Suprachoroidal Drug Delivery for Macular Edema Associated With Noninfectious Uveitis

Abstract

Purpose: To evaluate clinical trials in the literature that focus on suprachoroidal drug delivery for the treatment of noninfectious uveitis and other posterior segment diseases. Methods: A synthesis of the literature was performed. Results: In 2021, suprachoroidal space triamcinolone acetonide, a corticosteroid delivery system used for the treatment of uveitic macular edema (ME), was approved by the US Food and Drug Administration. The drug-delivery system targets the suprachoroidal space using a microneedle-based device and has a favorable pharmacokinetic profile. Suprachoroidally administered investigational therapies have also been assessed in clinical trials for other posterior segment diseases, including diabetic ME, retinal vein occlusion, age-related macular degeneration, and choroidal melanoma. Conclusions: The safety and efficacy of suprachoroidal corticosteroid injections to treat uveitic ME have been shown in recent phase III clinical trials. Multiple programs are also investigating this modality of drug delivery for use in many other retinal and choroidal pathologies.

Introduction

Uveitis is the third leading cause of blindness worldwide, and macular edema (ME) associated with noninfectious uveitis increases the risk for long-term vision loss and reduced quality of life. ¹ Despite the use of intravitreal and local corticosteroid therapy in treating uveitic ME, long-term use and recurrent dosing are associated with adverse events, including high intraocular pressure (IOP), glaucoma, and cataract development. ² Suprachoroidal injections target the suprachoroidal space, a potential area between the sclera and choroid that is collapsed under physiologic conditions. This new drug-delivery method limits anterior segment exposure and could potentially reduce corticosteroid-related side effects, such as elevated IOP and cataract formation.

The triamcinolone acetonide injectable suspension (Xipere, Bausch + Lomb and Clearside Biomedical, Inc, is the first therapy approved by the US Food and Drug Administration that uses suprachoroidal drug delivery for treatment of uveitic ME. ³ The favorable pharmacokinetic profile of suprachoroidal drug delivery seen in patients with uveitic ME has led to investigations of its use in other ophthalmic conditions affecting the posterior segment, including diabetic ME (DME), age-related macular degeneration (AMD), retinal vein occlusion (RVO), and choroidal melanoma. In addition, preclinical studies have shown promising chorioretinal targeting and durability of small-molecule suspensions from different therapeutic classes, including plasma kallikrein inhibitor, receptor tyrosine kinase inhibitor, corticosteroids, and complement factor D inhibitor. ⁴ Recent clinical trials have extended beyond triamcinolone acetonide suspensions to include small molecules, gene therapy, and virus-like drug conjugates.

This review summarizes the key principles, advantages, and techniques of suprachoroidal drug delivery as well as clinical trials evaluating its use for the treatment of uveitic ME and other chorioretinal diseases.

Methods

A review of the literature was performed using PubMed and the National Institutes of Health website, ClinicalTrials.gov. Clinically relevant pharmacokinetic and anatomic studies coinciding with the development of suprachoroidal drug-delivery systems were compared with other local drug-delivery methods. A search of clinical trials (ie, phase 1, phase 1/2, phase 2, phase 3, and post hoc analysis of studies) included in this review was detailed; specifically, early-phase and late-phase trials that assessed the safety and efficacy of suprachoroidal delivery for the treatment of ME secondary to noninfectious uveitis and other posterior segment diseases (eg, RVO, DME, choroidal melanoma). Additional data for this review included visual acuity (VA) and anatomic outcomes as well as a summary of key findings.

