Retinal vein occlusion (RVO) is one of the most commonly encountered vascular diseases of the retina, with a prevalence of approximately 0.5% to 1% and a 10-year incidence of 2 per 100 persons, resulting in a prevalence closer to 2% as we age.^1-3 Presenting in 2 forms, central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO), affecting the central or smaller tributary vessels, respectively, RVO results from the blockage of outflow of these veins. The initial blockage compromises the retinal circulation and leads to ischemia and the increased production of hypoxia-regulated gene products. These gene products, particularly vascular endothelial growth factor (VEGF), give rise to macular edema, a major cause of vision loss in RVO. Agents targeting VEGF have been shown to be an effective treatment of macular edema in RVO.^4,5

In phase 3 trials for BRVO and CRVO, BRAVO⁴ and CRUISE,⁵ patients receiving monthly ranibizumab gained between 15 and 18 letters at month 6 and largely maintained that gain with subsequent as-needed treatment at the 1-year mark. Between 50% and 60% of subjects gained ≥3 lines of vision. In similar phase 3 trials for aflibercept, VIBRANT,⁶ COPERNICUS,⁷ and GALILEO,⁸ patients gained 17-18 letters after 6 months of monthly treatment, with 50% to 60% gaining ≥3 lines of vision. These gains were maintained at the 1-year mark after switching to treatment every 2 months for BRVO and as-needed for CRVO.

Given this robust response, anti-VEGF agents are considered first-line therapy for RVO with macular edema. However, the treatment burden remains high. Longer-term follow-up suggests that the majority of patients have persistent activity, defined as fluid on imaging. At year 2, 66% of subjects in COPERNICUS still had edema and required approximately 3 as-needed injections that second year.⁷ At year 4, 50% to 56% of a BRAVO/CRUISE subset also continued to have unresolved edema and required a mean of 6 injections during that year.⁹

As effective as they are, one possible reason that anti-VEGF agents do not achieve universal resolution of macular edema in RVO is their specific focus on VEGF, to the exclusion of other hypoxia-stimulated factors that play a role in vascular leakage and edema.¹⁰ Another broader approach consists of corticosteroids, known to suppress gene products involved in inflammation, angiogenesis, and permeability.^11-13

Triamcinolone acetonide (TA) injections at 4-month intervals showed efficacy in patients with CRVO and macular edema in the SCORE trial.¹⁴ Mean change in vision favored TA over observation by 11 letters; however, it represented a loss of 1 letter vs 12 letters from baseline, respectively. Approximately 26% of participants in the TA groups (1 mg and 4 mg) gained ≥3 lines at 1 year, compared to 7% in the control (no treatment) group. While these results were not as robust as those seen with anti-VEGF agents, they were achieved with a lower treatment frequency. They were also, however, accompanied with a higher rate of intraocular pressure (IOP) elevation and cataract formation. Up to 35% of subjects in the steroid groups required IOP-lowering treatment (8% in control group) and 21 eyes in the 4 mg TA group underwent cataract surgery in the second year (0 in control group).

An injectable dexamethasone implant, given at 6-month intervals, also showed similar results. The peak visual acuity gain occurred at month 2, with 10 letters gained in the treatment group compared to 3 letters in the no-treatment control group.¹⁵ Similarly, 29% of patients achieved ≥3 lines visual acuity gain at month 2 vs 11% of control subjects. While somewhat lower than with TA, cataract formation and IOP rises were still seen. Twenty-five percent of patients required IOP-lowering treatment in the dexamethasone group (0% in the control group) by month 615 and an additional 10% required it by month 12.¹⁶ At month 6, cataract formation was not statistically different, seen in 7% of subjects in the dexamethasone group compared to 5% in the control group.¹⁵ However, with a second injection, cataract progression was observed in 30% of dexamethasone-treated patients at month 12 (6% control group).¹⁶

Because of these additional concerns, intravitreal steroids are typically reserved as second-line treatment for macular edema in RVO, in patients with a suboptimal response to anti-VEGF treatment. If the effects on cataracts and IOP could be ameliorated while maintaining the comparatively longer duration of action, steroids could play a larger role as an adjunct to anti-VEGF therapy.

To address this unmet need, suprachoroidal injection is being developed as a novel approach to drug delivery.¹⁷ In contrast to intravitreal injection, suprachoroidal injection has the potential to maximize the benefit and minimize the side effects of steroid administration. In the rabbit model, using fluorescein and fluorescently tagged dextrans, suprachoroidal injection achieved chorioretinal concentrations 10+ times greater than that seen with intravitreal injection at all measured time points.¹⁸ Not only were the concentrations significantly higher at the target tissues, they were also very localized. With suprachoroidal injection, there was a rapid decline in concentration upon reaching the vitreous; no significant levels were detected in the anterior chamber.

Also, nondegradable particles as small as 20 nm remained at consistent concentrations in the suprachoroidal space for the 2-month duration of the study, suggesting that there would be no premature clearance of degradable particles from this potential space.¹⁸ Therefore, the suprachoroidal injection of TA in patients with RVO and macular edema has the potential to more selectively achieve therapeutic concentrations at the posterior target tissue while minimizing exposure to the anterior segment. This increased selectivity could potentially translate to efficacy outcomes with lower rates of cataract formation and IOP spikes.

