Drug delivery via the suprachoroidal space (SCS), with the potential to achieve chorioretinal concentrations 10 times greater than that of typical intravitreal injections,^1,2 has shown safety and efficacy in the treatment of uveitic macular edema with a proprietary formulation of triamcinolone acetonide, CLS-TA.³ Administration of CLS-TA in the SCS, combined with aflibercept, may also have the potential for reduced treatment burden over aflibercept monotherapy in diabetic macular edema.⁴ Although early efforts exploring SCS injections focused on steroid delivery, a wide range of additional agents and indications are currently under development.

TYROSINE KINASE INHIBITORS

Much of the conventional clinical treatment of retinal pathology hinges on the vascular endothelial growth factor (VEGF) cascade, with a particular focus on the blockade of VEGF-A. Although the class of anti-VEGF agents have revolutionized the treatment of diseases such as age-related macular degeneration (AMD), there is evidence to suggest that the blockade of VEGF-A upregulates the expression of VEGF-C⁵ and VEGF-D.⁶ This may blunt the overall response of treatment. In fact, a recent phase 2b trial demonstrated the benefit of broader inhibition: AMD patients receiving a combination of a VEGF-C and VEGF-D inhibitor along with a traditional VEGF-A inhibitor achieved superior visual acuity outcomes compared to those receiving anti-VEGF-A monotherapy.⁷

Whereas current agents block VEGF-A extracellularly, the class of tyrosine kinase inhibitors (TKIs) attack this same cascade by inhibiting the intracellular signaling of the VEGF receptors. One such TKI, axitinib, achieves broad blockade of the VEGF cascade by inhibiting VEGF receptors 1, 2, and 3. In vitro studies have shown axitinib to decrease retinal and choroidal neovascularization better than anti-VEGF-A or anti-PDGF-B, alone or in combination.⁸ Animal studies have established its ability to prevent neovascularization when applied topically in a murine ocular burn model, more effectively than equivalent doses of other TKIs.⁹ Axitinib also demonstrated decreased choroidal and retinal neovascularization when dosed systemically in rodents⁸ or in the SCS in pigs.¹⁰ A phase 1/2a trial of SCS-administered axitinib (CLS-AX; Clearside Biomedical) for the treatment of AMD is currently enrolling.¹¹

GENE THERAPY: VECTOR-BASED

There has been substantial interest in adeno-associated virus type 2 (AAV2) and type 8 (AAV8) vector gene therapy, for its therapeutic potential for indications ranging from AMD to diabetic macular edema (DME) and diabetic retinopathy (DR).^12-16 Much of the focus is on developing the delivery to optimize transduction and minimize inflammation, with approaches including surgical subretinal injection, intravitreal injection, and injection into the SCS.

The SCS route of administration holds the potential of fostering gene expression near the target tissues, while avoiding the potential inflammatory pitfalls that may occur with intravitreal treatment or the inherent surgical risks present with subretinal injections.

Animal models have established the feasibility of the SCS approach. An SCS injection of AAV8 vectors yielded expression of the transgene product in the photoreceptors and RPE of a significant portion of the eye, with a second injection further increasing the distribution of expression.¹⁷ More specifically, the suprachoroidal administration of RGX-314 (Regenxbio), an AAV8 vector with an anti-VEGF transgene product, resulted in significantly less vasodilation and vascular leakage than control eyes when challenged with VEGF165 injections.¹⁷ These SCS results in the rodent model were similar to the subretinal administration of the equivalent dose of RGX-314.¹⁷

Two phase 2 clinical trials for the SCS injection of RGX-314 (Figure 1) are currently enrolling, one for AMD and one for DR,^15,16 with the first cohort of AMD patients fully enrolled.¹⁸ As of December 31, 2020, SCS delivery of RGX-314 was noted to be generally well tolerated with no signs of inflammation.¹⁸

GENE THERAPY: DNA NANOPARTICLES

DNA nanoparticles (DNPs) represent a nonviral approach to gene therapy. They are composed of compacted single molecules of DNA with the ability to achieve similar gene expression compared to the AAV-vector based approach.¹⁹ Unlike traditional AAV vectors, DNPs offer the ability to deliver large genes,²⁰ as well as a potentially lower risk of immune-mediated inflammation.²¹ Animal models of retinitis pigmentosa have illustrated the possibility of efficacy, repeat delivery, and lack of toxicity of DNP technology.^22-25

Positive results were recently reported as to the tolerability and transfectability of DNPs delivered via the SCS in a rabbit model.²⁶ Similar rates of transfection of the RPE-choroid and retina were noted after either subretinal or SCS administration.²⁶ Given the encouraging preclinical data to date, further research is warranted.

VIRAL-LIKE PARTICLE BIOCONJUGATES

Although radiation therapy is highly effective and thus the gold standard for the treatment of choroidal melanomas, it is often associated with collateral damage and vision loss.²⁷ Given that injection into the SCS achieves drug delivery that is inherently compartmentalized in proximity to the choroid, its application may be of benefit in the search for alternative, vision-sparing treatment of choroidal tumors.

To that end, AU-011 (Aura Biosciences), a viral-like particle bioconjugate (VPB), is a first-in-class agent composed of viral nanoparticles derived from the human papillomavirus (HPV) and conjugated with infrared-activated particles, being developed for the treatment of choroidal melanoma.²⁸ Its capsids are derived from human papillomavirus to take advantage of this virus’s ability to preferentially bind to tumor cells.²⁹ Once AU-011 has targeted and bound to the tumor, it is activated with a near-infrared laser, leading to destruction of cell membranes and cell necrosis.

A phase 1b/2 open-label, ascending dose trial achieved a tumor control rate of 80% in phase 3 eligible subjects receiving 2 maximum-dose intravitreal treatments.³⁰ The rate of vision preservation, defined as a loss of 15 letters of visual acuity or less, was approximately 90%.

Although intravitreal treatment achieved high rates of tumor control and vision preservation, it was also associated with anterior chamber inflammation in close to 70%, vitreous inflammation in 85%, and increased intraocular pressure in approximately 40% of subjects.³⁰ Suprachoroidal space delivery of AU-011 would result in a more targeted administration of the drug, with possibly higher bioavailability at the tumor and less intraocular inflammation, potentially allowing for the treatment of a wider range of tumor sizes. The phase 2 trial exploring the delivery of AU-011 via the SCS has completed enrollment of its first 3 single-dose cohorts with a favorable safety profile to date, and is expected to complete enrollment early in 2021.³⁰

CONCLUSION

By way of its targeted and compartmentalized nature, injection via the SCS has the potential to maximize treatment effect and minimize exposure of other ocular tissues. SCS injection of CLS-TA has shown efficacy in the treatment of uveitic macular edema and the potential of addressing the treatment burden of DME. With strong continued interest in harnessing the benefits of SCS drug delivery, multiple agents, from TKIs, to vector-based and DNP-based gene therapy, to light-activated VPBs, are at different stages of development for a spectrum of indications. RP

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