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Retinal Physician

Article

Suprachoroidal Drug Delivery Technology

The first FDA approval ushers in a new clinical reality.

By: Thomas A. Ciulla, MD, MBA, Rafael V. Andino, MSBE, MBA, Shelley Hancock, MBA
Retinal Physician August 1, 2022 Vol 19, Issue Special Edition 2022 Page(s): 13-18

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After the 2021 approval by the US Food and Drug Administration of Xipere (Bausch + Lomb) triamcinolone acetonide injectable suspension for suprachoroidal use (CLS-TA), for the treatment of uveitic macular edema (UME), suprachoroidal (SC) drug delivery became a clinical reality. Multiple therapies are now being assessed for SC delivery in clinical trials, including a small molecule suspension of a tyrosine kinase inhibitor (TKI), a small molecule suspension of a corticosteroid, a gene therapy, and a virus-like drug conjugate. This article summarizes the key aspects of SC delivery, development of the microneedle technology, and current clinical trials (Table 1).

Table 1: Key Aspects of Suprachoroidal Delivery of Therapeutics
  • Suprachoroidal (SC) drug delivery is now a clinical reality, after the first FDA-approved therapeutic into the suprachoroidal space (SCS).
  • Current trials involving SC delivery include evaluation of a small molecule suspension of a tyrosine kinase inhibitor, a small molecule suspension of a corticosteroid, a gene therapy, and a virus-like drug conjugate.
  • Potential advantages of SCS administration include targeted delivery to affected chorioretinal tissues for efficacy, compartmentalization away from unaffected tissues for safety, and bioavailability.
  • For small-molecule suspensions delivered via the SCS, particle size and relative insolubility contribute to durability.
  • After SC injection, a natural pressure gradient (intraocular pressure > anterior SCS pressure > posterior SCS pressure) drives injectates posteriorly toward the macula, with potential to treat macular disorders.
  • A procedural performance study with the SCS Microinjector (Clearside Biomedical) showed that a large majority of physician-investigators did not perceive suprachoroidal injections to be meaningfully more challenging than other ocular injections, following first use of the injector.

ANATOMY

Potential spaces in the body can serve as “druggable” targets, and epidural anesthesia represents one such commonly performed application of this concept. In the eye, the suprachoroidal space (SCS) is the potential space between the choroid and sclera that circumferentially extends from the scleral spur posteriorly (Figure 1). Potential advantages of treating via the SCS include targeted delivery to affected chorioretinal tissues for efficacy and compartmentalization away from unaffected tissues for safety and bioavailability, because these chorioretinal tissues are essentially bathed with therapy.1,2 For small molecule suspensions, there is potential prolonged pharmacokinetics that may yield favorable durability.1,2

BIOMECHANICS OF SUPRACHOROIDAL DELIVERY

After suprachoroidal injection, a natural pressure gradient between the intraocular pressure, the anterior SCS, and the posterior SCS pressure drives SC injectates posteriorly and circumferentially towards the macula, with potential to treat macular disorders.3 Multiple factors appear to drive durability in the SCS, including particle size. Particles ranging from the size of gene therapy viral vectors to small molecule suspensions remain primarily in the suprachoroidal space and choroid for a period of months.4 The physiologic upper limit of pore size in the fenestrated choriocapillaris is estimated between 6 nm and 12 nm, which may limit transcapillary passage of larger macromolecules and particles.5 In addition to particle size, the relative insolubility of small molecule suspensions contributes to durability.6-10 Preclinical studies with small molecule suspensions have shown durable high levels of drug in the targeted retina, retinal pigment epithelium, and choroid, while also limiting exposure to the anterior chamber, iris, ciliary body, and lens.6-10 Consequently, by both maximizing drug levels in the targeted chorioretina and minimizing levels in the anterior segment of the eye, suprachoroidal injection has the potential to facilitate efficacy and safety.