Results

Current Methods of Local Therapy for Uveitis and Advantages of Suprachoroidal Delivery

The established methods for ocular drug delivery, including intravitreal, periocular, and sustained-release implants, have varying levels of efficacy as well as unique benefit and risk profiles. ⁵ Intravitreal injections are frequently used to treat uveitic ME and have an established risk profile. ⁶ The PeriOcular vs INTravitreal corticosteroids for uveitic ME (POINT) trial compared the efficacy of 3 local therapies for uveitic ME and found that intravitreal triamcinolone acetonide or dexamethasone implants lead to better VA gains and lower rates of ME than periocular triamcinolone acetonide. However, the risk for elevated IOP was greater with intravitreal drug delivery than with periocular drug delivery. ⁷

Sustained-release devices can also be placed in the vitreous to improve durability and reduce the frequency of injections. ⁸ The intravitreal fluocinolone acetonide injectable insert (0.18 mg Yutiq, Alimera Sciences) and fluocinolone acetonide intravitreal surgical implant (0.59 mg Retisert, Bausch + Lomb) are nonbiodegradable, long-acting treatments for noninfectious uveitis that were shown to improve anterior chamber and vitreous inflammation and uveitic ME. Side effects of intravitreal drug delivery included a corticosteroid-related elevation in IOP, glaucoma, and cataract formation as well as injection-related subconjunctival hemorrhaging, an increased risk for endophthalmitis, vitreous hemorrhage, and retinal detachment.^7–11

Periocular drug delivery is another local therapy that is performed via subconjunctival, sub-Tenon, retrobulbar, or peribulbar injection. This method relies on passive diffusion of the drug across the sclera and does not require penetration into the eye, which makes it a safer option with a lower risk for injection-related complications than intravitreal injections. In the POINT trial, periocular injections had a lower risk for IOP elevation but were also less effective for uveitic ME than intravitreal injections; however, this method of delivery may be less desirable in patients with severe ME. ⁷

Systemic corticosteroids are also frequently used to treat acute sight-threatening inflammation; however, their long-term use can lead to undesirable side effects including weight gain, hypertension, elevated blood glucose, poor wound healing, and increased systemic infection risk. ¹² The blood–retina barrier also limits the amount of the drug that reaches the posterior segment. ¹³ Although topical corticosteroid drops offer a noninvasive method of drug delivery, patient adherence can be suboptimal.^14,15 In addition, topical treatments are highly concentrated in the anterior segment and increase the risk for corticosteroid-associated cataracts. The need for medication to traverse the anterior segment also reduces the concentration of medication needed for the treatment of ME.

Suprachoroidal injection is a new drug-delivery method targeting the suprachoroidal space, which is collapsed in its physiologic state (Figure 1). ¹⁶ After administration, the medication flows posteriorly as a result of the natural difference in pressures between the intraocular space and the suprachoroidal space and circumferentially spreads toward the macula.^14,17 This technique was initially investigated in animal models of uveitis as a minimally invasive method to target the choroid and retina and was found to reduce inflammation.^8,18 Suprachoroidal injections have a favorable pharmacokinetic profile and were shown in preclinical studies to compartmentalize to chorioretinal tissues over the anterior segment.^18,19

Figure 1.

Anatomic diagram of the eye with the suprachoroidal space shown as a dashed line.

Suprachoroidal Delivery Technique

Suprachoroidal injections involve a nuanced technique using a different needle than intravitreal and periocular injections that is specifically engineered for the anatomic characteristics of the suprachoroidal space. Virtual and hands-on training are currently available to learn the principles and practice in wet-lab and dry-lab settings. Local anesthesia with subconjunctival lidocaine or topical anesthetic agents can ease the pressure sensation or discomfort associated with expansion of the suprachoroidal space. After anesthesia administration, aseptic conditions with an eyelid speculum and a broad-spectrum microbicide (eg, 5% povidone–iodine) are recommended. Two lengths of microneedle are available (ie, 900 µm and 1100 µm), with the 900 µm needle used to complete successful suprachoroidal injections in 70% of injections in 2 clinical trials of patients with noninfectious uveitis. ²⁰ To minimize the possibility of intravitreal delivery, a 900 µm needle is recommended before switching to the 1100 µm needle. ²⁰

A successful injection can be performed by placing the microneedle perpendicular to the surface and then applying enough pressure to visualize dimpling of conjunctiva, which indicates spreading of the conjunctiva. Slow and steady administration of the drug minimizes the sensation of pressure secondary to choroidal expansion. ¹⁷ A loss of resistance while depressing the plunger indicates that the medication was successfully administered in the suprachoroidal space (Supplemental Video). Indirect ophthalmoscopy can be performed to verify optic nerve perfusion and a successful injection (ie, the absence of corticosteroid or other therapeutic in this setting).

