Posurdex Implant Technology

BARUCH D. KUPPERMANN, MD, PHD

The Dexamethasone Posterior Segment Drug Delivery System (dexamethasone DDS; Posurdex, Allergan, Irvine, CA) was developed to address the challenges of intravitreal corticosteroid therapy. It is a novel intravitreal drug delivery system that gradually releases dexamethasone over a period of several months while the carrier matrix slowly degrades into carbon dioxide and water, eventually dissolving completely. Clinical studies suggest that dexamethasone DDS is well tolerated and provides benefits in the treatment of persistent macular edema. Incisional placement of dexamethasone DDS is simple and well tolerated, but the introduction of the dexamethasone DDS applicator is likely to simplify the procedure further and may improve safety.

THE DEXAMETHASONE DDS

The dexamethasone DDS is a novel intravitreal drug-delivery system composed of a biodegradable copolymer of lactic acid and glycolic acid impregnated with the corticosteroid dexamethasone. The polymers used are found in a variety of medical products such as absorbable sutures.^1-3 Dexamethasone (9α-fluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione) is a commonly used and potent synthetic glucocorticoid steroid hormone.

Once inside the eye, the dexamethasone DDS gradually releases dexamethasone over an extended period of time. In preclinical studies, dexamethasone levels in the retina were observed for at least 4 months following intravitreal placement of dexamethasone DDS (Data on file, Allergan, Inc.).⁴ The polymer matrix eventually dissolves completely, obviating the need for surgical removal before retreatment.⁵ Dexamethasone exerts its multiple physiological effects by binding to glucocorticoid receptors followed by genomic and nongenomic intracellular signaling.⁶

The dexamethasone DDS is small and can be placed surgically through a small pars plana incision or using an applicator (Figure) designed for this purpose. The dexamethasone DDS was originally developed in 2 dose sizes, 350 μg and 700 μg, but a large phase 2 clinical study of dexamethasone DDS in the treatment of macular edema determined that the 700 μg size was more appropriate for use in this indication and this is the dose being used now in clinical trials.⁷

APPLICABILITY OF DEXAMETHASONE DDS

A great deal of interest exists in the potential of intravitreal corticosteroid therapy for the treatment of a variety of retinal vascular diseases, including age-related macular degeneration (AMD),^8-10 diabetic macular edema (DME),^11-14 uveitis,^15,16 and macular edema associated with retinal vein occlusion (RVO).^17-21 These conditions affect millions of people and are leading causes of vision loss.^22-29

This interest comes from growing appreciation of the role of inflammatory processes in retinal vascular disease. For example, pathophysiological processes contributing to the breakdown of the blood-retinal barrier in DME have been shown to include the production of inflammatory mediators (eg, prostaglandins and interleukin-6), increased amounts of permeability factors such as vascular endothelial growth factor (VEGF),³⁰ and the loss of endothelial tight junction proteins.^31,32 Corticosteroids can inhibit these processes,^33-36 reducing edema and improving the barrier properties of blood vessels.^35,37 The challenge is to deliver effective concentrations to the back of the eye while limiting systemic exposure and avoiding ocular adverse effects.

Figure. Applicator for the insertion of the Posurdex implant.

Topical administration of corticosteroids does not achieve sufficient levels of drug in the posterior segment to be effective in treating retinal disease.⁵ Oral administration is potentially more effective and has been shown promise in the treatment of posterior segment uveitis.³⁸ Oral corticosteroids, however, are associated with many systemic adverse effects, including the potential to aggravate diabetes.³⁸ Intravitreal administration is potentially much more effective and greatly reduces the risk of systemic adverse effects.

For example, intravitreal injection of the corticosteroid triamcinolone acetonide (IVTA; Kenalog, Bristol-Myers Squibb) is currently used off-label as a treatment for DME^11-13 and is being explored as a treatment for inflammatory cystoid macular edema,¹⁵ uveitis,¹⁵ RVO,^20,39 and AMD.⁹ IVTA has shown promise in the treatment of these conditions, but the most commonly used formulation, Kenalog 40, is an injectable suspension of triamcinolone acetonide that is approved only for intramuscular use; it was not designed and has not been approved for ophthalmic use. Moreover, IVTA injections are associated with some worrisome ocular adverse effects. Clinically significant increases in intraocular pressure (IOP) occur in approximately 30% to 40% of patients^12,40 and sometimes cannot be controlled with medication, leading to a need for filtering surgery.^11,41,42 Other complications of IVTA include cataract^11,41 and sterile endophthalmitis (most commonly seen with the Kenalog formulation).⁴³ Adverse effects such as retinal detachments and vitreous hemorrhage are less common but do occur and may be related to the injection procedure itself rather than the medication.

To maintain the benefits of intravitreal corticosteroid therapy in chronic or progressive retinal disease, treatments need to be repeated periodically.^11,41,44 This increases the risk of certain adverse effects and has led to the investigation of drug delivery systems that can provide sustained corticosteroid release.

The dexamethasone DDS was developed to address the challenges associated with intravitreal corticosteroid therapy by using a potent corticosteroid in a biodegradable delivery system. Dexamethasone is a more potent corticosteroid than triamcinolone, exhibiting anti-inflammatory activity at lower concentrations⁴⁵ and producing limited toxic effects at high concentrations.^46-48 The system was designed to provide sustained release of dexamethasone for several months while gradually degrading into inert compounds.

