Development of a dexamethasone intravitreal implant for the treatment of noninfectious posterior segment uveitis

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1 Ann. N.Y. Acad. Sci. ISSN ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: Pharmaceutical Science to Improve the Human Condition: Prix Galien 2014 Development of a dexamethasone intravitreal implant for the treatment of noninfectious posterior segment uveitis Scott M. Whitcup 1 and Michael R. Robinson 2 1 Jules Stein Eye Institute, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California. 2 Allergan, Inc., Irvine, California Address for correspondence: Michael R. Robinson, MD, Allergan, Inc., 2525 Dupont Drive, Irvine, CA robinson_michael@allergan.com Uveitis is a group of ocular inflammatory disorders that can lead to severe vision loss. Despite advances in antiinflammatory therapy, many patients are resistant to or intolerant of existing treatments. A biodegradable, sustainedrelease implant, dexamethasone intravitreal implant 0.7 mg (Ozurdex), has been developed to deliver dexamethasone to target tissues in the posterior segment of the eye, minimizing systemic drug exposure and limiting side effects. The implant releases dexamethasone over a period of up to 6 months as the poly(d,l-lactide-co-glycolide) polymer matrix of the implant is metabolized to carbon dioxide and water. The implant is placed in the vitreous of the eye with a single-use applicator in a sutureless, office-based procedure. Treatment with a single dexamethasone intravitreal implant in patients with noninfectious intermediate or posterior uveitis has been shown to produce significant improvements in intraocular inflammation and best-corrected visual acuity with treatment benefit sustained for 6 months. Dexamethasone intravitreal implant has also been shown to reduce central retinal thickness and improve best-corrected visual acuity in patients with macular edema of various etiologies. The implant has been approved for treatment of noninfectious uveitis involving the posterior segment, diabetic macular edema, and macular edema associated with branch and central retinal vein occlusion. Keywords: corticosteroids; drug delivery system; inflammation; intravitreal injection; poly(d,l-lactide-co-glycolide); visual acuity Introduction Uveitis is an internal inflammation of the eye that can cause devastating vision loss. It may affect any part of the uvea (the middle layer of the eye including the iris, ciliary body, and choroid), as well as the adjacent retina, optic nerve, and vitreous. In the developed world, uveitis is the fifth most common cause of visual loss, estimated to account for 10 15% of cases of total blindness and 5 20% of cases of legal blindness. 1 Because visual loss may be attributed to complications of uveitis, such as macular edema, secondary glaucoma, cataract, vitreous opacities, and retinal scars, rather than to the underlying disease, the contribution of uveitis to blindness may be underestimated. 2 The most sight-threatening forms of the disease involve the posterior segment of the eye. Categorized according to the primary site of ocular inflammation, intermediate uveitis involves the vitreous, peripheral retina, and pars plana of the ciliary body, whereas posterior uveitis involves the choroid and/or retina. Uveitis of the posterior segment occurs most often in the working age population. In the 2004 Northern California Uveitis Epidemiology study, the highest incidence of intermediate and posterior uveitis (4.8 and 3.2 per 100,000 person-years, respectively) was seen in individuals years of age. 3 Uveitis may be associated with systemic autoimmune disease, such as sarcoidosis, Behçet s disease, or juvenile arthritis, or result from infection or a drug reaction, but often the cause is unknown. In a retrospective study of the records of 1237 patients with uveitis who were referred to a large tertiary eye center, most of the patients (83.1%) had doi: /nyas Ann. N.Y. Acad. Sci (2015) 1 12 C 2015 The Authors. Annals of the New York Academy of Sciences 1 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

