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Retinal Physician

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Flow Mechanics of Suprachoroidal Injection

A compartmentalized delivery route facilitates more targeted retinal drug delivery.

By: VENKATKRISH M. KASETTY, MD, Luke G. Qin, Diego Espinosa-Heidmann, MD, Dennis M. Marcus, MD
Retinal Physician August 1, 2022 Vol 19, Issue Special Edition 2022 Page(s): 19-23

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Multiple drug-delivery routes exist for retinal therapy (Figure 1). Intravitreal drug delivery is the most common route used. It is the established route of anti-vascular endothelial growth factor (anti-VEGF) therapy as the first-line therapy for neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), and macular edema (ME) secondary to retinal vein occlusion (RVO). Intravitreal drug delivery has been easily adopted by retina specialists due to its proven safety, efficacy, and ease of office-based administration.

Figure 1. Retinal drug delivery routes.
Figure 1. Retinal drug delivery routes.

The suprachoroidal space (SCS) has recently been investigated for retinal drug delivery. It is a potential space defined as the area between the choroid and overlying sclera, approximately 35 μm thick. Similar to intravitreal injections, suprachoroidal injections are performed in the office setting with the benefits of direct delivery to the retina, choroid, and retinal pigment epithelium (RPE) without having to penetrate the internal limiting membrane (ILM) as well as limiting anterior-segment drug delivery and related side effects.1

CHALLENGES WITH INTRAVITREAL INJECTIONS

Although anti-VEGF intravitreal injections have greatly improved outcomes for patients with DME, nAMD, and RVO, the frequency of injections and treatment burden remains a challenge to optimize real-world outcomes.2-4 In addition, the Diabetic Retinopathy Clinical Research (DRCR) Network Protocol W and the PANORAMA study confirmed the role of intravitreal aflibercept in the reduction of vision-threatening consequences and in improving diabetic retinopathy (DR) severity in eyes with severe nonproliferative diabetic retinopathy (sNPDR) without DME.5,6 As a significant number of anti-VEGF injections for DR eyes without DME are required, the retina community has not readily adopted anti-VEGF treatment in these sNPDR eyes without DME that may be otherwise observed with close follow-up. Intravitreal steroids are currently used as treatment for noninfectious ocular inflammation, and as a second-line therapy for DME and ME secondary to RVO.7-10 However, side effects include intraocular pressure elevation, especially in “steroid responder” eyes, as well as increased rates of cataract formation.10 Although intravitreal retinal drug delivery has been generally proven a safe, effective, and easily utilized mode of therapy, anti-VEGF treatment burden and anterior-segment side effects remain drawbacks in optimizing visual outcomes.3,11 In addition, patient noncompliance, especially among patients with diabetes, limits real-world outcomes.

Therefore, the dogma for improving retinal pharmacotherapy has long been recognized as the need for longer acting, more durable anti-VEGF therapy. Faricimab (Vabysmo; Genentech) and the Port Delivery System with ranibizumab (Susvimo; Genentech) are intravitreal therapies recently approved by the FDA that demonstrated decreased injection burden for nAMD and DME eyes.12-15 Intravitreal injections of gene therapy with an anti-VEGF transgene product (Adverum Biotechnologies) have shown promise in reducing treatment burden in early trials in nAMD and DME, but there was a significant inflammatory response in the DME population in the OPTIC and INFINITY trials. Alternative delivery methods, such as subretinal and suprachoroidal drug delivery, have the potential to be longer acting routes resulting in a decreased injection burden, while also limiting anterior segment side effects as well as gene therapy–induced inflammation.

