The leading causes of global blindness, with the exception of cataract and glaucoma, are primarily localized to the posterior segment, including age-related macular degeneration (AMD), diabetic retinopathy and uveitis.¹ Specifically, uveitis has a worldwide prevalence of 38 to 730 cases per 100,000 cases with a prevalence of about 200 cases per 100,000 cases in the United States. However, there is a huge disparity between prevalence and blindness, with posterior segment uveitis accounting for approximately 10% to 15% of blindness in the United States.² A possible explanation for the disparity is a younger age at onset of uveitis.

Corticosteroids have been the mainstay for uveitis management because of their broad spectrum of biologic action that includes down-regulation of inflammatory mediators, anti-angiogenic properties and anti-permeability properties.³

The administration of steroids can vary (topical, systemic, periocular, intravitreal or intraocular depot) depending on the cause, location and severity of disease. Despite their benefits, each therapeutic option has its drawbacks. Topical steroids require frequent administration and do not effectively penetrate the posterior segment. Systemically administered drugs must be given in high doses if given for sole treatment to reach an effective concentration in the posterior ocular segment, which is often complicated by systemic side effects (commonly hyperglycemia and osteoporosis).^4,5

For these reasons, drugs for the treatment of diseases of the posterior ocular segment, such as AMD, macular edema of various causes and non-infectious uveitis, are now mainly given via intravitreal or periocular injections. Periocular corticosteroids, via the subconjunctival, peribulbar or retrobulbar routes, do not penetrate the globe, but their potency is inferior to that of intravitreal injections.⁶ To reduce treatment burden with frequent injections, some patients may be good candidates for intraocular depot steroids.

We will discuss the currently available technology for intraocular and periocular depot steroids below.

INJECTIONS

Periocular corticosteroids

Periocular corticosteroid injections through the sub-Tenon or transseptal route are commonly used for patients with chronic refractory or recurrent inflammation who do not tolerate systemic therapy. They are less invasive than intravitreal injections but have to be repeated at two to four month intervals to maintain adequate control.

A large multicenter retrospective study enrolling 914 patients (1,192 eyes) who had received at least one periocular injection during follow-up showed that periocular injections of 1 cc of triamcinolone 40 mg were very effective in treating persistent active uveitis, decreasing macular edema and improving visual acuity. Cumulatively in less than six months, 72.7% of eyes achieved complete control of inflammation and 49.7% showed an improvement in visual acuity (VA) from worse than 20/40 to 20/40 or better. Among the subset with VA worse than 20/40 attributed to macular edema, 33.1% improved to 20/40 or better. The one-year incidence of intraocular spikes above 30 mm Hg was low, and the incidence of glaucoma surgery for persistent IOP elevation was small (2.4%). It is important to note that within one year, among phakic eyes initially 20/40 or better, cataract surgery was required in a substantial number (13.8% of the initially phakic eyes).⁷

A U.K. study further substantiated these results, demonstrating that posterior sub-Tenon’s triamcinolone injections significantly decrease cystoid macular edema (CME) and increase VA in patients with posterior uveitis. Complications included transient elevation of IOP in four patients and persistent residual ptosis in two patients, which has been reported in other clinical trials as well. Other potential risks reported in the literature are transient pain (which is common), globe perforation, orbital fibrosis and orbital fat prolapse.⁸

Intravitreal steroid injections

Intravitreal steroids have gained a popular presence for the treatment of posterior uveitis, especially when CME is present. The duration of a 4 mg triamcinolone acetonide intravitreal dose in a nonvitrectomized eye is about three months.^9,10

Triescence (Alcon) is a commercially available, preservative-free preparation of triamcinolone acetonide. The concentration is 40 mg/mL, and the recommended dose is between 1 to 4 mg (25-100 mL). Trivaris (Allergan) is another preservative-free triamcinolone acetonide preparation available as a single-use syringe for intravitreal injection. It is available, albeit less readily than Triescence, in a gel preparation with a concentration of 80 mg/mL.

From a uveitic standpoint, intravitreal triamcinolone acetonide seems to be very effective for the treatment of Behcet’s disease with resolution of inflammation and improvement in VA. It also has been advocated for use in acute and chronic sympathetic ophthalmia and Vogt-Koyanagi-Harada disease⁹. Also, intraocular triamcinolone is frequently used to better visually identify prolapsed vitreous during cataract, glaucoma and corneal transplantation surgery, therein imparting concomitant anti-inflammatory measure.¹⁰

The downside of intravitreal triamcinolone injections is that the drug lasts for about three months. Therefore, the patient requires repeated injections — which increase the risks of vitreous hemorrhage, retinal detachment and endophthalmitis.¹¹

INTRAOCULAR DEPOT STEROIDS

Overview

Concerns for a delivery system that reduces the need for frequent intraocular injections and the rate of ocular complications while maintaining high levels of drug directly to the posterior segment paved the introduction of sustained-release intravitreal corticosteroid implants.

