Ophthalmology has witnessed a revolutionary advancement in drug delivery with the emergence of suprachoroidal administration as a clinically viable therapeutic platform. The 2021 US Food and Drug Administration (FDA) approval of Xipere (triamcinolone acetonide injectable suspension; Clearside Biomedical) for suprachoroidal use in treating uveitic macular edema marked a historic milestone, representing the first approved therapy delivered via the suprachoroidal space (SCS).
Traditional approaches to ocular drug delivery, including systemic administration and topical application, each present distinct limitations. Systemic therapy often results in inadequate ocular penetration and systemic side effects, whereas topical medications struggle to reach posterior-segment tissues effectively. Although intravitreal injection has become the gold standard for retinal diseases, it may expose anterior-segment structures to unintended drug effects. The suprachoroidal approach represents a paradigm shift by offering targeted delivery to chorioretinal tissues while minimizing exposure to unaffected ocular structures; for small molecule suspensions, there is potential for sustained delivery.
Anatomic Foundation and Biomechanics
The suprachoroidal space is a potential space located between the choroid and sclera that extends circumferentially from the scleral spur posteriorly. Under normal physiologic conditions, this space remains collapsed due to the natural pressure differential between intraocular pressure and suprachoroidal space pressure, which also drives uveoscleral outflow.1 When accessed therapeutically, the SCS can expand to accommodate injectate, creating a unique drug reservoir adjacent to target tissues.
Figure 1. Catheter-based injection into the suprachoroidal space, using the iTrack microcatheter system. Reproduced from Kicińska AK, Rękas M. Expert Opin Drug Deliv. 2023;20(9):1201-1208. Licensed for reuse under CC BY 4.0.
The biomechanics of suprachoroidal drug delivery are governed by several key principles that contribute to its therapeutic advantages.2,3 Following suprachoroidal injection, a natural pressure gradient drives injectates posteriorly toward the macula, because intraocular pressure exceeds anterior SCS pressure, which in turn exceeds posterior SCS pressure.1 This directional flow facilitates targeted delivery to macular tissues, making the approach particularly relevant for treating macular disorders.
Drug durability within the SCS is influenced by multiple factors, with particle size playing a crucial role.4 Particles ranging from gene therapy viral vectors (approximately 25 nm) to small molecule suspensions (several microns) can remain in the suprachoroidal space and choroid for months. This extended residence time is partly attributed to the physiologic upper limit of pore size in the fenestrated choriocapillaris, estimated between 6 and 12 nm, which limits transcapillary passage of larger macro-molecules and particles.5
For small molecule suspensions, relative insolubility contributes significantly to durability.6,7 Preclinical studies have demonstrated that suprachoroidal administration achieves durable high levels of drug in targeted retina, retinal pigment epithelium, and choroid while limiting exposure to anterior chamber structures, including the iris, ciliary body, and lens.8,9 This compartmentalization effect maximizes therapeutic efficacy while minimizing adverse effects associated with anterior-segment exposure.
The clinical implementation of suprachoroidal drug delivery has been enabled by the development of diverse technological platforms, broadly categorized into catheter-based and microneedle-based systems. These innovative delivery approaches allow for outpatient administration under local anesthesia, significantly enhancing both patient and provider convenience while expanding access to advanced ocular therapeutics.
Catheter-Based Delivery Systems
Catheter-based systems represent sophisticated approaches to suprachoroidal drug delivery, typically involving manual insertion of a catheter through a scleral incision with posterior advancement to the target site. The foundational technology in this category was the iTrack 250A microcatheter, developed by iScience Interventional and connected to the iLumin laser diode–based microillumination system.10 This pioneering device demonstrated the feasibility of delivering therapeutic agents to the suprachoroidal space and played a crucial role in early gene therapy validation studies (Figure 1).
Oxular Limited, headquartered in the United Kingdom, developed the Oxulumis, a significant advancement in catheter-based suprachoroidal delivery. This semiautomated, minimally invasive device operates through pars plana site administration using an illuminated flexible microcatheter. The illumination feature provides real-time visual confirmation of precise microcatheter placement, enhancing procedural accuracy and safety. Early clinical trials have evaluated the Oxulumis system for delivering OXU-001, a specialized dexamethasone formulation delivered to the posterior suprachoroidal space using biodegradable Oxuspheres. In clinical trials, OXU-001 is being assessed as a long-duration treatment for diabetic macular edema.11 In late 2024, Regeneron Pharmaceuticals acquired Oxular Limited.12 This strategic acquisition highlights the growing recognition of suprachoroidal delivery technology’s potential.
