Hindawi Publishing Corporation
`The Scientific World Journal
`Volume 2014,Article ID 989501 , 14 pages
`http:l/dx.doi.org/10.1155/2014/989501
`
`H indaw i
`
`Review Article
`Intravitreal Steroids for the Treatment of Retinal Diseases
`
`Valentina Sarao, 1 Daniele Veritti, 1 Francesco Boscia, 2 and Paolo Lanzetta 1
`
`1 Department of Ophthalmology, University of Udine, Piazza Santa Maria de/la Misericordia, 33100 Udine, Italy
`2 Department of Ophthalmology, University of Sassari, Piazza D'Armi, 07100 Sassari, Italy
`
`Correspondence should be addressed to Paolo Lanzetta; paolo.lanzetta@uniud.it
`
`Received 19 August 2013; Accepted 10 October 2013; Published 8 January 2014
`
`Academic Editors: N. Gupta and F. M. Penha
`
`Copyright © 2014 Valentina Sarao et al. This is an open access article distributed under the Creative Commons Attribution License,
`which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
`
`Diabetic macular edema (DME), pseudophakic cystoid macular edema (CME), age-related macular degeneration (AMD), retinal
`vascular occlusion (RVO), and uveitis are ocular conditions related to severe visual impairment worldwide. Corticosteroids have
`been widely used in the treatment of these retinal diseases, due to their well-known antiangiogenic, antiedematous, and anti(cid:173)
`inflammatory properties. Intravitreal steroids have emerged as novel and essential tools in the ophthalmologist's armamentarium,
`allowing for maximization of drug efficacy and limited risk of systemic side effects. Recent advances in ocular drug delivery methods
`led to the development of intraocular implants, which help to provide prolonged treatment with controlled drug release. Moreover,
`they may add some potential advantages over traditional intraocular injections by delivering certain rates of drug directly to the site
`of action, amplifying the drug's half-life, contributing in the minimization of peak plasma levels of the drug, and avoiding the side
`effects associated with repeated intravitreal injections. The purpose of this review is to provide an update on the use of intravitreal
`steroids as a treatment option for a variety of retinal diseases and to review the current literature considering their properties, safety,
`and adverse events.
`
`I. Introduction
`
`The use of corticosteroids for the treatment of ocular inflam(cid:173)
`matory diseases was first described in the early 1950s [l).
`Corticosteroids have anti-inflammatory, antiangiogenic, and
`antipermeability properties that make them an attractive
`therapeutic option for a variety of posterior segment diseases.
`The rationale for using a steroidal drug for the treatment
`of edematous and proliferative diseases is that abnormal
`proliferation of cells is often associated with and trigged by
`inflammation. Moreover, intraretinal accumulation of fluid is
`usually accompanied by a blood-retinal barrier dysfunction
`that can be restored with steroid therapy. The principal effects
`of steroids are thought to be stabilization of the blood-retinal
`barrier (BRB), reduction of exudation, and downregulation
`of inflammatory stimuli, but the exact mechanisms remain
`unknown. Steroids are thought to act by the induction
`of proteins called lipocortins, in particular phospholipase
`A2. These proteins reduce leukocyte chemotaxis, control
`biosynthesis, and inhibit the release of arachidonic acid
`from the phospholipid membrane, which is one of the most
`important common precursors of potent inflammatory cell
`
`mediators such as prostaglandins and leukotrienes. Based
`on experimental studies, corticosteroids have been shown
`to control gene expression of inflammatory mediators. This
`regulation influences the expression of vascular endothe(cid:173)
`lial growth factor (VEGF), inhibits pro-inflammatory genes
`such as tumor necrosis factor-alpha (TNF-a) and other
`inflammatory chemokines, and induces the expression of
`anti-inflammatory factors such as pigment-derived growth
`factor (PEDF) [2-4) . Additionally, steroids seem to reduce
`the expression of matrix metalloproteinases (MMPs) and
`to downregulate intercellular adhesion molecule 1 (ICAM-
`1) on choroidal endothelial cells [S-11]. Several routes of
`administration have been considered for the treatment of
`various ocular diseases. Oral dosing, unfortunately, causes
`a spectrum of systemic side effects, including osteoporo(cid:173)
`sis, cushingoid state, adrenal suppression, and exacerba(cid:173)
`tion of diabetes [12, 13). Topical steroids have not been
`shown to penetrate adequately to the posterior segment [14).
