The suprachoroidal space is a potential space spanning from the limbus to the optic nerve, allowing for a depot reservoir where therapeutics can remain in close apposition to their intended target, ie the retina, photoreceptors, or retinal pigment epithelium (RPE), while avoiding exposure of the drug to anterior structures such as the lens, aqueous, and trabecular meshwork.¹ Pharmacokinetic studies have found that agents delivered into the suprachoroidal space diffuse circumferentially from the site of injection, potentially allowing for panretinal therapeutic effect.^2,3

In recent years, suprachoroidal delivery of ocular therapies has garnered interest and yielded advancements in a number of retinal diseases, owing to the tandem development of therapeutics engineered for suprachoroidal injection (ie, long-lasting corticosteroids⁴ and viral vectors⁵ with good penetration to the retina) and effective delivery devices for suprachoroidal access. Suprachoroidal injection of triamcinolone acetonide (Xipere, formerly known as CLS-TA; Clearside Biomedical), delivered via a novel transscleral microinjector, was the first suprachoroidal drug to receive FDA approval for the treatment of macular edema due to noninfectious uveitis, in 2021. Adoption of this delivery method for other indications, such as neovascular age-related macular degeneration (AMD),⁶ diabetic retinopathy (DR),⁷ and ocular melanoma,⁸ among others, is anticipated (Table 1). Gene therapy and cell-based therapy, delivered via suprachoroidal or suprachoroidal-to-subretinal cannulation, have also matured from preclinical investigation to human trials. In this article, we review the progress made thus far and the state of clinical trial testing for suprachoroidal therapies.

SUPRACHOROIDAL ACCESS VIA MICRONEEDLE INJECTION

Transscleral microneedle injection is the best studied modality for suprachoroidal drug delivery (Figure 1). To date, the SCS Microinjector (Clearside Biomedical) is the suprachoroidal device with the most experience in human studies. The injector incorporates a microneedle with a length of only 900 µm or 1,100 µm, calibrated to reproducibily access the suprachoroidal space without overpenetration.⁹ Thus far, the procedure has a well validated safety profile without major injection-related safety concerns, such as suprachoroidal hemorrhage, endophthalmitis, or retinal detachment following more than approximately 1,200 injections in clinical trials. With the FDA approval of CLS-TA, postmarket surveillance for drug-related and injection-related safety signals will continue as the therapy enters more widespread clinical use.

The injection technique shares similarities with standard intravitreal injection. In-office injection begins with sterilization of the ocular surface followed by insertion of the microneedle in the mid-quadrant of the globe. Pressure is applied to the plunger while the needle is pushed against the globe with enough force to dimple the scleral surface. When the needle tip enters the suprachoroidal space, the user will feel a loss of resistance in the plunger, allowing the plunger to readily advance and deliver the drug. If continued resistance is felt with the 900 µm needle, the longer 1,100 µm needle should then be used.

Small Molecules

The advantage of suprachoroidal injection is closer approximation of the drug depot to the posterior segment compared to periocular injection while reducing cataractogenesis and steroid response glaucoma.¹ CLS-TA is a formulation of triamcinolone acetonide with optimized pharmacokinetic properties for suprachoroidal administration.¹⁰ The phase 3 sham-controlled trial for macular edema secondary to non-infectious uveitis demonstrated the efficacy of CLS-TA, leading to FDA approval in October 2021.⁴ In the trial, 47% of patients receiving CLS-TA achieved an improvement in best corrected vision of at least 15 letters compared to 16% in the control arm.

Another small molecule that has been explored is axitinib (CLS-AX, Clearside Biomedical), a tyrosine kinase inhibitor (TKI) currently approved for renal cell carcinoma that exhibits pan-VEGF inhibition, with possible applications for neovascular AMD, DME, and other neovascular disorders. Suprachoroidal axitinib injection was well-tolerated in rabbit models, leading to quantifiable drug levels over the 91-day study period. Currently, the drug has entered phase 1/2a clinical testing for neovascular AMD.¹¹

Gene Therapy

Microneedle delivery of gene therapy has also progressed from preclinical to human trials. RGX-314, an AAV8 viral vector delivered anti-VEGF Fab transgene, has entered phase 2 clinical trials for neovascular AMD⁶ and DR.⁷ These have met with early success. The interim 3-month results of ALTITUDE for DR demonstrated ≥2-step improvement in DR severity score for 33% of patients in the treatment arm compared with 0% in the control arm. The interim 6-month AAVIATE results for neovascular AMD demonstrated approximately 75% reduction of anti-VEGF treatment burden with a mean of 1.2 injections over 6 months in cohort 1 treated at the 2.5x10¹¹ genome copies/eye dose level. If successful, these therapies may realize the promise of in-office, single-treatment gene therapy for common retinal diseases.