2 Dexamethasone implant for uveitis treatment Whitcup & Robinson noninfectious uveitis. 4 In 34.9% of patients, the uveitis was nondifferentiated/idiopathic. 4 Noninfectious uveitis affecting the posterior segment of the eye is typically a chronic, debilitating condition with a high risk of irreversible vision loss. It is usually painless and typically presents with blurred or decreased vision and floaters. Inflammatory cells that infiltrate the vitreous chamber of the eye cause vitreous haze that can contribute to vision loss. Macular edema (swelling in the central area of the retina caused by breakdown of the blood retinal barrier and vascular leakage) is one of the leading causes of vision loss in uveitis affecting the posterior segment. 5,6 Chronic macular edema can result in structural damage, leading to permanent loss of central vision and blindness. Noninfectious posterior segment uveitis presents a therapeutic challenge for several reasons: the target tissues are deep within the eye; the pathophysiology involves inflammation and vascular leakage; and the condition is often chronic, requiring longterm therapy to prevent loss of vision. 7 There is a need for treatments that deliver sustained, effective therapy to target tissues in the back of the eye while limiting systemic exposure. Approach to treatment Potent anti-inflammatory agents, corticosteroids are usually effective in reducing the macular edema and inflammatory haze associated with uveitis, and despite the development of novel anti-inflammatory therapy, these drugs remain the first-line treatment for noninfectious uveitis. 8,9 Strategies for delivery of corticosteroids to the posterior segment of the eye include topical and systemic administration, peribulbar and subconjunctival injections, and intravitreal placement. A relevant issue has been that many patients are intolerant to prolonged systemic therapy. Locally administered steroids can minimize systemic drug exposure, but it has been especially difficult to deliver therapeutic levels of corticosteroids to the retina and vitreous for extended periods of time. Topical corticosteroid eye drops that are applied to the ocular surface are often ineffective for treatment of diseases of the posterior segment because of poor bioavailability, as only a very small percentage of the applied drug is absorbed into the eye and penetrates ocular structures to reach the vitreous and retina. 10 Oral corticosteroids are generally used as first-line systemic therapy in sight-threatening uveitis, 11 but the high plasma concentrations required to achieve therapeutic drug levels in the eye are associated with a high risk of systemic side effects such as hypertension, diabetes, osteoporosis, and increased susceptibility to infection. 12 Sub-Tenon s, peribulbar, or subconjunctival injections of corticosteroids are useful because they provide higher concentrations at the retina and lower systemic concentrations than oral dosing, 13 but frequent repeat injections are typically needed to maintain a therapeutic effect over an extended period. 14 Placement in the vitreous is the most targeted approach to drug delivery, providing drug directly to the target tissues in the back of the eye while limiting systemic exposure. With appropriate precautions for sterility, drug can be injected into the vitreous in an office setting. The challenge with this approach is in providing safe and effective therapy over the long term because drugs characteristically have a very short half-life in the vitreous. Particulate formulations (crystals) of corticosteroids, such as triamcinolone acetonide, are used to extend the duration of drug effect after intravitreal injection, 15 but frequent intravitreal injections of drug suspensions are still needed to treat chronic disease. These triamcinolone acetonide injections may result in visual obscuration from particle dispersion, and particles and preservative in the formulation may cause complications of inflammation and sterile endophthalmitis The optimal approach to treatment may be to combine intravitreal placement with sustainedrelease drug delivery implants. Sustained-release intravitreal implants share the advantages of intravitreal injections in delivering drug in close proximity to the target tissues and limiting systemic exposure. In addition, sustained-release implants have the potential to provide a consistent therapeutic drug level at the target tissue and reduce the need for frequent intravitreal injections. Differentiating corticosteroids Dexamethasone is a synthetic corticosteroid that is 25 times more potent than cortisol in antiinflammatory activity. 19 The structure of dexamethasone is identical to the structure of cortisol with three modifications: an extra double bond between carbons 1 and 2, a 16- -methyl substituent, and the addition of a 9- -fluoro group (Fig. 1). These modifications provide high selectivity for 2 Ann. N.Y. Acad. Sci (2015) 1 12 C 2015 The Authors. Annals of the New York Academy of Sciences