`Geroski and Edelhauser reported that therapeutic doses of
`steroids could reach the posterior segment via transscleral
`absorption with periocular administration [15]. Thus, other
`routes of administration, such as subconjunctival, subtenon,
`
`Novartis Exhibit 2303.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`2
`
`The Scientific World Journal
`
`and posterior juxtascleral infusions, have been studied [16–
`18]. Periocular delivery of steroids has offered for many years
`a valid compromise between better penetration and lack of
`systemic side effects. However, peribulbar injections seem to
`result in lower morphological and functional outcomes as
`compared with those reported with the use of intravitreal
`administration [19–22]. But, two interventional case series
`have demonstrated that posterior juxtascleral infusion of a
`viscoelastic formulation of triamcinolone acetonide is an
`effective treatment for diffuse diabetic macular edema (DME)
`unresponsive to laser photocoagulation [23, 24].
`Based on experimental studies, clinical observations,
`and pathogenic considerations, Robert Machemer, among
`others, suggested the intravitreal delivery of steroids to
`locally suppress intraocular inflammation, proliferation of
`cells, and neovascularization [25]. Intravitreal delivery of
`corticosteroids has allowed many posterior segment diseases
`to be locally treated without the adverse systemic side effects.
`Intravitreal steroids have been widely studied in many ran-
`domized clinical trials, demonstrating significant improve-
`ments both in morphological and functional outcomes in
`many posterior segment diseases [26–28]. Intravitreal ther-
`apy also allows for the steroid to bypass the BRB, leading to
`a more concentrated dose of steroid for a prolonged period
`of time. Delivery of steroids to the vitreous cavity can be
`achieved via direct injection through the pars plana, intro-
`duction of a sustained-release or biodegradable implants,
`or injection of conjugate compounds. Several intravitreal
`biodegradable and nondegradable steroid releasing implants
`have been designed to provide long-term drug delivery
`to the macular region. Different steroid molecules have
`varying potencies and toxicities. There are several ways
`to distinguish among the steroids used in ophthalmology,
`including chemical structure, anti-inflammatory potency,
`ability to translocate the glucocorticoid receptor complex to
`the nucleus, ability to transactivate or transrepress ligand-
`dependent gene sets and biologic responses, neuroprotection
`of the photoreceptors/retinal pigment epithelium, and direct
`cytotoxic effects [29]. These differences may help to explain
`the differences among steroids in their safety and efficacy
`for the treatment of retinal disease. The purpose of this
`paper is to review the current status of intravitreal steroidal
`drugs,
`including triamcinolone acetonide, biodegradable
`dexamethasone implant, and nondegradable fluocinolone
`acetonide implant in the treatment of various retinal diseases
`such as diabetic macular edema (DME), central and branch
`retinal vein occlusion (CRVO and BRVO), neovascular age-
`related macular degeneration (AMD), pseudophakic cystoid
`macular edema (CME), and macular edema secondary to
`uveitis.
`
`2. Triamcinolone Acetonide
`Triamcinolone acetonide (TA) is a synthetic steroid of the
`glucocorticoid family with a fluorine in the ninth position
`[30]. It is commercially available as an ester and represents
`one of the most commonly used steroid agents for the
`treatment of several retinal conditions [31]. TA has an
`
`anti-inflammatory potency five times higher than hydro-
`cortisone with a tenth of the sodium-retaining potency. It
`appears as a white- to cream-colored crystalline powder
`and it is practically insoluble in water and very soluble in
`alcohol [14]. The decreased water solubility accounts for
`its prolonged duration of action. It has been observed that
`adequate concentrations of TA could provide therapeutic
`effects for approximately three months after 4 mg intravitreal
`TA injection [32]. Maximum effect duration of 140 days has
`been suggested [33].
`The current commercial preparations of TA include prod-
`ucts that received dermatologic and orthopedic indications
`and are considered off-label for the intraocular use, products
`registered as devices for assisting the visualization of the
`vitreous during vitreoretinal procedures, and products that
`are registered for intraocular use in uveitis, and other ocular
`inflammatory conditions. Kenalog-40 (40 mg/mL, Bristol-
`Myers Squibb, NJ) is the most commonly used intraocular
`steroid and has been widely utilized as intravitreal injections
`since 2004 for the treatment of several retinal diseases. This
`formulation is US Food and Drug Administration (FDA)-
`approved only for intramuscular and intra-articular use
`and is currently employed off-label for intraocular injec-
`tions. TrivarisTM (80 mg/mL, Allergan Inc., Irvine, CA)
`and Triesence (40 mg/mL, Alcon Inc., Fort Worth, TX) are
`preservative-free brands of TA recently FDA approved for
`ophthalmic use in the treatment of sympathetic ophthalmia,
`temporal arteritis, uveitis, and other ocular inflammatory
`diseases, unresponsive to topical corticosteroids. Vitreal S
`(Sooft s.p.a., Fermo, Italy) is a medical device used in
`endocular surgery to stain the vitreous during vitrectomy
`and it is not registered as drug for intraocular use. There
`are some issues regarding the formulation of TA used
`for intraocular administration. A previous phase-contrast
`microscopy study showed a notable difference of crystal size
`depending upon the drug formulation [34]. Very large and
`irregular crystals, with a significant heterogeneity in crystal
`size, were occasionally found in the off-label, commercially
`available, benzyl-alcohol-preserved TA, whereas the crys-
`tals of a preservative-free in-label, commercially available,
`TA suspension appeared to be relatively uniform in size.