Clinical Trials Studying Suprachoroidal Space Triamcinolone Acetonide to Treat Uveitis

Early Phase I/II Clinical Trials of Suprachoroidal Corticosteroid Delivery

Among the clinical trials focusing on suprachoroidal space triamcinolone acetonide for the treatment of uveitic ME are a phase 1/2 study (NCT01789320) that found preliminary safety and efficacy of a single injection in patients with noninfectious uveitis over 26 weeks (Table 1). ²¹ This was followed by the phase 2 DOGWOOD clinical trial (NCT02255032), which found that a single injection of suprachoroidal space triamcinolone acetonide was well tolerated and significantly improved the mean central subfield thickness (CST) and VA in patients with uveitic ME over 2 months. ²²

Table 1.

Randomized Clinical Trials of Suprachoroidal Drug Delivery in Noninfectious Uveitis.

Clinical Trial	Design	Inclusion	Cohort	Intervention	Primary Outcome	Additional Outcome(s)	Adverse Events
NCT01789320 [Completed]	Phase 1/2 Open-label	NIU	N = 9	1 dose of 4.0 mg SC CLS-TA	0 eyes w/ inc. IOP at 26 wk; 8 eyes w/ improved BCVA at 26 wk	−107 μm mean CST at 0–26 wk in 7 eyes w/ ME; 4 eyes required additional treatment for uveitis	7 eyes w/ ocular TEAE related to uveitis; 1 eye required cataract extraction
DOGWOOD (NCT02255032) [Completed]	Phase 2 Masked	ME due to NIU	Active (n = 17)	1 dose of 4.0 mg SC CLS-TA	−164 μm mean CST at 0–2 mo	33% eyes w/ ≥+15 ETDRS letters at 0–2 mo; +9.2 mean ETDRS letters at 0–2 mo	1 eye w/ transient inc. IOP ≥10 mm Hg
			Exploratory (n = 5)	1 dose of 0.8 mg SC CLS-TA	−78 μm mean CST at 0–2 mo	Not reported	0 eyes w/ inc. IOP ≥10 mm Hg
PEACHTREE (NCT02595398) [Completed]	Phase 3 Masked	ME due to NIU	Active (n = 96)	1 dose of 4.0 mg SC CLS-TA	+13.8 mean ETDRS letters at 0–24 wk	−153 μm mean CST at 0–24 wk; 13.5% w/ rescue therapy at 24 wk	11.5% eyes w/ inc. IOP 7.3% cataract incidence
			Control (n = 64)	Sham SC procedure	+3.0 mean ETDRS letters at 0–24 wk	−18 µm mean CST at 0–24 wk; 72% w/ rescue therapy at 24 wk	15.6% eyes w/ inc. IOP 6.3% cataract incidence
MAGNOLIA (NCT02952001) [Completed]	24-wk extension study of PEACHTREE	Patients who completed PEACHTREE w/out rescue therapy	Active (n = 28)	None	257 median days to rescue therapy	+12.1 mean ETDRS letters at 0–48 wk; −174.5 µm mean CST at 0–48 wk	14.3% eyes w/ inc. IOP ≥10 mm Hg; 25.0% eyes w/ cataract AE
			Control (n = 5)	None	55.5 median days to rescue therapy	Not reported	0 eyes w/ inc. IOP ≥10 mm Hg; 20.0% eyes w/ cataract AE
AZALEA(NCT03097315) [Completed]	Phase 3 Open-label	NIU	N = 38	2 doses of 4.0 mg CLS-TA	18.4% of eyes w/ drug-related TEAE; 0 eyes w/ SAE	+7.0 mean ETDRS letters at 0–24 wk; −15% mean CST at 0–24 wk	15.8% eyes w/ inc. IOP ≥10 mm Hg

Abbreviations: AE, adverse event; BCVA, best-corrected visual acuity; CST, central subfield thickness; ETDRS, Early Treatment Diabetic Retinopathy Study; inc., increased; IOP, intraocular pressure; ME, macular edema; N or n, number of eyes; NIU, noninfectious uveitis; SAE, serious adverse event; SC, suprachoroidal; TA, triamcinolone acetonide; TEAE, treatment-emergent adverse event.