Viral nanoparticle conjugates (VNCs) have also been delivered into the SCS. One such agent is AU-011 (belzupacap sarotalacan; Aura Biosciences), a light-activated VNC modeled on the human papillomavirus, that binds to cells through a modified heparin sulfate proteoglycan moiety. In mouse animal models, injection of AU-011 followed by laser activation led to regression of implanted melanoma cells within the suprachoroidal space. AU-011 entered phase 2 clinical testing for early choroidal melanoma.⁸ The drug maintains approximately 5x higher concentrations at the site of the tumor when administered suprachoroidally as compared to intravitreal injection.¹²

Tunneled Suprachoroidal Catheter

Another modality for access of the suprachoroidal space is by introduction of a tunneled suprachoroidal catheter. The catheter runs within the potential space and can be directed to the posterior pole, allowing for more targeted treatment of the macula with gene or cell-based therapies. This technique requires an operative procedure, but unlike pars plana vitrectomy (PPV) with retinotomy creation, suprachoroidal catheterization avoids PPV-related complications such as cataract formation. A number of device iterations have been studied. The most recent Orbit Subretinal Delivery System (Orbit SDS; Gyroscope Therapeutics) features a catheter terminating in an extendable needle that advances from the tip of the catheter and penetrates through the choroid and RPE into the subretinal space, achieving suprachoroidal-to-subretinal injection. A localized conjunctival peritomy and scleral cutdown is performed approximately 5 mm posteriorly to the limbus, exposing the suprachoroidal space where the catheter is inserted. The catheter indents the internal retinal/choroidal surface along its path, enabling visualization with a standard vitrectomy widefield lens (contact or noncontact) and chandelier illumination. The needle at the catheter tip is deployed when the desired location has been reached.

The delivery modality may be suitable for gene therapy or cell therapy delivery. Regarding cell delivery, the suprachoroidal technique avoids retinotomy creation, which reduces the potential of reflux of cellular material into the vitreous space. This both avoids the potential for dose loss and minimizes concerns for epiretinal proliferation, which has been seen with PPV and retinotomy delivery of therapeutic cell suspensions.¹³

The technology was evaluated in phase 1/2 trials of human umbilical tissue–derived cells (palucorcel; Janssen Research and Development) of advanced AMD with geographic atrophy.^14,15 The phase 2b study met its primary safety endpoint and effectively delivered the full cellular dose (3.0x10⁵ cells in a 50 µL dosing volume) to the posterior pole in 18 of 21 subjects (86%).¹⁵ Treatment-related adverse events (AEs) occurred in 90% of participants, although all were mild and self-resolving. No specified AEs of interest were noted, including endophthalmitis, retinal detachment, serious subretinal or suprachoroidal hemorrhage, retinal perforation, cell egress, or need for unplanned vitrectomy. At the same time, no specific visual benefit was noted with palucorcel treatment.

The suprachoroidal-to-subretinal delivery system has also been employed in a phase 1/2a clinical trial of transplanted allogeneic RPE cells in advanced dry AMD (Opregen; Lineage Cell Therapeutics). Results of the study are forthcoming. Finally, suprachoroidal cannulation has been employed for GT005 subretinal gene therapy, an AAV viral vector expressing complement factor I, in phase 1/2 testing (Gyroscope Therapeutics) for geographic atrophy.^16,17 The delivery system was split between transvitreal delivery using traditional PPV/retinotomy and the Orbit SDS. Data from the initial cohorts (n=28 patients) demonstrated no dose-related trends in frequency/type of adverse events. There was no evidence of clinically significant drug-induced/immunogenic inflammation. A possible GT005-related event (n=1) was development of neovascular AMD treated with anti-VEGF injections. Eleven of 13 patients with biomarker data demonstrated increased levels of vitreous CFI expression.

CONCLUSION

Use of the suprachoroidal space for delivery of ocular therapies is now currently available, with several trials currently underway for various indications. Trial results and data from “real world” studies will continue to add the breadth of clinical experience utilizing suprachoroidal delivery. RP

Editor’s note: This article is part of a special edition of Retinal Physician that was supported by Bausch + Lomb.