The Everads Therapy system, developed by an Israeli company, employs a distinctly different approach, using a proprietary geometrically optimized nonsharp tissue separator to create a pathway into the SCS.13 This innovative design allows for tangential injection, which may facilitate more rapid distribution throughout the suprachoroidal space. Successful preclinical validation in nonhuman primates has demonstrated the system’s potential, leading to a strategic partnership with Kriya announced in September 2023 for ocular gene therapy development using the Everads delivery technology.14
The first-in-human clinical results for the Everads Injector were recently reported at the 2025 ARVO Annual Meeting.15 This study evaluated 6 diabetic macular edema (DME) patients who were unresponsive to standard intravitreal treatments. Each patient received a single 4 mg triamcinolone acetonide injection using the Everads Injector under topical anesthesia in an office setting. The study demonstrated successful suprachoroidal delivery in all patients, confirmed by real-time thermal imaging showing immediate posterior flow.
Developed by Gyroscope Therapeutics/Novartis, the Orbit Subretinal Delivery System (Orbit SDS) represents a hybrid approach for suprachoroidal-to-subretinal injection. This system circumvents the need for complex pars plana vitrectomy procedures while avoiding iatrogenic risks associated with retinotomy and subretinal bleb formation. The device features a catheter with an extendable needle capable of penetrating the choroid and retinal pigment epithelium to achieve targeted subretinal delivery. The procedure requires localized conjunctival peritomy and scleral cut-down in an operating room setting, with visualization aided by standard vitrectomy equipment including widefield lenses and chandelier illumination.
Clinical validation of the Orbit SDS has been encouraging, with phase 1/2 trials demonstrating successful delivery of human umbilical tissue–derived cells (Palucorcel; Janssen) for advanced AMD treatment.16 The technology achieved its safety endpoints, delivering full cellular doses in 86% of subjects with only mild, self-resolving adverse events. The system has also been evaluated for allogeneic RPE cell delivery in advanced dry AMD and GT005 subretinal gene therapy for geographic atrophy.
Figure 2. Microneedle injection into the suprachoroidal space (SCS), illustrating anterior-to-posterior fluid flow in the SCS. From Wan C-R, Muya L,Kansara V, Ciulla TA. Pharmaceutics. 2021;13:288. Licensed for reuse under CC BY 4.0.
Microneedle-Based Delivery Systems
Microneedle systems represent a more streamlined approach to suprachoroidal access, designed with precise length specifications approximating scleral thickness to facilitate drug delivery without penetrating the retina or vitreous (Figure 2). These systems leverage the natural pressure gradient where intraocular pressure exceeds anterior SCS pressure, which in turn exceeds posterior SCS pressure, driving anteriorly injected fluids posteriorly toward target tissues.1
The Bella-vue silicon microneedle system, developed by Uneedle in the Netherlands, comprises an ultrashort-bevel ocular needle specifically designed to facilitate easy-to-perform suprachoroidal injections. These needles allow for perpendicular suprachoroidal injection. The technological innovation of the Bella-vue system lies in its proprietary silicon manufacturing process that overcomes the inherent trade-off between sharpness and bevel length found in conventional steel needles. Uneedle’s technology leverages the crystal planes of silicon to define needle shape through established semiconductor etching processes, eliminating the need for grinding or polishing.17 The short microneedle is fully inserted into the eye until the hub touches the surface of the sclera, after which fluid is injected at a controlled depth. Preclinical studies across multiple animal models, including rabbits, pigs, and nonhuman primates, have demonstrated the system’s ability to safely and effectively deliver therapeutic compounds to the SCS. The technology platform shows promise for collaboration with pharmaceutical partners developing therapies targeting retinal diseases.
The SCS Microinjector (Clearside Biomedical) represents the most extensively studied and clinically validated suprachoroidal delivery platform.18 This sophisticated system uses precision-engineered microneedles of 900 μm or 1,100 μm length to accommodate anatomic variations in patient scleral thickness. The device incorporates a custom-designed hub with gasket-like sealing properties to minimize reflux during injection, ensuring efficient drug delivery. The injection procedure is performed perpendicularly to the sclera at the pars plana under local anesthesia in an office-based setting. The technique involves recognizing initial resistance as the naturally collapsed SCS is accessed, followed by characteristic loss of resistance as the space expands to accommodate the injectate.18 If continued resistance is encountered during the procedure, clinicians can transition to the longer needle for additional depth access.
Clinical validation of the SCS Microinjector has been comprehensive across multiple retinal disorders.18 The safety profile of the SCS Microinjector is comparable to intravitreal injections, with extensive clinical trial data demonstrating no serious adverse events involving lens injury, suprachoroidal hemorrhage, endophthalmitis, or retinal tear across 8 major clinical trials.18 Animal studies have shown sustained drug levels in retina and choroid following SCS injection, with minimal systemic exposure.7
Clinical Evidence and Therapeutic Applications
The clinical validation of suprachoroidal drug delivery was established through comprehensive trials of CLS-TA for uveitic macular edema. The pivotal PEACHTREE trial demonstrated that 47% of subjects receiving 2 CLS-TA injections gained at least 15 ETDRS letters at 24 weeks, compared to only 16% in the sham control group (P<.001).19 Importantly, elevated intraocular pressure events occurred in only 11.5% of CLS-TA patients compared to 16% of controls. The MAGNOLIA extension study demonstrated durability, with 50% of patients avoiding rescue therapy for up to 36 weeks following their second injection.20
Real-world data reveal that patients with neovascular AMD receive fewer anti-VEGF injections than is optimal, creating a need for longer-acting alternatives.20 Suprachoroidal delivery provides opportunities for small molecule suspensions with sustained drug-release kinetics.