RELIABLE ACCESS TO THE SUPRACHOROIDAL SPACE

The SCS Microinjector (Clearside Biomedical) precisely delivers therapies to the SCS utilizing a 900 µm or 1,100 µm length microneedle.1,11 The 2 lengths accommodate anatomic variations in patient ocular anatomy. Suprachoroidal injection is carried out at the pars plana under local anesthesia. In clinical practice, SC injections are typically performed with the 900 μm needle by inserting the needle perpendicularly to the eye at the injection site until the needle tip penetrates through the conjunctiva and sclera to access the SCS (Figure 2). Pressure is then applied to the microinjector syringe plunger, followed by an initial resistance to injectate flow, because the SCS is naturally collapsed and requires some pressure to be accessed. During the process of injection, as the SCS gradually begins to open, a loss of resistance to flow is felt through the syringe system as the injectate gradually flows into the SCS and it expands. During the procedure, if continued resistance is experienced by the physician, the needle can be switched to the longer 1,100 μm needle for additional depth to access the SCS.

Preclinical studies with the SCS Microinjector have shown expansion of the SCS posteriorly to the optic nerve head in animal models,12 and clinical studies have shown acute opening of the SCS in humans.13 In a preclinical study using the SCS Microinjector for suprachoroidal delivery of a small molecule suspension, there were similar durable drug levels in the central vs peripheral chorioretinal tissues,14 supporting the potential to treat both peripheral retinal and macular disorders.

The SCS Microinjector has been assessed in more than 1,200 suprachoroidal injections across multiple retinal disorders with a safety profile comparable to intravitreal (IVT) injections. It has been well accepted by physician investigators. A procedural performance study, which included a user survey and analysis of procedural variables, showed that 84% (31/37) of physician investigators did not perceive suprachoroidal injections to be meaningfully more challenging than other types of ocular injections, following their first use of the microinjector device in a patient, and that the 2 needle lengths accommodate a wide range of anatomic and demographic variables.11

CORTICOSTEROIDS FOR SUPRACHOROIDAL USE

Uveitis, a heterogeneous group of mostly noninfectious inflammatory disorders, affects approximately 350,000 patients in the United States and more than 1 million patients globally. Uveitic macular edema, affecting approximately one-third of these patients, is the leading cause of vision loss in uveitis.

Corticosteroids, the standard of care for uveitis, are effective, but when delivered locally, as drops, periocularly, or intravitreally, are associated with significant side effects, such as cataracts, elevated intraocular pressure (IOP), and even glaucoma with long-term use. CLS-TA is a proprietary suspension of the corticosteroid triamcinolone acetonide, or TA, for suprachoroidal injection. After SC injections of TA in preclinical models, concentrations were high in the retina and choroid with limited exposure to the anterior segment; TA was detectable in chorioretinal tissues for up to 3 months (the length of these studies).15-17 These studies demonstrate that SC delivery can compartmentalize therapy away from the anterior segment while targeting chorioretinal tissues with prolonged pharmacokinetics for durability. Pharmacodynamically, this targeting may potentiate efficacy, because one-tenth the dose of TA administered suprachoroidally demonstrated similar efficacy as the full dose administered intravitreally in a porcine model of acute uveitis.18

The PEACHTREE trial was the first phase 3 clinical trial for noninfectious uveitis (NIU) patients in which best-corrected visual acuity improvement was the primary efficacy endpoint; 47% of the subjects treated with 2 CLS-TA injections administered 12 weeks apart gained at least 15 ETDRS letters from baseline at 24 weeks, compared to 16% in the sham control group (P<.001).19 PEACHTREE was also the first pivotal trial that included patients with all types of uveitis: anterior, posterior, intermediate, and panuveitis. In the control arm, 72% received rescue therapy compared to 14% in the CLS-TA arm, with IVT and periocular corticosteroids being most used. Adverse events of nonacute elevated IOP, defined as not occurring on the day of the injection procedure, or occurring on the day of injection and not resolving the same day, occurred in 11.5% of the CLS-TA arm and 16% of the control arm.20

In October 2021, the FDA approved CLS-TA for the treatment of UME. Bausch + Lomb is commercializing CLS-TA (Xipere) in the United States and Canada, and Arctic Vision plans to commercialize it in greater China, South Korea, India, the ASEAN countries, Australia, and New Zealand. Currently, Arctic Vision is evaluating CLS-TA in a phase 3 trial for macular edema associated with uveitis, and in a phase 2 trial for diabetic macular edema.

