Advancing ocular pharmacotherapy through the suprachoroidal space

(Image credit: ©YURII MASLAK/AdobeStock)

Suprachoroidal space (SCS) injection is an exciting method for the targeted delivery of therapies directly adjacent to affected chorioretinal tissues, potentially addressing several unmet needs in ophthalmology. A key site situated between the sclera and choroid, the SCS traverses the posterior segment of the eye, allowing the choroid, retinal pigment epithelium (RPE), and retina to be directly targeted, minimizing exposure to other tissues in the eye.¹

As pharmacological therapies continue to advance, traditional delivery routes, namely topical eye drops and intravitreal (IVT) injections, come with certain limitations for treating ophthalmic diseases, such as incomplete penetration or variable and unwanted diffusion to other parts of the eye.^1,2 Similarly, subretinal injections, an alternative to IVT injections, present challenges of their own as they are invasive surgical procedures that require pars plana vitrectomy and a small retinotomy.^3,4

In contrast, SCS injection is a minimally invasive procedure that can be performed in an office setting.^1,5 By potentially reducing treatment burden and improving patient adherence while facilitating direct drug delivery to the retina, choroid, and RPE, SCS drug delivery offers ophthalmologists and retina specialists a new route of administration for pharmacotherapeutics. The SCS is being explored as an attractive delivery site for many medications in development. SCS injections hold promise for the future delivery of agents, including steroids, gene therapy, and other small molecules.

Due to the anatomical barriers of the SCS and its location outside the blood-retinal barrier, another advantage of this route of administration is that the drug is compartmentalized and, therefore, may be less likely to elicit a systemic immune response compared with intravitreal delivery. This is an important consideration for certain therapies, such as adenovirus vector-based gene therapy, of which several are being investigated in ongoing clinical trials, as the route of vector delivery is a major determinant of host immune responses.^6-8 Additionally, compartmentalization of therapies in the SCS can potentially allow for long-acting delivery to these target tissues. However, additional factors, including particle size, may affect durability in the SCS. As such, further studies are warranted to establish the durability of different drugs in this space.^9,10

As the first therapy approved by the FDA delivered into the suprachoroidal space, triamcinolone acetonide injectable suspension (Xipere; Bausch + Lomb) has demonstrated a safety and efficacy profile via the SCS route. This treatment is a corticosteroid indicated for macular edema associated with uveitis.¹¹

The suspension delivered through the SCS offers several key advantages through its unique mechanical properties and anatomical location near the posterior segment of the eye. Using specialized microneedles, SCS administration can provide targeted and compartmentalized delivery to the choroid, RPE, and retina, thereby optimizing local drug bioavailability while minimizing the impact on anterior segment tissues and associated adverse effects.^1,2,12 Elevated IOP is one of the main concerns commonly observed with intraocular steroids.^2,3

Setting oneself up for success at SCS delivery

Although this approach could offer advantages to current intraocular injections, it still comes with certain considerations, including the time it takes to learn how to perform the technique. However, as the role and adoption of suprachoroidal injections continue to increase for the treatment of multiple ophthalmological conditions, ophthalmologists must learn how to perform SCS injections. In a survey of experienced physicians participating in SCS injection trials, 84% indicated that they did not perceive SCS injection to be
meaningfully more challenging than other ocular injections.¹³

In my clinic, I have been performing SCS injections since shortly after the 2021 approval of Xipere. I have employed this technique successfully to treat macular edema associated with noninfectious uveitis, including chronic postoperative inflammation. I have found the following guidelines helpful in simplifying the learning curve when first incorporating the SCS technique in the clinic.

First, because of the differences in the techniques for SCS injections compared with IVT injections, it is important to manage patient expectations and discuss the procedure before the injection. All patients should know that the injection will require careful positioning, may cause discomfort, and take a little more time than an IVT injection. It is important to highlight these differences, particularly if patients have experienced an IVT injection previously.²

When initially learning this technique, I recommend administering subconjunctival anesthesia so that patients do not feel discomfort while you establish your familiarity and preferences with the procedure. It is helpful to inject the subconjunctival anesthesia slightly away from the planned location of SCS injection and to inject only a small amount to minimize the risk of subconjunctival hemorrhage or conjunctival chemosis impacting visualization.²