PEACHTREE

PEACHTREE, which was a phase 3 clinical trial (NCT02595398), evaluated suprachoroidal space triamcinolone acetonide in 160 patients with ME secondary to noninfectious uveitis for 24 weeks. ²³ ME was defined as a CST of 300 µm or greater. A best-corrected VA (BCVA) of 5 or more and 70 or fewer Early Treatment Diabetic Retinopathy Study (ETDRS) letters were required in the study eye. The study was broadly inclusive, with inactive uveitis, active uveitis, and uveitis of any anatomic location (ie, anterior, intermediate, posterior, and panuveitis). Patients were allowed to be on systemic corticosteroids equivalent to up to 20 mg of oral prednisone per day, systemic immunomodulatory therapies with a stable dose in the past 2 weeks, or both.

Of 160 patients in the trial, 96 were randomized to 4.0 mg of suprachoroidal space triamcinolone acetonide (study arm) given at day 0 and week 12 and 62 had a sham procedure (control arm). Rescue therapy was allowed at any point in the study for patients who met the following criteria: a decrease of 10 or more ETDRS letters from baseline, a mean CST increase of 100 µm or greater or of 20% or greater and an increase in inflammation by 1.5 or more steps or any increase from 3+ or greater or 4+ based on the investigator’s clinical judgment.

At 24 weeks, 45 patients (46.9%) in the study arm and 10 patients (15.6%) in the control arm (P < .001) reached the primary outcome of an increase in BCVA of 15 or more ETDRS letters from baseline (P < .001). The mean CST was reduced by 153 µm from baseline in the study arm and by 8 µm in the control arm (P < .001). The change in BCVA and CST was significantly different between the arms at all follow-up visits from week 4. Rescue therapies were required in 13 patients (13.5%) in the study arm and 46 patients (72%) in the control arm. The median time to the use of rescue therapy was 89 days in the study arm and 36 days in the control arm (P < .001).

The IOP increased by 10 mm Hg or more from baseline in 11.5% of patients in the study arm and 15.6% in the control arm. Elevated IOP was observed primarily in the patients in the control arm who received rescue therapy with intravitreal or periocular steroid injections. The rates of cataract were low but comparable between the 2 arms of the study (7.3% and 6.3%, respectively). No serious adverse events occurred as a result of the intervention.

MAGNOLIA

The MAGNOLIA study (NCT02952001) was a noninterventional 24-week extension study that included 33 patients who completed the PEACHTREE phase 3 clinical trial without receiving rescue therapy. ²⁴ Of the 28 patients in the study who were treated with suprachoroidal space triamcinolone acetonide (study arm), 14 (50%) did not require rescue therapy through approximately 9 months after the second treatment. The primary outcome was the time from the last dose of study drug to rescue therapy, which was 257 days in the study arm and 55.5 days in the control arm (P < .001).

The mean number of ETDRS letters gained in the study arm decreased from 16.8 at entry in the study to 12.1 at week 48. The mean decrease in CST remained relatively stable, from 178.1 µm at study entry to 174.5 µm at week 48. Measures of inflammation, including anterior chamber cells, anterior chamber flare, and vitreous haze, were stable or improved between week 24 and week 48. In that period, 4 patients (14.3%) in the study arm had at least 1 incidence of elevated IOP of 10 mm Hg or greater compared with no patients in the control arm. Cataract-related treatment-emergent adverse events were reported in 7 patients (25%) in the study arm, 4 of which occurred between week 24 and week 48. Only 1 patient (20%) in the control arm had a cataract-related treatment-emergent adverse event during 48 weeks.