SUBRETINAL DRUG DELIVERY

Retinal gene therapy for retinal degeneration and retinal vascular disease is an exciting, potentially durable approach. Subretinal delivery has been the most evaluated route for retinal gene therapy delivery. Here, viral vectors are directly delivered to the subretinal space, targeting treatment to the RPE and outer retina. This space is immune-privileged and therefore immune reactions to the injectate are potentially limited. However, compared to other delivery methods, this method is invasive and requires a vitrectomy for administration, posing a significant barrier to administration as well as increased risks for the patient. Additionally, the injectate does not spread within the subretinal space and is typically localized to the area around the injection site.16

Voretigene neparvovec-rzyl (Luxturna; Spark Therapeutics) is the first FDA-approved gene therapy for RPE65-associated inherited retinal dystrophy.17 The therapy is an RPE65 gene-containing adeno-associated virus (AAV) vector that has demonstrated improvements in navigation, light sensitivity, and visual fields with a good safety profile over 3 to 4 years.18 Gene therapy is also being studied for DR and AMD patients with the aim of providing an endogenous supply of anti-VEGF. This has the potential to be the next frontier in retinal therapy as a “one and done” approach for these conditions. Early clinical data using subretinal adenoviral vector anti-VEGF gene therapy (Regenxbio) indicate a significant reduction in treatment burden and encouraging safety profile in nAMD eyes previously treated with intravitreal anti-VEGF drugs.19

SUPRACHOROIDAL DRUG DELIVERY

Suprachoroidal delivery represents a promising minimally invasive route of a potentially durable treatment, avoiding the invasiveness of vitrectomy needed for subretinal delivery or Port Delivery System insertion. In addition to providing direct targeted therapy to the retina and choroid, suprachoroidal delivery avoids barriers such as the ILM and the creation of floaters in visual axis encountered in intravitreal drug administration. The SCS can be accessed by catheters, needles, and microneedles. Microneedle (SCS Microinjector; Clearside Biomedical) delivery allows for in-office delivery to the SCS with more control than hypodermic needles.16 The advantages of suprachoroidal delivery include the potential to provide a higher bioavailability to a large surface area of the diseased retina and choroid when compared to intravitreal injections.16,20 While systemic absorption through the SCS delivery is unknown, it is likely to be limited because this injection method compartmentalizes the drug in the SCS, preventing unnecessary exposure to the anterior segment.16,21 It is also less likely to cause a systemic immune response compared to intravitreal delivery.22 In the INFINITY trial, the intravitreal injection of ADVM-022 vector (encoding for anti-VEGF) was therapeutically effective, but also resulted in significant intraocular inflammation and hypotony in DME patients who were given a high genomic load. This led to study termination to determine the etiology of this inflammation.23,24

FLOW DYNAMICS OF SUPRACHOROIDAL INJECTIONS

Lampen et al evaluated the anatomic changes to the SCS after the suprachoroidal injection of triamcinolone acetonide (CLS-TA) for diabetic macular edema (phase 1/2 HULK study). They found immediate but transient SCS opening following injections with no significant short-term changes seen in the SCS after injection when compared to the SCS of fellow eyes (Figure 2).25 However, the TANZANITE trial demonstrated significant short-term SCS expansion after suprachoroidal CLS-TA for macular edema secondary to retinal vein occlusion.26 Therefore, data on long-term anatomic and physiologic changes to the SCS after drug delivery remain preliminary and speculative.

Figure 2. Anterior-segment optical coherence tomography demonstrating spread of suprachoroidal injection of triamcinolone acetonide within the suprachoroidal space 30 minutes after suprachoroidal injection.25 Image courtesy of Clearside Biomedical, Inc
Figure 2. Anterior-segment optical coherence tomography demonstrating spread of suprachoroidal injection of triamcinolone acetonide within the suprachoroidal space 30 minutes after suprachoroidal injection.25 Image courtesy of Clearside Biomedical, Inc