The consideration for intraocular depot steroids relies on the diagnostic challenge of first determining that a uveitic process is noninfectious. This is determined in the initial workup of the patient’s uveitic syndrome, which is usually tailored towards the patient’s history and symptoms. Beyond the decreased risk for intraocular complications and adverse side effects, steroid depots help treat chronic inflammatory conditions.

Corticosteroid implants may be biodegradable or nonbiodegradable. Nonbiodegradable systems are generally preferred for treating chronic, long-term disease, while biodegradable systems are generally used for short-term therapy.¹²

Nonbiodegradables

Retisert (Bausch + Lomb), the first intravitreal implant containing cortisone, is an ocular depot with a nondegradable matrix that contains 0.59 mg of fluocinolone acetonide. The FDA approved it in 2005 for the treatment of macular edema due to noninfectious uveitis. The implant is surgically introduced into the eye through a 3.5-mm incision in the pars plana and sutured to the wall of the globe.¹³ It was shown to be effective in controlling uveitis for 2.5 to three years and offered an alternative paradigm for medium and long-term management of uveitic cases. It has also been shown to effectively control CME secondary to central retinal vein occlusions (RVOs) and diabetes.¹⁴

In a three-year, multicenter, randomized controlled trial, the 0.59-mg FA implant was introduced into 110 patients compared with the 0.21-mg FA implant in 168 patients. Uveitis recurrence was reduced in implanted eyes substantially in both groups, with comparable effects at one and two years for both doses and, interestingly, a greater long-term effect at three years with the 0.59-mg dose compared to the 2.1-mg dose group (20% vs. 41%, respectively). More implanted eyes than nonimplanted eyes had improved VA. As expected, implanted eyes had a significantly higher incidence of IOP spikes, almost 10 mm Hg or more above baseline, with a higher incidence of glaucoma surgery. Nearly 11% of implanted eyes required cataract extraction within the period of the study. In the same trial, two-year safety data indicated that almost 100% of phakic patients would require cataract removal.¹⁵ However, cataract surgery was generally uncomplicated with less inflammation that the contralateral unimplanted eye.¹⁶ Furthermore, in a retrospective study conducted at the Cole Eye Institute, during removal and/or exchange of Retisert implants, there was a high complication for dissociation of the suture strut and the drug reservoir (40.7% incidence rate among 27 eyes). Intraoperative complications relating to retrieval of the drug reservoir included posterior retinal tear and limited suprachoroidal hemorrhage.¹⁷

The MUST (Multicenter Uveitis Steroid Treatment) trial assessed whether these side effects were limited to the steroid implants or expanded to included systemic steroids as well. Furthermore, the MUST trial also compared these two treatment modalities for patients with vision-threatening, non-infectious intermediate uveitis, posterior uveitis or panuveitis. Both treatment modalities were shown to achieve the same final VA. The patients who received implants had lower rates of active uveitis. But, similar to previously mentioned studies, there were higher rates of cataract surgeries and glaucoma surgeries in the implant group. The study ultimately concluded that both forms of treatment play important roles in the treatment of non-infectious uveitis based on an individual approach. The follow-up portion called the MUST trial Follow-up study is still ongoing.¹⁸

Iluvien (Alimera Sciences) utilizes the third generation of Durasert technology. This FDA-approved fluocinolone implant delivers a sustained dose for three years for the treatment of diabetic macular edema (DME). It is unique because of its small size (about 3.5 mm x 0.37 mm) and contains 190 mcg of fluocinolone acetonide. Iluvien can be injected through a 25-gauge inserter, which has the advantage of creating a self-sealing hole as an outpatient office procedure. Furthermore, the material is nonerodible but does not have to be removed from the eye. Phase 2 studies in wet AMD, dry AMD and RVO are also ongoing.^18,19

A new drug application for Durasert three-year treatment for posterior segment uveitis has been accepted by the FDA (Yutiq, EyePoint Pharmaceuticals).¹⁹

The efficacy and safety of Iluvien was examined in the FAME (fluocinolone acetonide for diabetic macular edema) controlled trials. These two clinical trials, FAME A and FAME B, randomized 956 patients in a 2:2:1 ratio to receive 0.2 micrograms/day of fluocinolone acetonide, 0.5 micrograms/day of fluocinolone acetonide or a sham injection. At month 36, the low-dose group achieved the most statistically significant improvement of 15 letters or more of VA (28.7% in the low dose group and 27.8% in the high-dose group, compared with 18.9% in the sham group). As with the Retisert implant trial, there was a high rate of increased IOP and cataract formation in the implant group. However, in patients who had to undergo cataract surgery or glaucoma surgery, visual outcomes were not compromised.