AZALEA

AZALEA (NCT03097315) was an open-label phase 3 clinical trial that evaluated the safety profile of suprachoroidal space triamcinolone acetonide in 38 patients with active or inactive noninfectious uveitis over 24 weeks. ²⁵ Only 4 patients (10.5%) required rescue therapy during the study. Seven patients (18.4%) had treatment-emergent adverse events related to the intervention. Six patients (15.8%) had an IOP increase from baseline of greater than 10 mm Hg and 2 patients (5.3%) had an IOP increase greater than 30 mm Hg. No serious adverse events were observed. Of 91 blood samples, 53 were quantifiable and had less than 1 ng/mL of triamcinolone acetonide. Additional findings included significant improvements in inflammation, VA, and the mean CST.

PEACHTREE Post Hoc Analysis: Suprachoroidal Space Triamcinolone Acetonide vs Rescue Therapies

A post hoc analysis of the phase 3 PEACHTREE clinical trial compared patients receiving suprachoroidal space triamcinolone acetonide (study arm) who did not require rescue therapy with control patients who did require rescue therapy. ²⁶ The median time to rescue was 84 days. For rescue therapy, 63% of patients received intravitreal steroids and 17.4% received periocular steroids. A greater reduction in the mean CST was seen in unrescued patients in the study arm than in rescued controls (174 µm and 148.5 µm, respectively; P = .04). Unrescued study patients trended toward better BCVA outcomes than rescued controls. The incidence of an IOP elevation of 30 mm Hg or greater was higher in the rescued control patients than in the unrescued study patients (10.9% and 4.9%, respectively), and a greater proportion of rescued controls required 1 or more IOP-lowering medications than unrescued study patients (13.0% and 7.2%, respectively).

PEACHTREE Post Hoc Analysis: Systemic Corticosteroids and Steroid-Sparing Therapy

Merrill et al ²⁷ performed a PEACHTREE post hoc analysis of patients with and without systemic corticosteroids or immunomodulatory therapy at baseline. Twenty-eight patients (29.2%) received suprachoroidal space triamcinolone acetonide (study arm), and 15 patients (23.4%) were on corticosteroids or immunomodulatory therapy (control arm). There was a trend toward more severe and chronic disease features in patients receiving systemic therapy; however, the proportion of patients who required rescue therapy was not significantly different between the study arm and control arm (14.7% and 10.7%, respectively). Patients in the study arm trended toward better BCVA and CST outcomes whether or not they were on systemic therapy. There was no meaningful difference in treatment-emergent adverse events or the incidence of IOP-related events in patients with or without systemic therapy at baseline.

Suprachoroidal Drug Delivery in Other Ophthalmic Diseases

Diabetic Macular Edema

The HULK study (NCT02949024) was an open-label phase 1/2 trial of patients with DME that compared the combination of suprachoroidal space triamcinolone acetonide and intravitreal aflibercept in 10 treatment-naïve eyes, defined as no DME treatment in the last year, with suprachoroidal injection of triamcinolone acetonide alone in 10 previously treated eyes (Table 2). ²⁸ After 6 months, the treatment-naïve eyes gained more ETDRS letters than the previously treated eyes (8.5 and 1.1, respectively). The CST was reduced by 91 µm in treatment-naïve eyes and by 128 µm in previously treated eyes. An IOP elevation of 10 mm Hg or more occurred in 2 previously treated eyes.

Table 2.

Randomized Clinical Trials of Suprachoroidal Drug Delivery in Chorioretinal Diseases.