The suprachoroidal injection of a new preservative-free, terminally sterilized formulation of triamcinolone acetonide, CLS-TA (Clearside Biomedical Inc.) is currently being evaluated for multiple indications, including RVO with macular edema. A specifically designed hub and microneedle was developed to ensure consistent delivery of CLS-TA to the suprachoroidal space and minimize the risk of unintended intravitreal injection. The injection procedure is performed in an outpatient setting, and although it is similar to a typical intravitreal injection, it differs in that the microneedle length (between 900 µm and 1,100 µm) requires insertion that is both perpendicular to the sclera and complete (to the hub). Gentle pressure is maintained on the plunger throughout insertion, triggering the release of the TA only once the needle passes the dense sclera and reaches the correct, lower resistance potential space (Figure 1).

A recent phase 2 trial, the Tanzanite study,¹⁹ examined the safety and efficacy of the combination of suprachoroidally administered CLS-TA (4 mg) with intravitreal aflibercept (2 mg) compared to aflibercept (2 mg) alone in patients with RVO and macular edema. This multicenter, randomized, masked clinical trial enrolled 46 patients over the course of 1 year. Each subject had 1 eye affected by macular edema due to RVO within the last year, with a best-corrected visual acuity (BCVA) approximately between 20/40 and 20/400 (20 to 70 Early Treatment Diabetic Retinopathy Study [ETDRS] letter score). The central subfield thickness (CST) of each affected eye was ≥310 µm on spectral-domain optical coherence tomography (SD-OCT). All study eyes were naïve to anti-VEGF treatment and either naïve to corticosteroid therapy or after a minimum 3-month (steroid-specific) washout period. They had no history of steroid-induced IOP rise, glaucoma surgery, or recent onset of elevated IOP, but participants were included if they had ocular hypertension that was well controlled (≤22 mmHg) with a maximum of 2 topical medications.

Participants were randomized 1:1 to the CLS-TA/aflibercept combination group or the sham suprachoroidal injection/aflibercept group and underwent their respective treatment on day 1. At months 1, 2, and 3, both groups received as-needed retreatment with aflibercept with any of the following:

• fluid present on SD-OCT and the CST was ≥340 µm
• BCVA decreased by ≥10 letters from the prior visit
• new fluid present with a >50 µm increase of CST from the prior visit and a drop of ≥10 letters in BCVA from the best measurement.

Subjects not needing retreatment received sham intravitreal injections to maintain masking.

The primary outcome of the Tanzanite study was the number of required aflibercept retreatments. The purpose was to evaluate the potential for the combination of suprachoroidal CLS-TA and aflibercept to have a longer-lasting effect on macular edema than aflibercept alone and thus need less retreatment. Compared to the 23 retreatments in the aflibercept arm, the 9 needed in the combination arm represented a significantly lower retreatment rate (P=.013). For that matter, 78% of subjects in the combination therapy group required no retreatment throughout the entire study, compared to 30% in the aflibercept monotherapy group (P=.003).

As for secondary endpoints, the combination group demonstrated positive incremental gains in both visual acuity and anatomic outcomes. Mean improvement from baseline vision favored the combination group at all time points and was statistically significant at its month 2 zenith of approximately 20 letters gained (12 letters in the aflibercept group). At month 2, 61% of patients receiving CLS-TA/aflibercept gained ≥15 letters compared to 39% receiving aflibercept alone.

Anatomic results as measured with SD-OCT also favored the combination group at all times. The combination arm (CST 731 µm) and the control arm (728 µm) had balanced baseline CSTs. The combination treatment achieved and maintained a normalized CST under 290 µm at all time points. Patients with aflibercept monotherapy initially saw a decrease to 323 µm, but with a subsequent rebound to a CST in the 380 µm range. While not rising to the level of statistical significance, this is at least partly due to a ceiling effect; there is a point where the CST is normalized, beyond which further reductions are not achievable. In fact, approximately 80% of subjects in the combination arm achieved resolution of edema (CST of ≤310 µm) at all time points in the study, compared to 51% in the aflibercept arm.

Most of the ocular adverse events were well balanced and related to the injection procedure. One patient in the CLS-TA group had cataract progression (0 in aflibercept group), although it was deemed unrelated to the drug by the investigator. Two patients in the combination arm experienced an increase in IOP that responded to topical treatment. An additional 2 subjects, also in the combination group, had pre-existing glaucoma that required additional topical treatment for IOP control. No elevation of IOP was observed in the aflibercept monotherapy arm.

SUMMARY

Early results from the Tanzanite study suggest that suprachoroidal injection of CLS-TA is well tolerated. It may also have the potential to boost the efficacy of anti-VEGF treatment and reduce the treatment burden in macular edema secondary to RVO, one of the most commonly encountered retinal vascular disorders. While anti-VEGF monotherapy has been an effective first-line modality in this setting, RVO remains chronic by nature and necessitates a high treatment burden: 50% or more of patients still require ongoing anti-VEGF treatments 4 years after onset.⁹ Thus, decreasing the number of needed treatments represents an inherent and tangible benefit to the patient.

One concern with the typical attempts at reducing treatment burden, either via as-needed treatments or extension protocols, is the possibility of incremental regression. A state of “gradual decline” may be mistaken for one of maintenance. If, as these data suggest, the number of treatments can be reduced by using the combination of suprachoroidal steroid and intravitreal anti-VEGF, without sacrificing visual and anatomic outcomes, we will finally have reached a state of equilibrium and true maintenance.

While the results of the Tanzanite study are encouraging, it is important to remember it is a phase 2 trial (46 patients; 3 months) and thus limited in scope. Larger trials with longer follow-up are needed, particularly as cataract formation and IOP elevation may be exacerbated after multiple administrations of steroids. To that effect, 2 phase 3 trials, each assessing 460 patients over 12 months, are currently under way and will hopefully address these questions in the near future. If the early results are corroborated, it will result in a paradigm shift in the management of RVO. RP

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