The relative benefit of the low dose implant compared with the sham group was markedly better for those patients with chronic CME (duration of more than three years). Further supportive studies suggest that, in vitrectomized eyes with persistent DME despite focal/grid laser or eyes with chronic DME with a functioning glaucoma filter, the addition of fluocinolone acetonide implants may be considered very early on.²⁰

Biodegradables

These implants possess unique biodegradable polymers that allow them to dissolve, eliminating the need for extraction and decreasing the risks associated with surgery.¹¹ The two implants currently on the market both contain dexamethasone, which is five times more potent than triamcinolone acetonide, more hydrophilic and has a shorter half-life, allowing it to have higher vitreous concentrations and also be eliminated faster.²¹

The first sustained-release biodegradable steroid implant was Surodex (Oculex), a 60-mcg dexamethasone pellet coated in PLGA and hydroxypropyl methylcellulose. Surodex has completed phase-3 U.S. clinical trials and has been approved for use in China and Singapore. It measures 1.0 mm x 0.5 mm and provides sustained release for seven to 10 days following insertion into the anterior chamber, mainly to address post-cataract surgery inflammation.^11,20

In a comparison study between the Surodex implant and the conventional dexamethasone 0.1% eyedrops, there was no difference in the clinical slit lamp assessment of anterior chamber flare and cells between these two groups. However, based on a standardized laser flare meter, flare reduction in the Surodex group reached statistical significance at days four, eight, 15 and 30 after surgery. At three months, flare reduced to preoperative levels in the Surodex group but was still raised in the dexamethasone eyedrop group.²⁰

Next, the optimum intraoperative position of the implant was evaluated. This study included a group of subjects that received two pellets in the anterior chamber, two pellets in the ciliary sulcus and a control group that only received conventional dexamethasone drops. No difference was seen between the AC and ciliary sulcus placement. A U.K. study found a similar safety profile between dexamethasone eyedrops compared to Surodex when controlling postoperative cataract surgery inflammation. There were no statistically significant differences in intraocular inflammation and corneal endothelial count (p=0.67).²¹ As commented on by an administrative head from the company, a big disadvantage for Surodex is that Medicare and most insurance companies do not reimburse for an implant placed during a cataract surgery, which is a primary reason why Surodex is falling off the market.²²

Ozurdex (Allergan) is an injectable, biodegradable implant that contains 0.7 mg preservative-free dexamethasone. The FDA approved it for the treatment of macular edema associated with RVO and for noninfectious posterior uveitis. It releases the drug by diffusion in a biphasic fashion: it achieves higher doses achieved in up to 60 days, followed by a rapid decline between days 60 and 90 then steady levels reached by up to six months. Each implant is supplied in a preloaded, single-use applicator, allowing the advantage of its administration as an in-office procedure.²³

The HURON study, a 26-week, prospective, multicenter, masked study that included 229 patients with intermediate or posterior uveitis, evaluated Ozurdex’s efficacy and safety. Patients either received a single treatment with a 0.7-mg dexamethasone implant, a 0.35-mg dexamethasone implant or a sham procedure. The percentage of vitreous haze was much lower in the 0.7-mg implant group (47%, 36 of 77; p<0.001) and the 0.35-mg implant group (36%, 27 of 76, p<0.001) than in the sham group (12%, nine of 76). Furthermore, both implant subgroups gained 15 or more letters from the baseline VA compared to the sham group. In addition, the mean decrease from baseline central macular thickness was greater in implant groups compared to sham at eight weeks. Eyes with an IOP of 25 mm Hg or more peaked at 7.1% for the 0.7mg group, 8.7% for the 0.35-mg group and 4.2% for the sham group. The incidence of cataract was nine of 52 (15%) in the 0.7-mg implant group, six of 51 (12%) in the 0.35-mg implant group and four of 55 (7%) in the sham group. Overall, the conclusion was that the 0.7-mg dexamethasone implant demonstrated much greater efficacy than the 0.35-mg implant with similar safety profiles.²⁴

Verisome (EyePoint Pharmaceuticals), another injectable delivery system, allows an efficient dosing regimen. It can be injected into the vitreous as a liquid via a standard 25-gauge needle. It coalesces into a single spherule that settles in the inferior vitreous and degrades in size as the drug is released in a controlled steady step fashion over one year. According to the manufacturer, physicians can observe the drug-containing system within the eye and, as a result, can plan for additional dosing according to the amount of residual drug left in the eye.²⁵ Theoretically, rather than having therapy dictated by the design of the specific delivery vehicles discussed above, physicians can administer the next dose based on their clinical assessment.