For the first injection attempt, the superior temporal or inferotemporal quadrant is often successful for most patients using the 900-μm SCS Microinjector needle. However, alternative locations may be considered depending on ocular comorbidities and physician preference. Usingan eyelid speculum is important to provide adequate exposure.²

The injector should be held perpendicular to the sclera. Following insertion of the microneedle through the conjunctiva and into the sclera, apply firm and deliberate pressure against the eye’s surface to form a localized depression or dimple. Once loss of resistance is felt, while maintaining this dimple and perpendicular positioning, the second hand should slowly introduce the prescribed dose volume of the injectate over 5 to
10 seconds into the SCS. The slow injection pace allows the SCS to expand in a controlled manner and the injectate to flow posteriorly, helping to minimize reflux and patient discomfort.²

If the loss of resistance is not felt or there is an egress of the injectate seen on the ocular surface before the intended volume is injected, the needle is no longer in the SCS.⁷ In such situations, the needle should be reintroduced by perpendicularly applying firm and deliberate pressure to dimple the sclera, feeling a loss of resistance.²

Once the procedure has concluded, postinjection monitoring, such as checking IOP or visualizing perfusion of the optic nerve, should be performed, like other standard office post–intraocular injection protocols. Caregivers and patients should be informed of common adverse effects, such as subconjunctival hemorrhage.² Use of corticosteroids, such as Xipere, may produce cataracts, increased eye pressure, and glaucoma and may increase the likelihood of eye infections. Patients being treated with Xipere for extended periods will be monitored for problems with the body’s hormonal system, which controls the ability to respond to stress. In clinical studies, the most common eye-related adverse effects were increased eye pressure and eye pain. The most common non–eye-related adverse effect was headache.¹¹

Case study

I have encountered several difficult cases in my practice where treatment with Xipere significantly improved visual acuity and reduced macular edema. One that comes to mind is a patient with chronic postoperative inflammation and cystoid macular edema following cataract surgery who had received multiple intravitreal steroid (dexamethasone) injections, which were effective for approximately 2 months each time. These injections resulted in a mild elevation in IOP to 28 mm Hg due to steroid response requiring ongoing topical IOP-lowering therapy.

Xipere treatment resolved the macular edema and improved this patient’s best-corrected visual acuity. There was sustained resolution of macular edema at 6 months post Xipere, and the steroid IOP response was reduced in magnitude, allowing discontinuation of IOP-lowering eyedrops in this case. In addition, a follow-up fluorescein angiogram showed significant improvement in angiographic leakage following Xipere.

The clinical impact and durability of SCS injections with triamcinolone acetonide continue to be seen through real-world data with minimal IOP elevations—even in patients with a history of steroid response and those already on IOP-lowering medications.¹⁴ Recent data from the Intelligent Research in Sight (IRIS) Registry show the safety and durability of Xipere in clinical practice.^15,16 In this real-world study, nearly 88% of Xipere-treated eyes did not receive an injection or corticosteroid implant for rescue at week 24,¹⁵ and only 2% of Xipere-treated patients received a second SCS injection around week 12, demonstrating the durability of Xipere as a treatment option for macular edema associated with uveitis.¹⁶ Similarly, an IOP safety analysis found that only 14.2% of patients had an IOP elevation of 10 mm Hg or more at 48 weeks in real-world practice, despite more than 40% having a history of glaucoma and ocular hypertension, validating the IOP outcomes and safety data seen in controlled trials of Xipere.¹⁵

Suprachoroidal space delivery facilitates specific targeting and sequestration of therapies to the SCS, thereby potentially addressing some of the efficacy, safety, and treatment burden limitations of current retinal therapies.

Dilraj S. Grewal, MD,

is a Vitreoretinal Surgeon and Uveitis Specialist and a Tenured Associate Professor of Ophthalmology at the Duke University Department of Ophthalmology in North Carolina.