3 Whitcup & Robinson Dexamethasone implant for uveitis treatment Figure 1. Chemical structure of dexamethasone. the glucocorticoid receptor and increase potency, placing dexamethasone within the category of highpotency corticosteroids. In comparison with the other corticosteroids commonly used in intravitreal therapy, the anti-inflammatory potency of dexamethasone is fivefold greater than the potency of triamcinolone and similar to the potency of fluocinolone acetonide. 21 The corticosteroids used in intravitreal therapy also can be differentiated based on their pharmacokinetic profiles. Dexamethasone is less lipophilic than triamcinolone acetonide or fluocinolone acetonide and is accumulated to a lesser extent in the trabecular meshwork and lens. 22 This may result in reduced risk of steroid-related increases in intraocular pressure and cataract with dexamethasone compared with triamcinolone acetonide and fluocinolone acetonide. 22 Dexamethasone implant drug-delivery system A sustained-release implant was developed to deliver effective concentrations of dexamethasone to the posterior segment of the eye over a period of several months without the need for frequent intravitreal injections. The sustained-release dexamethasone intravitreal implant (DEX implant; Ozurdex; Allergan Inc., Irvine, CA, USA) contains 0.7 mg dexamethasone embedded in a solid polymer drug delivery system (Novadur; Allergan Inc.) that consists of a biodegradable polymer matrix of poly(d,llactide-co-glycolide) (PLGA) formulated without a preservative. Biodegradable polymers and copolymers of lactic acid and glycolic acid have been used for many years in medical applications ranging from biodegradable sutures to drug delivery (Fig. 2). 23 PLGA is particularly useful in drug delivery applications because it is possible to manipulate the polymer composition during manufacturing to produce a desired rate of degradation that can vary from weeks to years. 24 DEX implant was designed and manufactured to release drug over a period of 6 months. 25 The DEX implant drug-delivery system is illustrated in Fig. 3. In clinical use, DEX implant is preloaded into a single-use applicator for injection into the vitreous. The injection procedure is performed with subconjunctival or topical anesthesia in an office setting using standard sterile preparation for intravitreal injections. After placement in the eye, water diffuses into the implant and dexamethasone is slowly released as the PLGA matrix degrades into the inert compounds lactic acid and glycolic acid, which are subsequently metabolized to carbon dioxide and water (Fig. 4). Because the implant eventually degrades completely, sequential implants can be placed in the eye over time with no need for surgical removal of residual implant. Pharmacokinetics of DEX implant When dexamethasone is injected into the vitreous, it is cleared rapidly with an estimated half-life of only 5.5 hours in human eyes. 26 Therefore, the therapeutic effects of an injection of dexamethasone solution can be expected to last no longer than a few days; intravitreal injections of this frequency would not be practical for patients. In contrast, pharmacokinetic studies in monkey eyes have shown that after treatment with a single DEX implant, the concentrations of dexamethasone in the retina and vitreous peak within 1 2 months and remain detectable for 6 months after treatment. 27 At day 60, the mean concentration of dexamethasone in the retina and vitreous (sample not containing the implant) were 1110 ng/g and 213 ng/ml, respectively. Mean plasma concentrations of dexamethasone were low through day 60 (1.1 ng/ml) and fell beneath the limit of quantitation after day 60. Although the pharmacokinetics of DEX implant in human eyes have not been studied, these results are consistent with the clinical effects of DEX implant in eyes with uveitis: in a 26-week phase III clinical trial of DEX implant for treatment of noninfectious posterior segment uveitis, DEX implant demonstrated peak effects at Ann. N.Y. Acad. Sci (2015) 1 12 C 2015 The Authors. Annals of the New York Academy of Sciences 3

4 Dexamethasone implant for uveitis treatment Whitcup & Robinson Figure 2. Timeline of development of sustained-release dexamethasone implant. PGA, polyglycolide; PLA, polylactide; PLGA, poly(d,l-lactide-co-glycolide). Adapted from Ref. 23, with kind permission of Springer Science+Business Media. 8 weeks and continued to provide treatment benefit up to 26 weeks. 28 Phase II evaluation of DEX implant A 6-month, multicenter (29 sites in the United States), randomized, double-masked, controlled phase II trial evaluated the effects of DEX implant in patients with persistent macular edema related to one of several eye conditions (Clinicaltrials.gov NCT ). 