`These morphologic aspects may have a significant impact
`on the half-life of the drug both in vivo and in vitro. This
`hypothesis is based on the fact that smaller crystals have a
`superior surface-area-to-volume ratio, allowing them to be
`dissolved more rapidly. The formulations containing crystals
`that widely vary in size and, thus, including larger crystals
`may theoretically generate a wider time–drug concentration
`curve because of their slower dissolution rate. Different TA
`formulations show variance in reducing the endothelial cell
`proliferation.
`The appropriate dose of intravitreal TA remains a subject
`of debate. Both Audren et al. and Hauser et al. showed that
`the use of a 4 mg dose of intravitreal TA does not have
`enough advantages over the lower 1 mg or 2 mg dose [35,
`36]. However, Lam et al. published a comparison between
`4 mg and 8 mg doses and showed that the higher dose had
`a more sustained effect on both visual acuity and central
`macular thickness, although with a trend to more ocular
`
`Novartis Exhibit 2303.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`The Scientific World Journal
`
`3
`
`complications [37]. By using a dose of about 20 mg of TA, the
`increase in visual acuity was mostly marked during the first
`three and six months after injection and was observable for
`a period of about six to nine months. Differently, by using
`a dose of 4 mg, the duration in the reduction of macular
`thickness as measured by optical coherence tomography
`(OCT) was less than six months [38].
`Based on several studies, intravitreal administration of
`triamcinolone acetonide (TA) has provided promising results
`for the treatment of disorders associated with an abnormal
`endothelial cell proliferation and conditions complicated
`by intraretinal and subretinal fluid accumulation. The anti-
`inflammatory, angiostatic, and antipermeability properties
`of TA have gained interest in chronic retinal diseases, such
`as proliferative diabetic retinopathy [39], DME [40, 41],
`exudative AMD [42–44], presumed ocular histoplasmosis
`syndrome [45], CRVO [46], BRVO [47], neovascular glau-
`coma [48], proliferative vitreoretinopathy [49], persistent
`pseudophakic CME [50], perifoveal telangiectasias [51], sym-
`pathetic ophthalmia [52], ischemic ophthalmopathy [53],
`exudative retinal detachment [54], radiation induced macu-
`lar edema [55], macular edema due to retinitis pigmentosa
`[56], Vogt-Koyanagi-Harada syndrome [57], and chronic
`uveitis [58].
`
`2.1. Diabetic Macular Edema. Intravitreal TA has been widely
`studied in many randomized clinical trials on DME demon-
`strating significant improvements both in morphological
`and functional outcomes [40, 41, 59–61]. Focal and grid
`laser photocoagulation have been considered the standard
`of care for the treatment of DME for many years. However,
`a substantial group of patients are unresponsive to laser
`therapy and fail to improve after photocoagulation. It has
`been reported that three years after initial grid treatment,
`visual acuity improved in 14.5% of the eyes, did not change
`in 60.9%, and decreased in 24.6% of patients with DME [59].
`Therefore, TA has been tested for the treatment of DME,
`either na¨ıve or diffuse and refractory to laser therapy. In most
`cases, TA has been administered intravitreally.
`A carefully designed prospective randomized trial con-
`ducted by the Diabetic Retinopathy Clinical Research Net-
`work (DRCR.net) investigated the efficacy and safety of 1-mg
`and 4-mg doses of preservative-free intravitreal TA (Trivaris)
`in comparison with focal or grid laser photocoagulation [60].