The flow dynamics of suprachoroidal delivery in ex vivo porcine eyes using multimodal imaging demonstrate that immediately after an SCS injection, the injectate quickly spread posteriorly from the scleral spur to the macula (Figure 3A) compared to a localization of the injectate bolus within the vitreous (Figure 3B). Therefore, immediately after SCS delivery, the same injectate is exposed to a greater surface area of retinal tissue compared to that from an intravitreal injection. Over time, the injectate also demonstrates a posterior and circumferential spread within the SCS (Figure 4). Endoscopic visualization of the injectate demonstrated similar posterior and circumferential spread within the SCS (Figure 5). These novel imaging modalities emphasize the potential benefits of suprachoroidal therapy — a targeted delivery to affected chorioretinal tissues, compartmentalization away from unaffected tissues for safety, and superior bioavailability when compared to intravitreal injections.27 Clinical applications of suprachoroidal delivery of RGX-314 in a DR eye from the ALTITUDE trial (Video 1) supports these preclinical findings.

Figure 3. Distribution of dye injectate in ex vivo porcine eyes immediately frozen after (A) suprachoroidal injection and (B) intravitreal injection. Image courtesy of Clearside Biomedical, Inc
Figure 3. Distribution of dye injectate in ex vivo porcine eyes immediately frozen after (A) suprachoroidal injection and (B) intravitreal injection. Image courtesy of Clearside Biomedical, Inc
Figure 4. Injection of fluorescing dye under ultraviolet light within the suprachoroidal space in an ex vivo porcine eye demonstrates posterior and circumferential spread. Image courtesy of Clearside Biomedical, Inc
Figure 4. Injection of fluorescing dye under ultraviolet light within the suprachoroidal space in an ex vivo porcine eye demonstrates posterior and circumferential spread. Image courtesy of Clearside Biomedical, Inc
Figure 5. Endoscopic visualization of suprachoroidal injection showing (A) deformation as injectate is started and (B) continued suprachoroidal space expansion as injectate delivered with the black arrows demonstrating inherent boundary of suprachoroidal space. Adapted from Marcus D. Comparison of suprachoroidal and intravitreal injection flow mechanics analyzed via multimodal imaging. Presented at The Retina Society Annual Meeting, 2021. Image courtesy of Clearside Biomedical, Inc
Figure 5. Endoscopic visualization of suprachoroidal injection showing (A) deformation as injectate is started and (B) continued suprachoroidal space expansion as injectate delivered with the black arrows demonstrating inherent boundary of suprachoroidal space. Adapted from Marcus D. Comparison of suprachoroidal and intravitreal injection flow mechanics analyzed via multimodal imaging. Presented at The Retina Society Annual Meeting, 2021. Image courtesy of Clearside Biomedical, Inc

Video 1. In this video, Dennis Marcus, MD, administers suprachoroidal RGX-314 in a patient with diabetic retinopathy as part of the ALTITUDE trial.

 

SUPRACHOROIDAL STEROID DELIVERY

Suprachoroidal steroid delivery proves to be an interesting alternative to intravitreal steroids. Xipere (Clearside Biomedical), a suprachoroidal triamcinolone acetonide formulation (CLS-TA), has recently been approved for macular edema (ME) secondary to noninfectious uveitis (NIU).28 The PEACHTREE trial demonstrated that CLS-TA resulted in significant improvements in best corrected visual acuity (BCVA) without increased rates of cataract formation or elevated intraocular pressure in ME secondary to NIU.29 The MAGNOLIA trial demonstrated that 50% of patients treated with CLS-TA for ME secondary to NIU did not require rescue medication for up to 9 months after treatment.30 Additionally, the TYBEE study demonstrated similar visual acuity results with a modest anatomic benefit and reduced treatment burden at 24 months in DME eyes treated with suprachoroidal CLS-TA and intravitreal aflibercept when compared to intravitreal aflibercept monotherapy.31 Tayyab et al further demonstrated that CLS-TA results in statistically significant short-term improvements in BCVA and central subfield thickness in treatment-resistant DME.32

