Suprachoroidal Administration for Retinal Drug Delivery

A promising targeted approach to treat posterior-segment ophthalmic disease


Suprachoroidal Administration for Retinal Drug Delivery

A promising targeted approach to treat posterior-segment ophthalmic disease


Retinal diseases are treated either surgically or pharmacologically. Over the last 10 years, the most common pharmacological method of administering drugs to access the retina or choroid, for the treatment of posterior-segment diseases, has been through the vitreous.

The successes seen with the anti-VEGF agents ranibizumab (Lucentis, Genentech, South San Francisco, CA) and aflibercept (Eylea, Regeneron, Tarrytown, NY) have revolutionized pharmacological intravitreous therapy for the treatment of neovascular age-related macular degeneration, retinal vein occlusion, and diabetic macular edema.1,2

However, with other drugs or drug combinations, both efficacy and safety could be further optimized, and in the cases of most pharmacological therapies, including with anti-VEGF agents, the question remains as to whether the intravitreal route is optimal, given the increasing burden such treatment imposes both on the patient and physician. In general, for a successful pharmacological therapy, the goals are to optimize efficacy at the intended site of action and to reduce complications.


Injecting a drug through the suprachoroidal space (SCS) of the eye delivers drug to posterior-segment tissues in high bioavailability (Figure 1) and with access to structures such as the retinal vasculature in RVO and DME or the choroidal neovascular membrane in exudative AMD, providing the potential both for high efficacy and for unique outcomes.

Figure 1. Drug spreads after suprachoroidal injection.

Seenu M. Hariprasad, MD, is Shui-Chin Lee Professor of Ophthalmology and Visual Science, chief of the Vitreoretinal Service, and director of clinical research at the University of Chicago School of Medicine & Biological Sciences in Illinois. He reports financial interests as a consultant or speaker for the following companies: Allergan, Alcon, Takeda, Janssen, Clearside Biomedical, Bayer, Spark, Regeneron, Optos, Leica, Ocular Therapeutix, and OD-OS. Dr. Hariprasad can be reached via e-mail at

Clearside Biomedical, Inc. (Alpharetta, GA), an ophthalmic pharmaceutical company, has developed a unique, minimally invasive method of injecting drugs to access the retina and the choroid through the SCS. Using this proprietary injection method, two clinical trials, a phase 1/2 trial and a phase 2 trial in noninfectious uveitis, were completed with successful outcomes.3,4

Results from a third clinical trial, a phase 2 study in RVO, are expected in the second quarter of 2016. A phase 3 study in noninfectious uveitis has been initiated and is currently enrolling patients. Preclinical studies in neovascular AMD are under way with an investigational new drug application expected to be filed by the end of 2016.

The SCS is an attractive route for local drug administration into the eye. There are potential advantages to being able to access the retina and the choroid directly, and the results from the completed phase 1/2 and phase 2 studies in uveitis from Clearside are encouraging; the results from the RVO phase 2 study, if the outcomes are positive, will provide support for the treatment of retinal vascular diseases by this route of administration.


While intravitreal injections are currently the mainstay of treatment for a wide variety of retinal diseases, they constitute an effective method to treat ophthalmic diseases with antibiotics, antivirals, antifungals, anti-inflammatories including steroids, and anti-VEGF drugs; most of these agents have a reasonably good safety profile, although it should be remembered that some of these drugs can cause ocular complications depending on the specific drug.

Topical administration of drugs is not commonly used for the treatment of retinal diseases because the limited attempts in which they have been tried have not shown success.5

Systemic treatment has also been limited because the blood-retina barrier limits the ability of many drugs to reach the eye, and high doses can cause systemic adverse effects. Periocular (subconjunctival, sub-Tenon, or retrobulbar) injections, although commonly used, have not yet been adequately studied or optimized for most classes of drugs.

The SCS itself is a narrow zone between the choroid and the sclera with a potential space6 extending from the limbus to the optic nerve. While the innermost layer of the choroid, Bruch’s membrane, is well defined, the outer border close to the sclera is a transition zone, consisting of several fibrous lamellae with variable thickness.7 Early studies relied on histology to visualize the SCS8; in vivo imaging of the SCS was performed by ultrasonography imaging under pathological conditions.9

Optical coherence tomography imaging has changed the practice of ophthalmology in the past 15 years and has enabled detailed in vivo imaging of retinal structures. Advanced OCT techniques, using enhanced depth or swept source imaging, have increased our understanding of retinal pathologies and enabled us to visualize the SCS, as well as begin to understand better the roles of retinal and subretinal structures under normal and pathological conditions.10


The utilization of the SCS as a potential pathway for drugs to target posterior ocular pathologies is more recent and has only been explored in a limited variety of ophthalmic diseases. Whether there are advantages is currently being evaluated through the clinical studies being conducted.

Fluid rapidly diffuses into the posterior segment following administration through the SCS in animal models; up to 1 mL of fluid is accommodated in the space.11 This volume is larger than what is required for achieving therapeutic levels that are clinically relevant for drugs. Injections of 10 to 50 µL into the SCS are well tolerated with a low risk of ocular complications.12

Fluid injected via the SCS spreads around the globe both on top of and through the choroid, distributing through the choroid and the retina. Should a drug be injected, the drug solution or suspension spreads in a similar manner, accessing the choroid and the retina. In contrast, when the same drug is injected into the vitreous, the drug spreads diffusely across all parts of the eye.

Utilizing the SCS therefore appears to provide a more targeted approach to retinal and choroidal tissues, resulting in a higher local concentration of drug and perhaps allowing for lower doses of drugs to be administered or less frequent dosing because of high effective drug levels being achieved.