Clinical Trial	Design	Inclusion	Cohort	Intervention	Primary Outcome	Additional Outcome(s)	Adverse Events
HULK (NCT02949024) [Completed]	Phase 1/2 Open-label	DME	Treatment naïve (n = 10)	1 dose 4.0 mg SC CLS-TA + 2.0 mg IVT aflibercept	+8.5 mean ETDRS letters from 0–6 mo	−91 μm mean CST at 0–6 mo; 331 μm mean CST at 6 mo	0 eyes w/ inc. IOP ≥10 mm Hg
			Previously treated (n = 10)	1 dose 4.0 mg SC CLS-TA	+1.1 mean ETDRS letters at 0–6 mo	−128 μm mean CST at 0–6 mo; 369 μm mean CST at 6 mo	2 eyes w/ inc. IOP ≥10 mm Hg
TYBEE (NCT03126786) [Completed]	Phase 2 Double-masked	DME	Active (n = 36)	2 doses 4.0 mg SC CLS-TA + 2 doses 2.0 mg IVT aflibercept	+11.4 mean ETDRS letters at 0–24 wk	−212.1 μm mean CST at 0–24 wk; 2.6 mean PRN IVT aflibercept in 24 wk	5 eyes w/ inc. IOP ≥10 mm Hg; 2 eyes w/ cataract AE
			Control (n = 35)	4 doses 2.0 mg IVT aflibercept	+13.8 mean ETDRS letters at 0–24 wk	−178.6 μm mean CST at 0–24 wk; 4.6 mean PRN IVT aflibercept in 24 wk	0 eyes w/ inc. IOP ≥10 mm Hg; 1 eye w/ cataract AE
TANZANITE (NCT02303184) [Completed]	Phase 2 Masked	ME due to RVO	Active (n = 23)	4.0 mg SC CLS-TA + 2.0 mg IVT aflibercept	9 mean PRN IVT aflibercept in 3 mo	+18.9 mean ETDRS letters at 0–3 mo; 84.1% eyes w/ resolved ME at 3 mo	2 eyes w/ inc. IOP’ 1 eye w/ cataract AE
			Control (n = 23)	2.0 mg IVT aflibercept	23 mean PRN IVT aflibercept in 3 mo	+11.3 mean ETDRS letters at 0–3 mo; 50.7% eyes w/ resolved ME at 3 mo	0 eyes w/ inc. IOP or cataract AE
SAPPHIRE (NCT02980874) [Terminated]	Phase 3 Triple-masked	ME due to RVO	Active (n = 231)	4.0 mg SC CLS-TA + 2.0 mg IVT aflibercept	49.4% eyes w/ ≥ +15 ETDRS letters in 2 mo	−354.3 μm mean CST at 0–6 mo	33 eyes w/ inc. IOP; 21 eyes w/ cataract AE
			Control (n = 229)	2.0 mg IVT aflibercept	55.5% eyes w/ ≥ +15 ETDRS letters in 2 mo	−416.2 μm mean CST at 0–6 mo	9 eyes w/ inc. IOP; 9 eyes w/ cataract AE
TOPAZ (NCT03203447) [Terminated]	Phase 3 Triple-masked	ME due to RVO	Active (n = 162)	4.0 mg SC CLS-TA + IVT Lucentis (0.5 mg) or Avastin (1.25 mg)	39.5% eyes w/ ≥ +15 ETDRS letters in 2 mo	−353.6 μm mean CST at 0–6 mo	11 eyes w/ inc. IOP
			Control (n = 163)	IVT Lucentis (0.5 mg) or Avastin (1.25 mg)	46.6% eyes w/ ≥ +15 ETDRS letters in 2 mo	−374.7 μm mean CST at 0–6 mo	1 eye w/ inc. IOP
ALTITUDE (NCT04567550) [Ongoing]	Phase 2 Open-label	DR w/out CI-DME	Cohorts 1–3 (n = 50)	SC RGX-314	20% eyes w/ ≥ 2-step DRSS improvement	54% eyes w/ any DRSS improvement	No drug-related SAE
			Control	Observation	10% eyes w/ ≥ 2-step DRSS improvement	20% eyes w/ any DRSS improvement
OASIS (NCT04626128) [Ongoing]	Phase 2/2 Open-label	nAMD	Cohorts 1–4 (n = 27)	1 dose of 0.03–1.0 mg SC CLS-AX	No SAE or TEAE	No dose limiting toxicities	No IOP related AE
			Cohorts 2–4 (n = 14)	3-month extension study		77%–85% reduction in treatment burden at 6 mo
AAVIATE (NCT04514653) [Ongoing]	Phase II Masked	nAMD	Cohorts 1–5 (n = 85)	2.5×1011 – 1×1012 genomic copies/eye SC RGX-314	Mean change in BCVA at 0–40 wk (Not reported)	85% reduction in treatment burden in 3rd dose level; 67% patients in Cohort 4 injection-free	No drug-related SAE
			Control (n = NR)	0.5 mg IVT ranibizumab monthly