THERAPIES CURRENTLY UNDER EVALUATION IN CLINICAL TRIALS

Currently, there are 6 clinical trials enrolling globally to evaluate 4 different therapeutic entities delivered to the SCS via the SCS Microinjector (Table 2).

Table 2: Development Progress of Therapeutic Entities Delivered via the SCS Microinjector Currently Under Evaluation in 6 Clinical Trials Globally

Small Molecules and the Suprachoroidal Space

Neovascular age-related macular degeneration (nAMD) represents the leading cause of legal blindness in adults over 55 years old in the industrialized world. The current standard of care is IVT anti-VEGF therapy. However, clinical outcome studies of IVT anti-VEGF therapy have demonstrated that patients receive only 6 to 7 injections per year on average, resulting in mean improvement of only 1 to 3 letters in visual acuity after 1 year of treatment.21,22

A promising small molecule suspension currently being evaluated utilizing SC delivery is axitinib. It is a highly potent TKI that inhibits vascular endothelial growth factor receptors VEGFR-1, VEGFR-2, and VEGFR-3 at picomolar concentrations.23 Axitinib is a more highly potent TKI than others that have been assessed in ocular clinical trials; in an animal model of neovascularization, axitinib was the most effective in inhibiting vascular growth of the TKIs sorafenib and sunitinib.24 Multiple preclinical studies demonstrate inhibition of neovascularization in corneal, retinal, and choroidal tissues.24-29 Axitinib has been shown not only to inhibit angiogenesis, but also regress established neovascularization in preclinical choroidal neovascularization models,25,26 which may be more relevant to potential clinical use. Furthermore, in vitro assessment of axitinib revealed better biocompatibility with ocular cells compared to other TKIs,30 suggesting the potential for intrinsic safety benefits.

Axitinib, with its pan-VEGF inhibition activity,25 may have therapeutic synergies with SC delivery, with its ability to target affected posterior tissues and compartmentalize drug away from unaffected tissues. Suprachoroidally administered axitinib (CLS-AX) has shown promise in a laser-induced choroidal neovascularization model, and retinal vascular leakage model, in rats and pigs. In a rabbit model, suprachoroidal injection of CLS-AX showed an 11-fold higher mean exposure in the posterior eye cup, compared to the IVT injection. The retinal pigment epithelium-choroid-sclera and retina also showed sustained levels of CLS-AX throughout the study after a single suprachoroidal injection.10 These results demonstrate the favorable pharmacokinetic properties of CLX-AX delivered suprachoroidally with long-acting potential that could reduce treatment burden to nAMD patients.

Suprachoroidally injected CLS-AX is being assessed in the ongoing phase 1/2a OASIS clinical trial31 in treatment-experienced patients with nAMD. OASIS is an open-label, dose-escalation clinical trial to assess the safety and tolerability of single doses of SC CLS-AX. The lowest planned doses of 0.03 mg and 0.1 mg CLS-AX were found to be well tolerated in patients and no serious adverse events were observed. The trial has advanced to cohort 3, using a dose of 0.5 mg CLS-AX.32

Gene Therapy and the Suprachoroidal Space

Several routes of administration have been used for ophthalmic gene therapy. Historically, the standard method involves operating room–based pars plana vitrectomy (PPV) followed by retinotomy and injection of the vector into the subretinal space. Subretinal administration creates a temporary limited retinal detachment, or “bleb,” but facilitates direct delivery to the RPE and photoreceptors. Currently, the only approved retinal gene therapy and most investigational retinal gene therapies are administered via PPV at a limited number of ocular gene therapy treatment centers. During PPV, there are iatrogenic risks associated with retinotomy and subretinal bleb, especially in eyes with already compromised retina and RPE. Consequently, the surgery requires extensive training, and the limited number of ocular gene therapy centers creates patient access issues.