29 Eligible patients were at least 12 years of age and had best-corrected visual acuity (BCVA; vision corrected if needed with eyeglasses and measured with an Early Treatment Diabetic Retinopathy Study [ETDRS] eye chart) of 20/40 (67 73 ETDRS letters) to 20/200 (34 38 ETDRS letters) in the study eye because of macular edema that had persisted for at least 90 days after laser treatment or medical therapy. The underlying cause of the macular edema was diabetic retinopathy, retinal vein occlusion, noninfectious uveitis, or Irvine Gass syndrome (macular edema occurring after cataract surgery), and the randomization was stratified by the underlying disease. Key exclusion criteria included history of vitrectomy, use of systemic, periocular, or intraocular corticosteroids within 30 days of enrollment, moderate or severe glaucoma, poorly controlled hypertension, and poorly controlled diabetes. Patients were randomized to observation (n = 105) or to a single treatment with DEX implant 0.7 mg (n = 105) or DEX implant 0.35 mg (n = 105) in the study eye. DEX implant was surgically implanted into the vitreous chamber of the study eye through a 19- to 20-gauge (1.15-mm) pars plana incision. After implant placement, the scleral and conjunctival wounds were closed with absorbable sutures. The primary efficacy endpoint was the percentage of patients achieving at least 10-letter gain in BCVA from baseline at 90 days after treatment. Secondary outcome measures included the percentage of patients achieving at least 15-letter gain in BCVA, fluorescein angiography (showing vascular leakage contributing to macular edema), central retinal thickness (an anatomic measure of central macular edema) assessed with optical coherence tomography, and safety measures. The trial results demonstrated that a single DEX implant in patients with persistent macular edema significantly improved BCVA at 90 days after treatment. At 90 days after treatment, the percentage of patients achieving at least 10-letter improvement in BCVA was significantly higher in the DEX implant 0.7 mg group (35%, P < 0.001) and DEX implant 0.35 mg group (24%, P = 0.04) than in the observation group (13%). At least 15-letter BCVA improvement also occurred in a greater percentage of patients treated with DEX implant 0.7 mg (18%) 4 Ann. N.Y. Acad. Sci (2015) 1 12 C 2015 The Authors. Annals of the New York Academy of Sciences

5 Whitcup & Robinson Dexamethasone implant for uveitis treatment Figure 3. Dexamethasone intravitreal implant (DEX implant). Adapted from Ref. 7 with permission. (A) Illustration of the implant inserted into the vitreous chamber of an eye with panuveitis and 3+ vitreous haze using a single-use applicator. (B) Size of the marketed 0.7 mg implant. Adapted from Ref. 7, copyright C 2012, Informa Healthcare. Adapted with permission of Informa Healthcare. than observed patients (6%, P = 0.006) at day 90, and the difference between groups remained significant through 6 months. Measurements of secondary outcomes at day 90 showed that both fluorescein leakage and central retinal thickness were significantly decreased in patients treated with DEX implant compared with patients in the observation group. The beneficial effect of DEX implant treatment was evident regardless of the underlying cause of macular edema. In a subgroup analysis of patients with macular edema due to uveitis or Irvine Gass syndrome (data pooled because both are inflammatory disease), the percentage of patients with at least 10-letter BCVA improvement at day 90 was 54% (7/13) in the DEX implant 0.7 mg group and 42% (5/12) in the DEX implant 0.35 mg group versus 14% (2/14) in the observed group (P = vs. DEX implant 0.7 mg). 30 A significantly higher proportion of patients treated with DEX implant 0.7 mg (7/13) than observed patients (1/14) had at least a two-grade improvement in vascular leakage measured with fluorescein angiography (P = 0.027). Phase IIb evaluation of an applicator system for nonsurgical placement of DEX implant In the phase II trial of DEX implant in persistent macular edema, adverse events of vitreous hemorrhage and eye pain were reported in at least one-third of patients with uveitis and Irvine Gass syndrome who received DEX implant, but these adverse events were attributed to the surgical implantation procedure rather than the implant. 30 To address this issue, an applicator system was developed to simplify the placement of DEX implant in the vitreous chamber and improve safety. The applicator is a sterile, single-use instrument that delivers one preloaded dose of DEX implant via injection through a 22-gauge needle. In a phase IIb trial that evaluated the safety and performance of DEX implant inserted with the applicator versus incisional placement, adult patients with macular edema due to diabetic retinopathy, retinal vein occlusion, uveitis, or Irvine Gass syndrome were randomized to receive DEX implant 0.7 mg by pars plana incisional placement (n = 10) or via the applicator (n = 20) and were followed for 6 months. 