Abbreviations: AE, adverse event; BCVA, best-corrected visual acuity; CI-DME, center-involving diabetic macular edema; CST, central subfield thickness; DME, diabetic macular edema; DR, diabetic retinopathy; DRSS, Diabetic Retinopathy Severity Scale; ETDRS, Early Treatment Diabetic Retinopathy Study; GC, genomic copy; inc., increased; IOP, intraocular pressure; IVT, intravitreal; ME, macular edema; N or n, number of eyes; nAMD, neovascular age-related macular degeneration; NR, not reported; PRN, as needed; RVO, retinal vein occlusion; SAE, serious adverse event; SC, suprachoroidal; TA, triamcinolone acetonide; TEAE, treatment-emergent adverse event.

A phase 2 clinical trial, TYBEE (NCT03126786), randomized 71 patients with DME to receive a combination of suprachoroidal injection of triamcinolone acetonide and intravitreal aflibercept or a sham suprachoroidal procedure with intravitreal aflibercept. ²⁹ Patients were then given as-needed treatment with intravitreal aflibercept. After 24 weeks, there was a greater reduction in the CST in the study arm than in the sham control arm in the per-protocol population (226.5 µm and 176.1 µm, respectively; P = .035). Patients who received the combination of suprachoroidal triamcinolone acetonide and intravitreal aflibercept ultimately required fewer additional treatments with intravitreal aflibercept than in the control patients who received aflibercept alone (2.6 and 4.6, respectively). These findings suggest the potential for reduced treatment requirement with intravitreal aflibercept when combined with suprachoroidal space triamcinolone acetonide. An increase in IOP of more than 10 mm Hg was reported in 5 patients in the study arm. No increase in IOP was reported in the control arm (P = .054).

Macular Edema Resulting From Retinal Vein Occlusion

TANZANITE (NCT02303184) was a phase 2 clinical trial that compared a suprachoroidal injection of triamcinolone acetonide with intravitreal aflibercept (study arm) against intravitreal aflibercept alone (control arm) in 46 patients with ME, defined as a CST of 300 µm or greater, resulting from RVO. ³⁰ Patients in the study arm required fewer additional treatments with intravitreal aflibercept than the control arm (P = .013). Resolution of ME, defined as a CST of 310 µm or less, was observed in 84.1% in the study arm and 50.7% in the control arm (P = .001).

Phase 3 clinical trials that targeted a primary endpoint of superiority included TOPAZ (NCT03203447), which evaluated suprachoroidal space triamcinolone acetonide with intravitreal antivascular endothelial growth factor (anti-VEGF) (eg, ranibizumab or bevacizumab) against a sham suprachoroidal procedure with intravitreal anti-VEGF, and SAPPHIRE (NCT02980874), which compared suprachoroidal space injection of triamcinolone acetonide with intravitreal aflibercept to intravitreal aflibercept alone in patients with RVO.^31,32 Early termination was elected for both studies because the primary endpoints were not met.