Suprachoroidal delivery of both nonviral and viral vectors recently has been under investigation.12,33-38 Unlike subretinal administration, SC administration does not require detachment of photoreceptors from the RPE, and consequently it avoids the risk of iatrogenic subretinal injection to an already compromised retina. A suprachoroidal injection procedure is an office-based procedure and could ultimately enhance access to care, because it would not require a specialized gene therapy surgery treatment center. In one preclinical study, SC and subretinal administration of DNA nanoparticles resulted in comparable marker gene activity in the retina and RPE-choroid.12 In another preclinical study, SC administration of an AAV8 vector expressing an anti-VEGF Fab (RGX-314) resulted in similar expression of anti-VEGF Fab and suppression of VEGF-induced vascular leakage, as subretinal administration at the same dose.33

Regenxbio is currently sponsoring 2 phase 2 clinical trials assessing suprachoroidal delivery of RGX-314: the phase 2 AAVIATE trial for the treatment of nAMD, and the phase 2 ALTITUDE trial for the treatment of diabetic retinopathy. Regenxbio reported positive initial data from both clinical trials in October 2021 and is continuing to enroll patients in both trials. In ALTITUDE cohort 1, RGX-314 was well tolerated in 15 patients with no intraocular inflammation or drug-related serious adverse events at 6 months. Importantly, 47% of patients treated with RGX-314 demonstrated a ≥2-step improvement from baseline on the ETDRS diabetic retinopathy severity scale at 6 months, compared to 0% of patients in the observational control.39 These results suggest the potential for disease modification of diabetic retinopathy with a one-time gene therapy.

Ocular Oncology and the Suprachoroidal Space

Aura Biosciences is currently evaluating a virus-like drug conjugate, AU-011, administered via the SCS for the treatment of choroidal melanoma (CM), the most common primary intraocular tumor in adults. AU-011 is a light-activated therapeutic, utilizing a virus-like particle and approximately 200 molecules of a phthalocyanine dye. AU-011 binds selectively to cancer cells through specifically modified heparan sulfate proteoglycans on the tumor cell surface.

When AU-011 is photoactivated via nonthermal infrared laser light, it induces cell membrane disruption, acute cancer cell necrosis, and a long-term antitumor response. In a preclinical xenograft model involving implanted human choroidal melanoma cells, tumor regression was observed, and clinical proof of concept was established in treating CM via a phase 1b/2 trial using IVT injection.40 Aura is currently sponsoring an open-label, dose-escalation, phase 2 clinical trial of AU-011 via SC administration in patients with CM, and preliminary results support a positive safety and tolerability profile. Aura plans to share initial efficacy data of the phase 2 SC trial in late 2022. A global pivotal trial in CM with suprachoroidal delivery will initiate by the end of 2022 in 70 subjects with 2 doses of AU-011 and a sham control in early-stage disease, which includes both indeterminate lesions and small melanomas.

CONCLUSION

The suprachoroidal space is a unique ocular potential space, with exciting possible applications for unmet needs in ophthalmology. Xipere may be the first of many therapies approved for delivery suprachoroidally. These ongoing trials could demonstrate the potential of suprachoroidal delivery to advance the practice of ophthalmology. RP

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

Thomas A. Ciulla, MD, MBA, is the chief medical officer/chief development officer at Clearside Biomedical in Alpharetta, Georgia, a volunteer clinical professor of ophthalmology at Indiana University School of Medicine, and a board member of Midwest Eye Institute in Indianapolis, Indiana. Dr. Ciulla reports employment by, and holds equity in, Clearside Biomedical. Rafael V. Andino, MSBE, MBA, is vice president of engineering and manufacturing at Clearside Biomedical. He reports employment by, and holds equity in, Clearside Biomedical. Shelley Hancock, MBA, is senior director of medical affairs at Clearside Biomedical. She reports employment by, and holds equity in, Clearside Biomedical. Reach Dr. Ciulla at thomasciulla@gmail.com.

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