intravitreal anti-VEGF injections,^2,3 which can be a significant burden for patients and caregivers.⁴

To counter this, health care providers often tailor individual treatment regimens using biomarkers. Retinal thickness is a key biomarker that can be easily monitored in office via optical coherence tomography (OCT).

Although increased retinal thickness generally correlates with nAMD disease activity, recent evidence suggests that greater fluid fluctuations over the treatment course and the type of fluid present may impact functional outcomes more than residual fluid alone.^5-9Accordingly, several recently approved and investigational treatment options aim to minimize the fluctuations observed with bolus anti-VEGF injections.

The importance of retinal thickness variation

Data from the comparison of age-related macular degeneration treatments in the phase 3 CATT trial (NCT00593450) and the inhibition of VEGF in age-related choroidal neovascularization in the IVAN trial (ISRCTN92166560) reveal that significantly worse vision outcomes were associated with greater retinal thickness variation, not just the presence or absence of retinal fluid.

Retinal thickness variation was reported as quartiles of SD of center point thickness (CPT).⁷ The difference in best corrected visual acuity (BCVA) between the first quartile (lowest variation) and the fourth quartile (highest variation) was −6.27 Early Treatment Diabetic Retinopathy Study letters at 2 years.⁷

Further, greater retinal thickness fluctuations were also associated with the development of fibrosis and macular atrophy.⁷ Similarly, post hoc analyses of the phase 3 HARBOR (NCT00891735) and HAWK (NCT02307682)/HARRIER (NCT02434328) trials showed that eyes with more stable retinas experienced better vision gains vs eyes with greater variations in retinal thickness.^6,8

Outside of clinical trials, an analysis of electronic medical records also found worse visual outcomes associated with the degree of fluid fluctuations.⁵ Eyes in all quartiles showed worse vision outcomes compared with quartile 1 (lowest fluctuations).⁵ Notably, quartile 4 (largest fluctuations) displayed a difference of −9.4 letters compared with quartile 1, further highlighting the inverse relationship between the degree of retinal thickness fluctuation and vision outcomes.⁵

In addition to fluid fluctuations, the location of fluid present may also affect vision outcomes. For instance, results of several studies have shown that the presence of subretinal fluid (SRF) was not associated with worse vision outcomes.^8,10,11 In some cases, presence of SRF alone was associated with better vision gains compared with eyes with SRF and intraretinal fluid (IRF) or IRF alone.^10,11

Conversely, presence of IRF has been associated with worse visual acuity gains. Therefore, the presence of fluid alone may not be determinative of visual acuity outcomes; fluid type and fluctuation may also affect outcomes.

Stabilizing retinal fluid fluctuations

Given the association between retinal fluctuations and poorer functional outcomes, there is a need for treatment options that offer long-term retinal stabilization without the burden of frequent injections, such as sustained-release therapies. For example, the port delivery system with ranibizumab (PDS; Susvimo, Genentech) is a surgically placed ocular implant that allows for continuous release of ranibizumab, with refills every 6 months.¹²

In a post hoc analysis of the phase 3 Archway trial (NCT03677934), the PDS was shown to maintain vision outcomes comparable to monthly ranibizumab injections regardless of retinal fluid or retinal anatomy through 96 weeks.⁹

Further, in eyes with residual IRF, BCVA change from baseline with the PDS was −1.9 letters vs −6.9 letters in the monthly ranibizumab arm, suggesting that continuous drug delivery may provide a benefit for eyes with IRF, which has been known to result in poorer vision outcomes.⁹

Another sustained-release treatment is the EYP-1901 vorolanib intravitreal insert (Duravyu; EyePoint Pharmaceuticals), a bioerodible insert under investigation by the FDA for nAMD and diabetic macular edema (DME). This insert uses next-generation Durasert E technology to deliver a daily therapeutic dose of vorolanib, a tyrosine kinase inhibitor, for at least 6 months.¹³

Unlike anti-VEGF monotherapy, which functions extracellularly by sequestering the VEGF-A/B ligands, vorolanib provides a novel mechanism of action by functioning intracellularly to inhibit all 3 VEGF receptors, PDGF receptor, and all JAK kinases, particularly JAK-1.^14,15 IL-6/JAK signaling plays a key role in retinal inflammation, promoting vascular leakage and neovascularization.¹⁶