Age-Related Macular Degeneration

A suspension of axitinib, Clearside-axitinib (Clearside Biomedical, Inc), a tyrosine kinase inhibitor against VEGF receptors, showed a favorable pharmacokinetics profile in preclinical studies and has potential as a long-acting therapeutic candidate in AMD. ³³ The drug is being evaluated in patients with neovascular AMD (nAMD) in the OASIS study (NCT04626128), an ongoing 12-week phase 1/2 clinical trial. ³⁴ Patients received suprachoroidal axitinib suspension ranging from 0.03 to 1 mg after intravitreal anti-VEGF. Results of a 3-month extension study showed that 67% of patients who received 0.5 mg and 1 mg of suprachoroidal axitinib suspension did not require additional anti-VEGF treatment for 6 months. To date, no serious adverse events or treatment-emergent adverse events have been reported. ³⁵ A randomized controlled phase 2b study (ODYSSEY) has recently commenced in which axitinib suspension using suprachoroidal delivery will be compared with aflibercept as maintenance therapy in nAMD. ³⁶

Choroidal Melanoma

In addition to its use in retinal vascular and macular disease conditions, suprachoroidal drug delivery was recently assessed for the treatment of choroidal melanoma. Belzupacap sarotalocan is a virus-like drug conjugate that selectively binds choroidal melanoma cells and induces cell death on activation with near-infrared light.^37,38 At present, phase 1/2 (NCT03052127) and phase 2 (NCT04417530) clinical trials are evaluating suprachoroidal belzupacap sarotalocan in patients with small primary choroidal melanoma.^39,40 The most common adverse event from the phase 1 clinical trial was intraocular inflammation. ⁴¹ Interim results of the phase 2 clinical trial showed a significant reduction in the tumor growth rate after 3 cycles of therapy and 6 months of follow-up. ⁴²

Suprachoroidal Delivery of Gene Therapy

Suprachoroidal injection of adeno-associated vector 8 (AAV-8) has significant potential for retinal gene therapy and was shown to target the RPE and sclera in nonhuman primates. ⁴³ Suprachoroidal injection of RGX-314, an AAV-8 that encodes an anti-VEGF fragment antigen-binding region, is being evaluated in patients with nAMD in AAVIATE (NCT04514653), an ongoing 40-week phase 2 clinical trial. ⁴⁴ Interim results showed that patients who received the highest dose of RGX-314 (1 × 10¹² genomic copies per eye) had the greatest reduction in additional intravitreal anti-VEGF treatments. Ten patients (67%) receiving the highest dose of RGX-314 did not require additional treatment for 6 months. ⁴⁵

In addition to nAMD, gene therapy with RGX-314 is being studied in patients with diabetic retinopathy (DR) without center-involving ME in an ongoing 48-week phase 2 ALTITUDE clinical trial (NCT04567550). ⁴⁶ Thus far, no serious adverse events have been reported in 50 patients for 6 months. An improvement in the Diabetic Retinopathy Severity Score of 2 or more steps was observed in 20% of patients in the study arm and in 10% of patients in the observational control arm. ⁴⁷

Conclusions

Suprachoroidal drug delivery is selective for the choroid and retina and limits the exposure of anterior segment tissues to corticosteroids. This advantage is seen in the relatively low rates of elevated IOP and cataract in randomized clinical trials of patients with uveitic ME compared with the rate of corticosteroid-related adverse events that were reported in the literature for intravitreal injections. ⁷ Although further studies are needed to directly compare the safety and efficacy profiles of suprachoroidal drug delivery with those of other local therapies, a post hoc analysis of PEACHTREE also found that patients who received suprachoroidal space triamcinolone acetonide had lower rates of elevated IOP and need for IOP-lowering medication than patients requiring rescue therapy with mostly intravitreal injections.

Because of the favorable pharmacokinetic profile of suprachoroidally administered therapies, recent ongoing clinical trials are evaluating their use in other posterior segment diseases, such as nAMD and choroidal melanoma. Suprachoroidally administered gene therapy has also shown promising interim results in DR and nAMD. Ongoing training opportunities for this technique will be of benefit to vitreoretinal surgeons and uveitis specialists given the recent approval of suprachoroidal injection for noninfectious uveitis and other potential disease indications currently being studied.