`In the DRCR.net study, 840 study eyes affected by DME were
`randomized to either focal or grid laser photocoagulation
`(𝑛 = 330), 1 mg TA (𝑛 = 256) or 4 mg TA (𝑛 = 254). At 36
`months, the mean change in the visual acuity from baseline
`was +5 letters in the laser group and 0 letters in both TA
`groups. A worsening in visual acuity of three or more lines
`occurred in 8%, 17%, and 16% of eyes, respectively, and an
`improvement in visual acuity by three or more lines occurred
`in 26%, 20%, and 21% of eyes, respectively. Mean (±SD)
`reductions in central macular thickness were 175 ± 149 𝜇m
`in the laser group, 124 ± 184 𝜇m in the 1 mg TA group, and
`126 ± 159 𝜇m in the 4 mg TA group. The mean number of
`treatments at the end of the follow-up was 3.1 for the laser
`group, 4.2 for the 1 mg, and 4.1 for the 4 mg TA groups.
`
`At the four-month visit, mean visual acuity improvement was
`higher in the 4 mg TA group (4 ± 12 letters improvement)
`than in either the laser group (0 ± 13 letters change) or
`the 1 mg TA group (0 ± 13 letters change). By 12 months,
`there were no significant differences among groups in mean
`visual acuity. Therefore, in this study, photocoagulation was
`shown to be more effective over time and had fewer side
`effects than TA. This was considered in support of focal/grid
`photocoagulation. However, it must be noted that during
`the 36 months of follow-up, patients received only four
`treatments with intravitreal TA, which is a low reinjection
`rate based on pharmacokinetic data. Recently, a new, large,
`randomized DRCR.net study investigated the efficacy of
`intravitreal TA in combination with laser photocoagulation
`in comparison with intravitreal ranibizumab with prompt
`or deferred laser photocoagulation or laser photocoagulation
`alone. At 2-year visit, mean change (±SD) in the visual acuity
`letter score from baseline was +7 ± 13 in the ranibizumab
`+ prompt laser group, +9 ± 14 in ranibizumab + deferred
`laser group, +2 ± 19 in the TA + prompt laser group, and
`+3 ± 15 the sham + prompt laser group. Compared with the
`sham + prompt laser group, the difference in mean change
`in the visual acuity letter score from baseline was 3.7 letters
`greater in the ranibizumab + prompt laser group (𝑃 = 0.03),
`5.8 letters greater in the ranibizumab + deferred laser group
`(𝑃 < 0.01), and 1.5 letters worse in the TA + prompt laser
`group (𝑃 = 0.35). A worsening of visual acuity of three
`or more lines occurred in 10%, 4%, 2%, and 13% of eyes,
`respectively, and an improvement in visual acuity by three
`or more lines occurred in 18%, 29%, 28%, and 22% of eyes,
`respectively. The mean change (𝜇m ± SD) in central retinal
`thickness from baseline was −141 ± 155 in the ranibizumab +
`prompt laser group, −150 ± 143 in ranibizumab + deferred
`laser group, −107 ± 145 in the TA + prompt laser group,
`and −138 ± 149 the sham + prompt laser group. Compared
`with the sham + prompt laser group, the difference in mean
`change in central macular thickness from baseline was 31 𝜇m
`worse in the ranibizumab + prompt laser group (𝑃 = 0.03),
`28 𝜇m worse in the ranibizumab + deferred laser group (𝑃 =
`0.01), and 10 𝜇m worse in the TA + prompt laser group (𝑃 =
`0.37). These results showed that intravitreal ranibizumab with
`prompt or deferred laser is more effective than prompt laser
`alone or intravitreal TA combined with laser for the treatment
`of DME involving the central macula. Among the eyes that
`were pseudophakic at baseline, the mean change (±SD) in
`the visual acuity letter score from baseline was +5 ± 17 in the
`ranibizumab + prompt laser group, +9 ± 17 in ranibizumab +
`deferred laser group, +8 ± 13 in the TA + prompt laser
`group, and +5 ± 15 the sham + prompt laser group. The
`difference in mean change in visual acuity letter score from
`baseline to the two-year visit was 1.6 letters greater in the TA
`+ prompt laser group compared with the sham + prompt laser
`group and was similar to difference in outcomes between
`the ranibizumab + prompt laser group (+0.5 letters) and the
`ranibizumab + deferred laser group (+3.5 letters) compared
`with the sham + prompt laser group. Cataract surgery was
`required in 12% of phakic eyes in the sham + prompt laser and
`in the ranibizumab + prompt laser groups, in 13% of phakic
`eyes in the ranibizumab + deferred laser group, and in 55%
`
`Novartis Exhibit 2303.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`4
`
`The Scientific World Journal
`
`of patients of the TA + laser group. An intraocular pressure
`(IOP)-lowering medication was required in 5% of eyes in the
`sham + prompt laser and ranibizumab + prompt laser groups,
`in 3% of eyes in the ranibizumab + deferred laser group, and
`in 28% of patients of the TA + laser group [61]. Other studies
`demonstrated promising results of combination therapy with
`intravitreal injection of TA and laser photocoagulation for
`the treatment of proliferative diabetic retinopathy (PDR) with
`clinically significant macular edema (CSME) [62–67]. In a 12-
`month randomized clinical trial conducted by Maia et al., 44
`eyes with PDR and CSME were enrolled and randomized to
`treatment with combined 4 mg of intravitreal TA and laser
`photocoagulation (𝑛 = 22) or to laser photocoagulation
`alone (𝑛 = 22). Mean best correct visual acuity (BCVA)
`improved significantly (𝑃 < 0.001) in the TA and laser
`group compared with the laser alone group at all study
`follow-up visits. An improvement of two or more Early
`Treatment Diabetic Retinopathy Study (ETDRS) lines was
`observed in 63.1% and 10.5% of eyes, respectively (𝑃 < 0.001).