Additionally, vorolanib does not inhibit the TIE2 receptor, which, when activated, plays a role in vascular stabilization.¹⁴ This technology is designed to prevent free-floating drug particles in the vitreous and does not contain polyethylene glycol or poly(lactic-co-glycolic) acid, which have been shown to cause allergic reactions in some patients.^17-19 The insert has completed phase 2 trials in nAMD and DME and is being evaluated with a 6-month redosing schedule in pivotal phase 3 trials in nAMD.^20-22 First patient dosing in the pivotal phase 3 program for DME is anticipated in first quarter of 2026.²³

Results of the DAVIO 2 trial

In the phase 2 DAVIO 2 trial (NCT05381948) for nAMD, 2 dose levels of EYP-1901 were evaluated vs on-label aflibercept (Eylea; Regeneron Pharmaceuticals) 2.0 mg every 8 weeks. At month 2, after 3 monthly loading doses of aflibercept 2.0 mg, patients received EYP-1901 2 mg, EYP-1901 3 mg, or sham. Patients were then followed monthly through end of study; in the aflibercept arm, patients continued to receive aflibercept every 8 weeks. In the EYP-1901 arms, sham injections were used to maintain masking. At each monthly visit, all patients were evaluated for supplemental aflibercept treatment based on visual and/or anatomic criteria, or per Investigator decision.

DAVIO 2 met its primary end point with both dose levels of EYP-1901 statistically noninferior to aflibercept every 8 weeks for change from baseline in BCVA.²³ Stable or improved vision was observed in more than 80% of EYP-1901–treated patients at month 7/8, averaged.^24,25 In addition to visual outcomes, EYP-1901 also maintained strong anatomical control comparably to aflibercept every 8 weeks. Six months after the EYP-1901 administration, change from baseline in central subfield thickness (CST) was +17.8 µm and +10.6 µm with EYP-1901 2 mg and 3 mg, respectively, vs +5.4 µm with aflibercept every 8 weeks.²⁴ Further, in the aflibercept arm, a sawtooth pattern was observed, with CST increasing between injections. However, no such pattern was observed in the EYP-1901 arms. In these arms, after an increase between months 3 and 4, CST remained steady through month 8.²⁴ Vision also remained steady through month 8 despite the increase in CST, further aligning with previous studies that noted that small amounts of stable fluid may not adversely affect vision.²⁴

Prior to enrollment in DAVIO 2, patients had an annualized mean of 10 anti-VEGF injections, suggesting that they were heavily pretreated. However, up to month 8, 6 months after EYP-1901 administration, greater than 60% of DURAVYU-treated eyes remained supplement-free.²⁴ When compared with pretrial injection rates, EYP-1901 substantially reduced treatment burden by 89% and 85% in the 2-mg and 3-mg arms, respectively.²⁴ EYP-1901 demonstrated a favorable safety profile in DAVIO 2, with no observed EYP-1901– related ocular or systemic serious adverse events or safety signals.²⁴ This aligns with the favorable safety profile in other phase 2 EYP-1901 trials in DME and diabetic retinopathy, suggesting an overall favorable safety profile with more than 190 patients evaluated across multiple indications.²⁴

Conclusion

Treatment options that stabilize retinal anatomy may improve functional outcomes for patients with retinal exudative disease by reducing fluid fluctuations that have been associated with poorer outcomes. Sustained release of vorolanib by the insert maintained CST on average through 6 months after administration without a sawtooth pattern as seen with aflibercept every 8 weeks. Furthermore, with a demonstrated reduction in treatment burden and a favorable safety profile, EYP-1901 has the potential to reduce treatment frequency while controlling disease and maintaining functional outcomes for patients with nAMD.

Danny Mammo, MD, Cleveland Clinic, Cleveland, OH

Financial disclosures: Consultant: ANI, Apellis, Bausch + Lomb, EyePoint, Genentech; Speaker: ANI, Apellis, Bausch + Lomb

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