CLS-AX (axitinib injectable suspension; Clearside Biomedical) represents a paradigm shift toward semiannual therapeutic options for neovascular AMD. Axitinib is a highly potent tyrosine kinase inhibitor targeting VEGF receptors VEGFR-1, VEGFR-2, and VEGFR-3 at picomolar concentrations.22-24 Preclinical studies showed 11-fold higher mean exposure in the posterior eye cup compared to intravitreal injection.7
The ODYSSEY phase 2b trial randomized 60 participants 2:1 to receive CLS-AX (1 mg) or aflibercept 2 mg (Eylea; Regeneron). CLS-AX demonstrated compelling intervention-free rates: 100% at 3 months, 90% at 4 months, 81% at 5 months, and 67% at 6 months, with 84% reduction in injection frequency.25 Following successful ODYSSEY results, Clearside announced positive FDA end-of-phase 2 meeting outcomes in March 2025, confirming alignment on 2 concurrent phase 3 noninferiority trials (225 participants per arm) comparing CLS-AX to aflibercept.26
Gene Therapy Applications
ABBV-RGX-314, developed by Regenxbio and AbbVie, uses AAV8 vector delivery of an anti-VEGF Fab. The therapy is being developed via both subretinal and suprachoroidal routes, with pivotal subretinal data expected in 2026.27
The AAVIATE phase 2 trial investigating suprachoroidal delivery of the gene therapy demonstrated promising results across 106 neovascular AMD patients with no drug-related serious adverse events. At the third dose level, patients achieved 80% reduction in annualized injection rates and 50% injection-free rates for 6 months following a single injection. In cohort 6, prophylactic topical steroids eliminated intraocular inflammation while maintaining therapeutic benefits.28
The ALTITUDE trial showed encouraging efficacy in diabetic retinopathy, with ABBV-RGX-314 being well tolerated from dose levels 1 and 2 (cohorts 1-3) with no drug-related serious adverse events. At 1 year, dose level 2 prevented disease progression and reduced vision-threatening events in nonproliferative diabetic retinopathy patients, with 70.8% of patients achieving Diabetic Retinopathy Severity Scale (DRSS) improvement vs 25.0% in control and 0% of patients worsening ≥2 steps vs 37.5% in control.27 Based on these promising phase 2 results, in January 2025 AbbVie and Regenxbio announced plans for phase 3 suprachoroidal ABBV-RGX-314 development in diabetic retinopathy.
Precision Oncologic Therapy
Belzupacap sarotalocan (bel-sar; Aura Biosciences) is a light-activated virus-like drug conjugate that binds selectively to cancer cells and induces targeted necrosis upon infrared laser activation. Phase 2 results with early stage choroidal melanoma demonstrated an 80% tumor control rate with complete growth cessation and 90% visual acuity preservation in the phase 3–eligible patient subset.29 The safety profile was exceptional, with no treatment-related serious adverse events and only mild ocular inflammation that resolved with topical steroids.29 The global phase 3 CoMpass trial is currently enrolling patients for first-line treatment of small choroidal melanoma and indeterminate lesions.30
Future Directions and Clinical Impact
The approval of Xipere has established suprachoroidal drug delivery as a clinically validated platform with broad therapeutic potential. Current development pipelines include multiple therapeutic modalities spanning small molecule suspensions, gene therapies, and specialized drug conjugates for diverse posterior-segment conditions. The versatility of the platform is evidenced by ongoing trials evaluating treatments for neovascular AMD, diabetic retinopathy, uveitis, and choroidal melanoma.
Technological advances continue to refine delivery systems and expand applications. Expert panel guidelines have been developed to standardize injection techniques, promoting widespread adoption and optimal patient outcomes.31 The ability to provide office-based administration of gene therapies could democratize access to advanced treatments that currently require specialized surgical centers.
The economic implications of suprachoroidal delivery are substantial, particularly for chronic conditions requiring frequent injections. Extended durability profiles could significantly reduce treatment burden, health care costs, and patient inconvenience while potentially improving long-term outcomes through enhanced treatment compliance.
Conclusion
Suprachoroidal drug delivery represents a meaningful advancement in ocular therapeutics, offering targeted delivery to affected chorioretinal tissues while minimizing exposure to unaffected structures. The clinical validation achieved through Xipere approval has paved the way for a new generation of therapies that leverage the unique anatomic and pharmacokinetic advantages of the suprachoroidal space.
The biomechanical principles underlying suprachoroidal delivery, including directed posterior flow, solubility-dependent and particle size–dependent retention, and compartmentalization effects, create a unique environment for sustained therapeutic action. As the field continues to evolve with advancing delivery technologies and expanding therapeutic applications, suprachoroidal drug delivery is poised to address significant unmet needs across the spectrum of posterior-segment diseases. RP
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