For example, drug administration through the SCS as a therapy for retinal disease has been studied using surgical cannulation, which was shown to be effective and safe in achieving drug delivery to the posterior pole,13 but the procedure that was used is complicated and cannot be performed in the office.

Realizing the therapeutic potential of the SCS requires an approach that allows drugs to be introduced through the SCS in a minimally invasive, yet consistent and efficient, manner.


The development of a minimally invasive method of administering drug to the eye through the SCS using a proprietary microinjector (Figures 2 and 3) is a novel approach for managing posterior-segment disease. The microinjector is a syringe with a needle that is approximately 1 mm in length.

Figure 2. Microinjector fits comfortably in hand allowing in-office delivery in a fashion similar to currently administered intravitreal injections.

Figure 3. Microneedle close-up housed in specially designed hub structure.

Specifically, the current version of the injector includes a 30-gauge needle, within a specially designed hub that allows the user to reliably inject the needle into the SCS for drug administration. This design ensures access to the SCS through the sclera. It also ensures that the suprachoroidal injection of any drug can be performed routinely in a similar fashion to intravitreal injections.

Steroid Treatment of Uveitis

Steroid administration to treat noninfectious uveitis has provided a robust demonstration of the advantages of the SCS-based approach. Triamcinolone acetonide (TA) was chosen as a proof-of-concept drug due to its routine use and documented efficacy for the treatment of uveitis.14,15 The results showed equal or improved anti-inflammatory activity by SCS administration at lower doses, compared to TA administered by intravitreal injection or prednisone given by systemic dosing in animal models.

For example, in a pig model of acute uveitis, it was shown that a 0.2-mg dose of TA injected suprachoroidally was more effective than a 0.2-mg dose of TA administered intravitreally and as effective as a 2.0-mg intravitreal dose. The data demonstrated that a 10-fold lower dose of TA administered to the SCS, compared to that dosed intravitreally, was sufficient to provide efficacy.16

Studies measuring the ocular distribution of drug in a rabbit model supported a higher concentration of drug in relevant tissues (choroid and retina) and a lower concentration in nontarget areas (lens, anterior chamber) when comparing suprachoroidal with intravitreal administration.

Over a 90-day period following a single suprachoroidal injection, TA was 12 times more available in the choroid and retinal pigment epithelial cells compared to the distribution following intravitreal administration.

In addition, while equivalent amounts of drug were found in the neural retina, suprachoroidal administration showed minimal levels of drug in the anterior chamber and in the iris-ciliary body, compared to intravitreal injection of TA.

Single and repeat-dose toxicology studies in rabbits suggested that triamcinolone administered to the SCS was tolerable and safe for the 13-week evaluation period following each administration, while systemic drug levels were low to undetectable.

Pharmacokinetic studies using a multikinase inhibitor injected via suprachoroidal injection showed a half-life in rabbits of more than 90 days, indicating that the months-long ocular distribution seen from the pharmacokinetic data on TA has the potential to be more broadly generalizable across other classes of drugs.17

Clinical Studies

Clearside entered the clinic with the CLS-TA preparation of triamcinolone for the treatment of noninfectious uveitis as proof of the concept of utilizing the SCS as a means for pharmacological treatment, with the broader objective of using suprachoroidal injections of the appropriate drug or drug combinations for the treatment of ophthalmic posterior-segment diseases.

Results from an open-label, phase 1/2 study in patients with noninfectious uveitis showed improvement ranging between 1 and 5 lines among the eight patients who were treated with a single suprachoroidal injection of TA (4.0 mg; 100 µL) and followed for 26 weeks.

When measured at week 12, the average improvement in BCVA exceeded 2 lines of improvement, while at week 26, the average improvement in BCVA was close to 3 lines of improvement.

Importantly, no patients in the trial experienced any meaningful increase in intraocular pressure at any time point following SCS administration, and none was required to use IOP-lowering medications in the trial.3

These findings are encouraging in that they suggest first that positive, long-lasting efficacy outcomes can be achieved via SCS administration of TA and that the adverse effects commonly associated with conventional ophthalmic use of corticosteroids, including IOP spikes and lens opacification, may be minimized by TA when injected into the eye through the SCS.

A randomized, masked, dose-controlled, multicenter phase 2 study evaluating the safety and efficacy of CLS-TA in 22 patients with macular edema associated with noninfectious uveitis was recently completed with top-line data showing favorable results.

The study successfully met its primary endpoint, with a statistically significant mean reduction from baseline in central subfield thickness at eight weeks (164 µm; P=.002) after a single treatment of triamcinolone (4.0 mg; 100 µL). Statistical significance was also achieved in the mean increase from baseline in best-corrected visual acuity (9.2 letters; P=.0004), which was a secondary endpoint.4

There were no treatment-related serious adverse events reported in the trial, including no steroid-related increases in IOP, confirming what was seen in the open-label phase 1/2 study and bringing to 25 the total number of uveitis patients treated with TA with no steroid-related increases in IOP seen (Clearside, data on file).

While both of these clinical trials have provided encouraging data, another phase 2 trial, a randomized, masked, controlled, multicenter study to assess the safety and efficacy of suprachoroidally administered triamcinolone in combination with intravitreally injected aflibercept in patients with RVO, is fully enrolled, with data expected by mid-2016.


With positive data from the two uveitis studies and with expected data from the phase 2 trial in RVO, the retina community will have the opportunity to see systematic evidence of the clinical utility of pharmaceutical therapy for retinal diseases through SCS drug administration.

As this technology develops, we look forward to continuing to learn its strengths and shortcomings. We do not yet understand whether there is any longer-term impact from this method of drug administration to access the retina and choroid, nor do we understand all of the potential advantages that this method may provide. We may have a new opportunity to improve patient care, and SCS injection of drugs could play a useful role in providing therapeutic benefit in the treatment of posterior-segment disease. RP


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