31 Overall, safety findings were more favorable in the applicator group. The insertion wound was self-sealing for all patients in the applicator group, and no sutures were required. The overall incidence of ocular adverse events was 13 of 19 (68.4%) in the applicator group versus 9 of 10 (90%) in the incisional group, and vitreous hemorrhage occurred in 0 patients in the applicator group versus two patients (20%) in the incisional group. The percentage of patients achieving at least 15-letter improvement in BCVA from baseline was 40% (8/20) in the applicator group and 30% (3/10) in the incisional group. On the basis of these findings, the applicator system was used to deliver DEX implant in phase III studies. Ann. N.Y. Acad. Sci (2015) 1 12 C 2015 The Authors. Annals of the New York Academy of Sciences 5

6 Dexamethasone implant for uveitis treatment Whitcup & Robinson Figure 4. Biodegradation of dexamethasone intravitreal implant. (A) Illustration of the bulk erosion of the implant as water diffuses into the implant and the PLGA matrix degrades, releasing dexamethasone. Adapted from Ref. 25 with kind permission of Springer Science+Business Media. (B) During degradation of the implant, the PLGA matrix is metabolized to carbon dioxide and water. PLGA, poly(d,l-lactide-co-glycolide). Reproduced from Ref. 7, copyright C 2012, Informa Healthcare. Reproduced with permission of Informa Healthcare. Phase III trial of DEX implant in noninfectious posterior segment uveitis A 26-week, multicenter, masked, randomized, sham-controlled phase III trial (the HURON study) evaluated the efficacy and safety of DEX implant for treatment of noninfectious posterior segment uveitis (Clinicaltrials.gov NCT ). 28 Adult patients with noninfectious intermediate or posterior uveitis, a vitreous haze score of at least +1.5 on a scale of 0 4, and BCVA of letters (20/630 to 20/32) were enrolled in the study. 6 Ann. N.Y. Acad. Sci (2015) 1 12 C 2015 The Authors. Annals of the New York Academy of Sciences

7 Whitcup & Robinson Dexamethasone implant for uveitis treatment Key exclusion criteria included a history of glaucoma, use of medication to lower intraocular pressure (IOP) within the previous month, and uveitis unresponsive to previous corticosteroid treatment. Patients were randomized 1:1:1 to a single treatment with DEX implant 0.7 mg (n = 77), DEX implant 0.35 mg (n = 76), or a sham procedure using a needleless applicator (n = 76) in the study eye. The randomization was stratified by the baseline vitreous haze score. DEX implant was inserted into the vitreous with the applicator, and a needleless applicator was used for the sham procedure. Following study treatment at day 0, efficacy and safety were evaluated at assessment visits at weeks 3, 6, 8, 12, 16, 20, and 26. The primary efficacy endpoint was the percentage of patients with a vitreous haze score of 0 at week 8. Other key efficacy outcome measures included vitreous haze through week 26, BCVA, and central retinal thickness evaluated with optical coherence tomography. Safety outcomes included adverse events, IOP measurements, and biomicroscopy/ophthalmoscopy. The treatment groups were well matched at baseline. The mean age of the study population was 45 years. The majority of the patients in the study (>60%) were female, and >60% were white. Most of the patients (81%) were diagnosed with intermediate uveitis. The mean duration of uveitis at study entry was over 4 years, and the mean vitreous haze score was approximately +2 in each treatment group. Approximately one-fourth of the patients were using systemic anti-inflammatory or immunosuppressant medication at study entry and continued its use with the same dosing regimen during the study. The study completion rate was high. Overall, 217 of 229 (95%) of enrolled patients completed the 26-week study. Only two patients (in the DEX implant 0.7 mg group) discontinued because of adverse events, and only one patient (in the DEX implant 0.35 mg group) discontinued because of lack of efficacy. DEX implant 0.7 and 0.35 mg provided substantial improvement in vitreous haze, BCVA, and central macular thickness throughout the study with peak effect at week 8. Improvement was most pronounced in the DEX implant 0.7 mg group, but both DEX implant 0.7 mg and DEX implant 0.35 mg met the primary efficacy endpoint. At week 8, the percentage of patients with a vitreous haze score of 0 was significantly higher in