REFERENCES

1. Wan CR, Muya L, Kansara V, Ciulla TA. Suprachoroidal delivery of small molecules, nanoparticles, gene and cell therapies for ocular diseases. Pharmaceutics. 2021;13(2):288. doi:10.3390/pharmaceutics13020288
2. Patel SR, Lin AS, Edelhauser HF, Prausnitz MR. Suprachoroidal drug delivery to the back of the eye using hollow microneedles. Pharm Res. 2011;28(1):166-176. doi:10.1007/s11095-010-0271-y
3. Patel SR, Berezovsky DE, McCarey BE, Zarnitsyn V, Edelhauser HF, Prausnitz MR. Targeted administration into the suprachoroidal space using a microneedle for drug delivery to the posterior segment of the eye. Invest Ophthalmol Vis Sci. 2012;53(8):4433-4441. doi:10.1167/iovs.12-9872
4. Yeh S, Khurana RN, Shah M, et al. Efficacy and safety of suprachoroidal CLS-TA for macular edema secondary to noninfectious uveitis: phase 3 randomized trial. Ophthalmology. 2020;127(7):948-955. doi:10.1016/j.ophtha.2020.01.006
5. Ding K, Shen J, Hafiz Z, et al. AAV8-vectored suprachoroidal gene transfer produces widespread ocular transgene expression. J Clin Invest. 2019;129(11):4901-4911. doi:10.1172/JCI129085
6. Regenxbio Inc. A phase 2, randomized, dose-escalation, ranibizumab-controlled study to evaluate the efficacy, safety, and tolerability of RGX-314 gene therapy delivered via one or two suprachoroidal space (SCS) injections in participants with neovascular age-related macular degeneration (nAMD) (AAVIATE). ClinicalTrials.gov identifier: NCT04514653. Updated April 7, 2022. Accessed May 26, 2022. https://clinicaltrials.gov/ct2/show/NCT04514653
7. Regenxbio Inc. A phase 2, randomized, dose-escalation, observation-controlled study to evaluate the efficacy, safety, and tolerability of RGX-314 gene therapy delivered via one or two suprachoroidal space (SCS) injections in participants with diabetic retinopathy (DR) without center involved-diabetic macular edema (CI-DME) (ALTITUDE). ClinicalTrials.gov identifier: NCT04567550. Updated March 29, 2022. Accessed May 26, 2022. https://clinicaltrials.gov/ct2/show/NCT04567550
8. Aura Biosciences. A phase 2 trial of AU-011 via suprachoroidal administration with a dose escalation phase (open-label, ascending single and repeat dose) and a randomized, masked dose expansion phase designed to evaluate the safety and efficacy of AU-011 in subjects with primary indeterminate lesions and small choroidal melanoma. ClinicalTrials.gov identifier: NCT04417530. Updated April 5, 2022. Accessed May 26, 2022. https://clinicaltrials.gov/ct2/show/NCT04417530
9. 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
10. 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
11. Clearside Biomedical. Safety and tolerability study of suprachoroidal injection of CLS-AX following anti-VEGF therapy in neovascular AMD (OASIS). ClinicalTrials.gov identifier: NCT04626128. Updated May 10, 2022. Accessed May 26, 2022. https://clinicaltrials.gov/ct2/show/NCT04626128
12. Savinainen A, Grossniklaus HE, King S, et al. Ocular distribution and exposure of AU-011 after suprachoroidal or intravitreal administration in an orthotopic rabbit model of human uveal melanoma. Invest Ophthalmol Vis Sci. 2021;62:2861.
13. Spencer R, Fisher S, Lewis GP, Malone T. Epiretinal membrane in a subject after transvitreal delivery of palucorcel (CNTO 2476). Clin Ophthalmol. 2017;11:1797-1803. doi:10.2147/OPTH.S140218
14. Ho AC, Chang TS, Samuel M, Williamson P, Willenbucher RF, Malone T. Experience with a subretinal cell-based therapy in patients with geographic atrophy secondary to age-related macular degeneration. Am J Ophthalmol. 2017;179:67-80. doi:10.1016/j.ajo.2017.04.006
15. Heier JS, Ho AC, Samuel MA, et al. Safety and efficacy of subretinally administered palucorcel for geographic atrophy of age-related macular degeneration: phase 2b study. Ophthalmol Retina. 2020;4(4):384-393. doi:10.1016/j.oret.2019.11.011
16. Gyroscope Therapeutics. FocuS: first in human study to evaluate the safety and efficacy of GT005 administered in subjects with dry AMD. ClinicalTrials.gov identifier: NCT03846193. Updated December 22, 2021. Accessed May 26, 2022. https://clinicaltrials.gov/ct2/show/NCT03846193
17. Gyroscope Therapeutics. EXPLORE: a phase II, outcomes assessor-masked, multicentre, randomised study to evaluate the safety and efficacy of two doses of GT005 administered as a single subretinal injection in subjects with geographic atrophy secondary to age-related macular degeneration. ClinicalTrials.gov identifier: NCT04437368. Updated December 2, 2021. Accessed May 26, 2022. https://clinicaltrials.gov/ct2/show/NCT04437368