SUPRACHOROIDAL GENE DELIVERY

The SCS is a unique target for gene therapy due to its immune privilege.16 Multiple clinical trials are under way evaluating suprachoroidal delivery of anti-VEGF gene therapy for both DR without DME and nAMD. Six-month phase 2 ALTITUDE trial data evaluating suprachoroidal RGX-314, an AAV8 vector with an anti-VEGF encoding gene, for DR without CI-DME demonstrated exceptional DRSS improvement rates (Figure 6), which were comparable to the improvements seen in severe NPDR eyes in the RIDE/RISE and PANORAMA trials.5,33,34 Importantly, no steroid prophylaxis was administered. Early phase 2 data for suprachoroidal RGX-314 for nAMD in the AAVIATE trial demonstrated promise as well compared to ranibizumab (Lucentis; Genentech) alone.35 Given the gene therapy–induced autoimmune intraocular inflammation and hypotony reported in the INFINITY trial with intravitreal delivery, the long-term safety and efficacy of suprachoroidal anti-VEGF gene therapy needs continued evaluation.23,24

Figure 6. Six-month ALTITUDE trial phase 2 data of diabetic retinopathy eyes without center-involved diabetic macular edema treated with suprachoroidal RGX-314 (Regenxbio) demonstrating exceptional Diabetic Retinopathy Severity Score improvement rates comparable to those seen in severe nonproliferative diabetic retinopathy eyes in RIDE/RISE and PANORAMA trials. Image courtesy of Regenxbio
Figure 6. Six-month ALTITUDE trial phase 2 data of diabetic retinopathy eyes without center-involved diabetic macular edema treated with suprachoroidal RGX-314 (Regenxbio) demonstrating exceptional Diabetic Retinopathy Severity Score improvement rates comparable to those seen in severe nonproliferative diabetic retinopathy eyes in RIDE/RISE and PANORAMA trials. Image courtesy of Regenxbio

CONCLUSIONS

Suprachoroidal injections have been met with good reception from physician investigators, with 84% not perceiving these as more challenging than other ocular injections.36 It is an exciting avenue of retinal drug delivery because it affords potential advantages over intravitreal and subretinal drug delivery. Suprachoroidal steroid therapy for DME and CME from NIU has already been proven successful. Short-term studies on suprachoroidal gene therapy for DR and nAMD appear promising in reducing treatment burden and addressing noncompliance, especially in diabetic patients. Further study will evaluate the long-term efficacy and safety of suprachoroidal retinal drug and gene therapy delivery. RP

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

Venkatkrish M. Kasetty, MD, is a PGY-2 ophthalmology resident at Henry Ford Hospital in Detroit. Luke G. Qin is a medical student at the Medical College of Georgia, Augusta University, in Augusta, Georgia. Diego Espinosa-Heidmann, MD, is a vitreoretinal surgeon, associate professor, and retina fellowship director in the department of ophthalmology at the Medical College of Georgia. Dennis M. Marcus, MD, is a vitreoretinal surgeon and managing physician at Southeast Retina Center, director of clinical research at Eye Health America, and professor of clinical ophthalmology at the Medical College of Georgia. Dr. Kasetty, Mr. Qin, and Dr. Espinosa-Heidmann report no disclosures. Dr. Marcus reports consultancy to Regenxbio, Genentech/Roche, Regeneron Pharmaceuticals, and Vial, and research grants from Allergan/Abbvie, Aiviva, Amgen, Boehringer Ingelheim, Alcon, Aerpio, Kalvista, Ionis, Xplore, Mylan, Samsung, Novartis, Opthea, Chengdu Kanghong Biotechnology, Clearside Biomedical, Astellas, Allegro, Alimera Sciences, Ophthotech/Iveric Bio, Outlook, Gemini Therapeutics, Genentech, Oxurion, Tyrogenex, Graybug Vision, Topcon, Optos, Gyroscope Therapeutics, Stealth Spiam, Aerie, Apellis, Roche, Novartis, OHR, Regenxbio, Kodiak Sciences, Zeiss, Annexon, Oculis, and Regeneron. Reach Dr. Marcus at dmarcus@southeastretina.com.

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