both the DEX implant 0.7 mg group (47%) and the DEX implant 0.35 mg group (36%) compared with the sham group (12%, P < 0.001). The percentage of patients in the DEX implant 0.7 mg group with resolution of vitreous haze was significantly higher than in the sham group by week 6, and this treatment benefit was maintained through week 26 (Fig. 5). Analysis of the results stratified by baseline vitreous haze scores showed that in the subgroup of patients with a baseline vitreous haze score of +1.5 or +2, the percentage of patients with a vitreous haze score of 0 was significantly higher in both DEX implant groups than in the sham group at all follow-up visits from week 3 through week 26, with the exception of the DEX implant 0.35 mg group at week 16. Improvement in vitreous haze was accompanied by significant and sustained visual improvement. Baseline mean BCVA in the study population was approximately 60 letters (20/63), but 48 of 229 patients (21%) had a baseline BCVA of more than 70 letters (20/40) and could not achieve a clinically significant gain in BCVA from baseline (defined as 15-letter improvement, or three lines on a standard visual acuity chart) even if they achieved 20/20 vision. Nonetheless, the percentage of patients achieving 15-letter improvement in BCVA from baseline was 2.5- to 6-fold higher in the DEX implant 0.7 mg group than in the sham group at each follow-up visit (Fig. 6). Between-group differences in the achievement of 15-letter BCVA gain were consistently statistically significant for the comparison of both DEX implant 0.7 mg (P < 0.001) and DEX implant 0.35 mg (P 0.027) with sham. Furthermore, mean changes in BCVA from baseline were statistically significantly larger with DEX implant 0.7 mg than with sham throughout the study period (P 0.002). Baseline mean central macular thickness in the DEX implant 0.7 mg, DEX implant 0.35 mg, and sham groups (344, 339, and 325 m, respectively) was higher than normal, indicating the presence of macular edema. Measurements of central macular thickness during follow-up showed a significant decrease from baseline in the DEX implant 0.7 and 0.35 mg groups at both week 8 ( 99 and 91 m, respectively) and week 26 ( 50 and 68 m, respectively; P 0.004). In contrast, changes from baseline central macular thickness in the sham group ( 12 matweek12and 36 mat Ann. N.Y. Acad. Sci (2015) 1 12 C 2015 The Authors. Annals of the New York Academy of Sciences 7

8 Dexamethasone implant for uveitis treatment Whitcup & Robinson Figure 5. Patients with a vitreous haze score of 0 in the phase III trial. Allergan; data on file. P values shown are for the comparison of DEX implant 0.7 mg (marketed dose) and sham. DEX implant, dexamethasone intravitreal implant. Figure 6. Patients with at least 15-letter improvement in best-corrected visual acuity in the phase III trial. Allergan; data on file. P values shown are for the comparison of DEX implant 0.7 mg (marketed dose) and sham. DEX implant, dexamethasone intravitreal implant. week 26) were not statistically significant. The differences in mean change from baseline central macular thickness between the DEX implant 0.7 and 0.35 mg groups and the sham group were statistically significant at week 8 only (P 0.004). Rescue treatment with nonstudy anti-inflammatory agents could be administered if it was considered necessary by the investigator and the vitreous haze score had increased by >1 unit from week3tojustbeforeweek8,orwas+1.5 or higher at or after week 8. At the first efficacy evaluation (week 3), the percentage of patients needing rescue treatment was 1%, 3%, and 15% in the DEX implant 0.7 mg, DEX implant 0.35 mg, and sham groups, respectively (P = for DEX implant 0.7 mg vs. sham). Patients in the sham group remained more 8 Ann. N.Y. Acad. Sci (2015) 1 12 C 2015 The Authors. Annals of the New York Academy of Sciences

9 Whitcup & Robinson Dexamethasone implant for uveitis treatment likely than patients in the DEX implant groups to need rescue treatment throughout the 26-week study. In summary, the results of the phase III study demonstrated that a single DEX implant produced significant improvement in intraocular inflammation and visual acuity that persisted for 6 months. The 0.7 mg dose demonstrated greater efficacy than the 0.35 mg dose. Adverse events associated with DEX implant A single dose of DEX implant 0.7 or 0.35 mg was well tolerated in both the phase II and phase III trials, and the safety profiles of the 0.7 and 0.35 mg doses were similar. The adverse events most commonly associated with intraocular corticosteroid treatment are increases in IOP and cataract development. 