Dexycu (dexamethasone intraocular suspension, EyePoint Pharmaceuticals) is now FDA approved for cataract surgery. Phase 1 multicenter trials have shown the effectiveness of triamcinolone acetonide formulated with Verisome to be effective for CME associated with RVO.²⁶ Ophthalmic indications will likely be expanded to include treatment for non-infectious uveitis.

FUTURE ADVANCES

Suprachoroidal steroids

To lower the significant side effects while maintaining the clear advantages of long-term intraocular depot steroids, Clearside Biomedical patented a delivery device that localizes corticosteroids in the suprachoroidal space. This device effectively delivers the drug to the posterior segment via a microcatheter or hollow microneedles while avoiding anterior chamber side-effects, mainly cataract and IOP spikes secondary to steroid-induced outflow resistance in the trabecular meshwork.^27,28

In the ongoing HULK trial funded by Clearside Biomedical, the safety and efficacy of 4 mg of Zuprata (suprachoroidal-delivered, preservative-free triamcinolone acetonide), was compared alone vs. in combination with 2 mg of intravitreal Eylea (aflibercept, Regeneron) for DME. Twenty patients were enrolled in the multicenter trial into two arms: treatment naïve and previously treated. Both arms received Zuprata at baseline, and the treatment naïve group also received intravitreal Eylea. Mean visual acuity improved in all patients, significantly more in the treatment naïve group (the treatment naïve group gained 8.5 mean letters at the six-month end-point versus 1.1 mean letters in the previously treated arm). Mean macular thickness improved 100 μm to 348 μm in all patients. IOP was relatively stabilized at months four and five, with only two patients in the previously treated arm experiencing an IOP increase greater than 10 mm Hg. Serious ocular or systemic events have yet be reported.

The pipeline for the suprachoroidal steroid delivery system looks promising for macular edema secondary to vein occlusion and diabetes as well as non-infectious uveitis. Though the official results have not been published, an earlier phase 2 study treated 22 uveitic patients with macular edema with Zuprata (prototype CLS-1001). Patients experienced a reduction in retinal thickness and improvement in visual acuity of an average of two lines. The ongoing six-month phase 3 trial in uveitis recruited 150 patients at 50 clinical sites — 90 patients received Zuprata and 60 received sham injections.^29,30

Suprachoroidal steroids

Particulate drug delivery uses small biodegradable colloidal particles (liposomes, microparticles and nanoparticles) for the long-term delivery of medication. These microparticles and nanoparticles can be further subdivided into micro- or nanospheres, where the drug is homogenously dispersed within a polymeric matrix, and micro- or nanocapsules, where the drug is encased in a polymeric membrane. Zhang et al demonstrated that dexamethasone-loaded nanoparticles (average size of 232 nm) injected intravitreally in rabbits lasted up to 50 days in the vitreous, with a mean concentration of 3.85 mg/l over 30 days. Microspheres loaded with triamcinolone acetonide were also tested in human patients suffering from diffuse macular edema. Eyes treated with intravitreal injection of triamcinolone-loaded microspheres showed a marked decrease of retinal thickness as well as improved visual acuity for 12 months.³¹

CONCLUSION

Uveitis continues to be a debilitating, vision-threatening disease that affects many patients’ quality of life. With corticosteroids as the mainstay of therapy, the traditional steroid delivery systems via the systemic, topical, intravitreal and periocular routes have significant disadvantages coupled with their successes.

Fortunately, the compartmentalized anatomy of the eye has allowed multiple novel methods of local depot steroid delivery systems. These delivery systems optimize the inherent benefits of corticosteroids while reducing the known corticosteroid side effects (systemic and/or ocular).

Intraocular nanoparticles and microparticles also show great promise in the targeted delivery of therapeutics and will likely be pivotal drug delivery platforms in the future. Ultimately, however, the cost of these medications and their ability to reduce treatment burden will be critical in forging their acceptance in the clinical setting. OM

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About the Authors

Dr. Sheppard is president of Virginia Eye Consultants in Norfolk, Va. He is a professor, research director for the ophthalmology residency program and clinical director of the Thomas R. Lee Center for Ocular Pharmacology at Eastern Virginia Medical School. He also serves as medical director with the Lions Medical Eye Bank and Research Center of Eastern Virginia.

Dr. Sodhi is a first year ophthalmology resident at Eastern Virginia Medical School. He graduated from George Washington University Medical School in Washington D.C., and completed a BS in biology from George Washington University.