Disclosures: Consultant to Regeneron, Genentech/Roche, Astellas, EyePoint, ANI Pharmaceuticals, Apellis, Zeiss, and Bausch & Lomb

References

1. Chiang B, Jung JH, Prausnitz MR. The suprachoroidal space as a route of administration to the posterior segment of the eye. Adv Drug Deliv Rev. 2018;126:58-66. doi:10.1016/j.addr.2018.03.001

2. Wykoff CC, Avery RL, Barakat MR, et al. Suprachoroidal space injection technique: expert panel guidance. Retina. 2024;44(6):939-949. doi:10.1097/IAE.0000000000004087

3. Wu KY, Gao A, Giunta M, Tran SD. What’s new in ocular drug delivery: advances in suprachoroidal injection since 2023. Pharmaceuticals (Basel). 2024;17(8):1007. doi:10.3390/ph17081007

4. Naftali Ben Haim L, Moisseiev E. Drug delivery via the suprachoroidal space for the treatment of retinal diseases. Pharmaceutics. 2021;13(7):967. doi:10.3390/pharmaceutics13070967

5. Qin LG, Kasetty VM, Espinosa-Heidmann D, Marcus DM. Review of suprachoroidal delivery and its application in small molecule therapy. touchREVIEWS in Ophthalmology. 2023;17(2):4-8. doi:10.17925/USOR.2023.17.2.6

6. Yiu G, Chung SH, Mollhoff IN, et al. Suprachoroidal and subretinal injections of AAV using transscleral microneedles for retinal gene delivery in nonhuman primates. Mol Ther Methods Clin Dev. 2020;16:179-191. doi:10.1016/j.omtm.2020.01.002

7. 7. Hancock SE, Wan CR, Fisher NE, Andino RV, Ciulla TA. Biomechanics of suprachoroidal drug delivery: from benchtop to clinical investigation in ocular therapies. Expert Opin Drug Deliv. 2021;18(6):777-788. doi:10.1080/17425247.2021.1867532

8. Kansara V, Muya L, Wan CR, Ciulla TA. Suprachoroidal delivery of viral and nonviral gene therapy for retinal diseases. J Ocul Pharmacol Ther. 2020;36(6):384-392. doi:10.1089/jop.2019.0126

9. Muya L, Kansara V, Cavet ME, Ciulla T. Suprachoroidal injection of triamcinolone acetonide suspension: ocular pharmacokinetics and distribution in rabbits demonstrates high and durable levels in the chorioretina. J Ocul Pharmacol Ther. 2022;38(6):459-467. doi:10.1089/jop.2021.0090

10. Kansara VS, Muya LW, Ciulla TA. Evaluation of long-lasting potential of suprachoroidal axitinib suspension via ocular and systemic disposition in rabbits. Transl Vis Sci Technol. 2021;10(7):19. doi:10.1167/tvst.10.7.19

11. Xipere. Prescribing information. Bausch + Lomb Americas Inc.; 2021. Accessed March 14, 2025. https://pi.bauschhealth.com/globalassets/BHC/PI/XIPERE-PI.pdf

12. Ciulla T, Yeh S. Microinjection via the suprachoroidal space: a review of a novel mode of administration. Am J Manag Care. 2022;28(suppl 13):S243-S252. doi:10.37765/ajmc.2022.89270

13. Wan CR, Kapik B, Wykoff CC, et al. Clinical characterization of suprachoroidal injection procedure utilizing a microinjector across three retinal disorders. Transl Vis Sci Technol. 2020;9(11):27. doi:10.1167/tvst.9.11.27

14. Zhou A, Philip A, Babiker F, Chang PY. Efficacy of suprachoroidal triamcinolone acetonide for uveitic cystoid macular edema. Invest Ophthalmol Vis Sci. 2023;64(8):3561.

15. Singer M, Nair A, LaPrise A, et al. Durability of Suprachoroidal Injection of Triamcinolone Acetonide Injectable Suspension for Uveitic Macular Edema and Use of Rescue Therapy in Clinical Practice. Presented at: The Retina Society 57th Annual Scientific Meeting; September 11-15, 2024; Lisbon, Portugal. Accessed March 14, 2025. https://www.retinasociety.org/content/documents/retina-society-2024-lisbon-program-web.pdf

16. Singer M, Garcia KM, Brevetti TL, Borkar D, Nair A. Safety and durability of suprachoroidal injection of triamcinolone acetonide injectable suspension for uveitic macular edema (UME) in real-world clinical practice. Presented at: The Macula Society 47th Annual Meeting; February 7-10, 2024; Palm Springs, CA.