32,33 In the phase III trial evaluating a single dose of DEX implant for treatment of noninfectious intermediate or posterior uveitis, less than 10% of patients in the DEX implant treatment groups had an IOP of 25 mm Hg or higher (an IOP above 21 mm Hg is considered higher than normal) at any study visit. 28 All increases in IOP that occurred were managed with observation or IOP-lowering medication, and no patient required a laser or surgical procedure to control an IOP increase related to DEX implant treatment. The percentage of patients treated with DEX implant 0.7 mg who required IOP-lowering medication for IOP control was 23% or less at study visits from week 3 through week In the phase II trial, among the 13 patients with uveitis or Irvine Gass syndrome who were treated with DEX implant 0.7 mg, four had an IOP measurement of 25 mm Hg or higher at any scheduled follow-up visit. In three of the patients, the IOP elevation was measured within 1 week of treatment, and in all four patients, the increase in IOP was managed with observation or IOP-lowering eye drops. In the phase III trial, cataract-related adverse events were reported in 15%, 12%, and 7% of phakic eyes in the DEX implant 0.7 mg, DEX implant 0.35 mg, and sham groups, respectively, during the 6 months following treatment, and three patients (one in the DEX implant 0.7 mg group and two in the sham group) had cataract extractions. Other adverse events reported showed no statistically significant difference in incidence among treatment groups. The most common of these adverse events were conjunctival hemorrhage (incidence of 30%, 16%, and 21% in the DEX implant 0.7 mg, DEX implant 0.35 mg, and sham groups, respectively) and ocular discomfort or eye pain. Patient-reported outcomes The National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) was administered to patients at screening and weeks 8, 16, and 26 in the phase III HURON trial to evaluate the effects of DEX implant treatment on patient-reported visual functioning. 34 This questionnaire includes 11 vision-related subscales (general vision, near vision, distance vision, driving, peripheral vision, color vision, ocular pain, and vision-specific role difficulties, dependency, social function, and mental health) as well as one general health question. An overall composite score is calculated as the mean of the vision-related subscale scores. At baseline before treatment, scores for patients were lower than scores in the general U.S. population, reflecting the negative impact of uveitis on vision-related functioning. 35 Statistical analysis of the results during the trial used analysis of covariance to adjust for baseline differences in scores among the treatment groups. By week 8, patients treated with DEX implant 0.7 mg reported improvement compared with sham-treated patients on the NEI VFQ-25 subscales of near vision (P = 0.031), distance vision (P = 0.023), peripheral vision (P = 0.045), and vision-specific social functioning (P = 0.019), and well as on the NEI VFQ-25 composite score (P = 0.007). Improvement with DEX implant 0.7 mg relative to sham persisted and was seen at week 26 on the subscales of distance vision (P = 0.003), vision-specific social functioning (P = 0.009), and on the composite score (P = 0.001). In addition, at week 26, patients reported improvement with DEX implant 0.7 mg relative to sham on the NEI VFQ-25 subscales of vision-specific role difficulties (P = 0.038), vision-specific dependency (P = 0.017), and vision-specific mental health (P = 0.036). The improvements in scores in the DEX implant 0.7 mg group relative to the sham group were both clinically and statistically significant. 34 These results demonstrate the value of DEX implant treatment for improving vision-related functioning in patients with noninfectious intermediate or posterior uveitis from the patient perspective. Ann. N.Y. Acad. Sci (2015) 1 12 C 2015 The Authors. Annals of the New York Academy of Sciences 9

10 Dexamethasone implant for uveitis treatment Whitcup & Robinson Patients treated with DEX implant 0.7 mg reported improved vision function outcomes as early as 8 weeks after treatment, and improved visionrelated functioning was sustained for 26 weeks after the implant. Postmarketing studies A recent retrospective study demonstrated that repeat treatment of noninfectious uveitis with DEX implant is effective in longer term disease control. 