When the dexamethasone DDS was evaluated in preclinical studies, it was found to block the breakdown of the blood-retinal barrier and vascular leakage produced by intravitreal injection of VEGF into rabbit eyes⁴⁹ and prevent the increase in macular thickness produced by VEGF in monkey eyes.⁵⁰ The results of preclinical studies supported the further clinical studies of dexamethasone DDS in humans with retinal vascular disease. As studies began using incisional placement of dexamethasone DDS, an applicator was being developed that would simplify the insertion procedure. Incisional placement requires the use of a surgical suite and appropriate surgical draping and preparation and creates a small wound that requires sutures to close. The applicator is designed to allow placement of the dexamethasone DDS through a 22-g self-sealing puncture. This will hopefully allow dexamethasone DDS to be an office-based procedure and eliminate the need for sutures to close the insertion site.

DEXAMETHASONE DDS CLINICAL STUDIES

To date, the dexamethasone DDS has been evaluated in 2 clinical trials in patients with macular edema.^7,51 Macular edema is a common sight-threatening element of many retinal and vascular diseases. In a 6-month, phase 2, multicenter, randomized, dose-ranging clinical trial, dexamethasone DDS was evaluated in patients with macular edema due to diabetic retinopathy, central or branch RVO, uveitis, or Irvine-Gass syndrome (also known as postsurgery macular edema). Eligible patients (N=315) had to exhibit macular edema that had persisted for at least 90 days after laser or medical treatment.⁷ In each patient, 1 eye was randomized to observation or treatment with 350 μg or 700 μg dexamethasone DDS. The dexamethasone DDS was inserted into the vitreal cavity through a small pars plana incision. Significantly more patients in each dexamethasone DDS treatment group achieved clinically significant improvement in best-corrected visual acuity (BCVA) 90 days after implantation than did patients in the observation group. At day 90, a 10-letter or greater improvement in BCVA was achieved by 35% and 24% of patients treated with dexamethasone DDS 700 μg and 350 μg, respectively, and by 13% of patients in the observation group. Improvement of 15 letters or more was achieved by 18% of patients treated with 700 μg dexamethasone DDS as compared with 6% of observed patients.

Significantly more patients in the dexamethasone DDS groups than in the observation group showed improvement in angiographic fluorescein leakage and macular thickness. These benefits were sustained for 180 days after treatment. Additionally, when separate subgroup analyses were performed based on the underlying cause of macular edema, the results were consistent across subgroups and similar to the results seen for the overall population.⁷ (The inclusion of an observation arm in the study protocol required that escape medications be available to ensure good patient care.) Investigators were allowed to administer nonstudy treatments for macular edema to any patient if they determined it to be medically necessary. As might be expected, a significantly higher percentage of patients in the observation group received nonstudy treatments than did patients in either treatment group. This likely improved clinical outcomes in the control group and made it more difficult for the benefits of dexamethasone treatment to achieve statistical significance — lending greater strength to the statistically significant differences that were observed.

Once the dexamethasone DDS applicator was developed, a small randomized, partially masked study (N=30) was performed to compare the safety and efficiency of applicator as compared to incisional placement of dexamethasone DDS 700 μg in patients with macular edema.⁵¹ The overall incidence of adverse events was lower in the applicator group than in the incision group, and none of the patients in the applicator group required sutures to close the insertion site. Improvements in BCVA were similar in the 2 treatment groups and similar to those seen in the phase 2 study.

Dexamethasone DDS was well tolerated in both clinical studies performed to date.^7,51 The most common adverse events seen in the phase 2 trial are online at http://www.retinalphysician.com/drug-delivery/. Most adverse events occurred during the first week after insertion of dexamethasone DDS and many, such as vitreous hemorrhage and anterior chamber cells and flare, could be expected as a result of the surgical procedure itself. IOP increased in 17% of patients in the 350-μg group, 13% of patients in the 700-μg group, and no patients in the observation group (P<.001 for either dexamethasone group vs observation). Increases in IOP were typically transient and all cases were successfully managed with ocular hypotensive medication or observation. There were no cases of endophthalmitis or rhegmatogenous retinal detachment associated with treatment. Tractional retinal detachment occurred in 1% of patients in the 350-μg group and the observation group, but no patients in the 700-μg group. Vitreous hemorrhage occurred in 21% and 22% of patients in the 350-μg and 700-μg groups, respectively, and in no patients in the observation group (P<.001 for either dexamethasone group vs observation). The observed vitreous hemorrhages were typically mild and transient and were associated with the surgical cut-down technique used in the phase 2 trial. No vitreous hemorrhages were noted in the phase 2b trial in the group undergoing applicator placement of the dexamethasone DDS, which does not require surgical cut-down. No increase in the incidence of cataract was seen in the 6-month phase 2 study, but 6 months may be too short a time for changes in lens opacity to be noticed.⁷

CONCLUSIONS AND FUTURE PERSPECTIVES

Dexamethasone DDS represents a novel approach to intravitreal posterior segment drug delivery in general and intravitreal corticosteroid therapy in particular. Dexamethasone DDS allows for therapeutic concentrations of a potent corticosteroid to be gradually released into the posterior segment over a period of several months while the delivery vehicle slowly biodegrades into lactic acid and water. Clinical studies suggest that it is well tolerated and provides benefits in the treatment of macular edema that has persisted despite other treatments. Incisional placement of dexamethasone DDS is simple and well tolerated, but the introduction of the dexamethasone DDS applicator is likely to simplify the procedure further and may improve treatment safety.

Phase 3 clinical trials are now under way to evaluate the safety and efficacy of dexamethasone DDS in populations of patients with macular edema due to particular causes. If these studies support the clinical findings of the phase 2 study, dexamethasone DDS may offer a new therapeutic option to patients with macular edema and provide hope to those who have failed laser surgery or other clinicaltreatments. RP

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