36 Patients were followed for a mean of 17 months after their first treatment; 37% (14/37) of the study eyes received a single implant and 63% (14/37) received sequential implants. BCVA, central retinal thickness, and vitreous haze improved significantly after the first implant, and the median duration of sustained improvement after treatment was 6 months. For patients who received more than one implant, similar benefit of treatment was seen after each implant. No cataract or glaucoma IOP-lowering surgeries were needed. Zarranz-Ventura et al. 37 recently reported a larger case series of eyes with noninfectious uveitis treated with DEX implant. The indications for treatment were cystoid macular edema and vitritis. Mean visual acuity improved significantly at all time points from 2 weeks to 12 months after the initial DEX implant injection. Among the 54 eyes that completed 12 months of follow-up, 32 (59.3%) required a single treatment with DEX implant, 22 (40.7%) required a second injection after a mean interval of 6.6 months, and five required a third injection at a mean of 11.0 months after the initial treatment. Increases in IOP occurred more frequently in this case series than in the phase III clinical trial but were well controlled with medication in most cases. Eight eyes with glaucoma were included in the case series, and two eyes required glaucoma surgery during the study period. DEX implant has also been reported to be effective in treating persistent macular edema resistant to other therapy in quiescent intermediate and posterior uveitis 38 and to be useful in the treatment of pediatric uveitis. 39 Place in therapy of noninfectious uveitis Treatment of noninfectious posterior segment uveitis with an implant providing sustained, targeted delivery of corticosteroid to affected tissues offers improved systemic safety compared with systemic corticosteroid therapy and could potentially become the mainstay of uveitis treatment. The favorable efficacy and safety results from the clinical development trials supported the 2010 U.S. Food and Drug Administration approval of DEX implant 0.7 mg for treatment of noninfectious uveitis involving the posterior segment. Approval of DEX implant for other indications Efficacy and safety findings in phase III trials of DEX implant in patients with macular edema associated with retinal vein occlusion 40 and diabetic retinopathy 41 were also favorable. The U.S. Food and Drug Administration approved DEX implant 0.7 mg for treatment of macular edema following central and branch retinal vein occlusion in 2009, and in 2014, approved DEX implant 0.7 mg for treatment of diabetic macular edema following completion of the 3-year MEAD study 41 comparing DEX implant with sham procedure for treatment of diabetic macular edema. The MEAD study had the longest follow-up of all reported trials of DEX implant and provides the only 36-month data for DEX implant among all its indications. Conclusion and future directions Sustained-release DEX implant is an advanced delivery system for corticosteroid to tissues in the back of the eye while limiting systemic drug exposure. The implant provides sustained release of dexamethasone for up to 6 months and has been shown to be effective and well tolerated in the treatment of noninfectious posterior segment uveitis, as well as in the treatment of macular edema of various etiologies, including diabetic macular edema and macular edema secondary to retinal vein occlusion. Clinical studies to establish the long-term safety of DEX implant in the treatment of uveitis and macular edema associated with diabetic retinopathy or retinal vein occlusion, and to evaluate the efficacy and safety of DEX implant for treatment of macular edema associated with pars plana vitrectomy and epiretinal membrane peeling, are in progress. Acknowledgments We thank the hundreds of investigators and thousands of patients who have participated in the DEX 10 Ann. N.Y. Acad. Sci (2015) 1 12 C 2015 The Authors. Annals of the New York Academy of Sciences

11 Whitcup & Robinson Dexamethasone implant for uveitis treatment implant clinical research program. Medical writing and editorial assistance was provided by Kate Ivins, PhD of Evidence Scientific Solutions, Philadelphia, PA, and funded by Allergan, Inc. Conflicts of interest ScottM.WhitcupwasanemployeeofAllergan,Inc. at the time of this work. Michael R. Robinson is an employee of Allergan, Inc. References 1. Durrani, O.M., C.A. Meads & P.I. Murray Uveitis: a potentially blinding disease. Ophthalmologica 218: Rothova, A. et al Causes and frequency of blindness in patients with intraocular inflammatory disease. Br.J.Ophthalmol. 80: Gritz, D.C. & I.G. Wong Incidence and prevalence of uveitis in Northern California; the Northern California Epidemiology of Uveitis Study. Ophthalmology 111: ; discussion Rodriguez, A. et al Referral patterns of uveitis in a tertiaryeyecarecenter.arch. 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