`A significant decrease in mean central macular thickness
`occurred in the TA and laser group when compared with the
`laser alone group at all study follow-up intervals (𝑃 < 0.001).
`At 12 months, mean (±SD) reductions in central macular
`thickness were 123 ± 68 𝜇m and 65 ± 51 𝜇m, respectively
`(𝑃 < 0.001) [67]. Several other studies reported positive
`results of intravitreal TA in refractory DME [68–71]. In a six-
`month prospective, placebo-controlled, randomized clinical
`trial conducted by Jonas et al., 40 eyes with persistent DME
`were enrolled and randomized to treatment with 20 mg TA
`(𝑛 = 28) or to placebo injection (𝑛 = 12). Visual acuity
`increased significantly (𝑃 < 0.001) in the TA group by
`3.4 ETDRS lines. In the placebo group, visual acuity did
`not change significantly (𝑃 = 0.07) during the six months.
`At the end of the follow-up period, 48% in the TA group
`improved by at least two ETDRS lines compared with 0%
`eyes in the placebo group [69]. Recently, Gillies et al. reported
`the longest-term data available concerning the outcomes of
`intravitreal injection of TA. This was a five-year prospective,
`double-masked, randomized clinical trial of 4 mg dose of
`preservative-free intravitreal TA in comparison with placebo.
`In this study, 67 study eyes with refractory DME were
`randomized to receive 4 mg TA (𝑛 = 33) or placebo (𝑛 = 34).
`At five years, an improvement in visual acuity of three or
`more lines occurred in 42% of the eyes in the TA group and
`32% of eyes in the placebo group (𝑃 = 0.4). A worsening of
`visual acuity by three or more lines occurred in 18% and 24%
`of eyes, respectively (𝑃 = 0.88). Mean (±SD) reductions in
`central macular thickness were 100 ± 79 𝜇m in the TA group
`and 184 ± 29 𝜇m in the placebo group (𝑃 = 0.45). After five
`years, the difference in visual acuity between the two groups
`was not statistically significant and there was no difference
`in mean central macular thickness reduction between two
`groups. Moreover, this study showed that, in the long term, a
`two-year delay in the beginning of intravitreal TA treatment
`did not seem to adversely affect outcomes in eyes affected
`with refractory DME [70].
`Novel preservative-free and sustained-release intravitreal
`implants have been evaluated for the treatment of DME to
`provide longer duration of pharmacologic effect with lower
`
`administration frequency and minimal side effects. I-vation
`(SurModics, Eden Prairie, MN, USA) is a nonbiodegradable,
`helical, metal alloy implant coated with polybutyl methacry-
`late, polyethylene vinyl acetate polymers, and TA. Drug
`delivery and duration rates can be tuned varying the ratios of
`the constituent polymers. This system is implanted through a
`25-gauge device. A phase I study have shown positive func-
`tional and morphological outcomes in 31 patients affected
`by DME [71]. However, phase IIb trial for I-vation TA was
`suspended in 2008 following the publication of the DRCR.net
`study. The Cortiject implant (NOVA63035, Novagali Pharma)
`is a preservative- and solvent-free emulsion that contains
`a tissue-activated proprietary corticosteroid prodrug. Once
`released, the prodrug is activated at the level of the retina.
`A single intravitreal
`injection of the emulsion provides
`sustained release of the corticosteroid over a 6- to 9-month
`period. An open-label, phase 1, dose-escalation clinical study
`to assess the safety and tolerability of NOVA63035 in patients
`with DME is currently underway.
`
`2.2. Macular Edema Secondary to Retinal Vein Occlusion.
`Macular edema is a common cause of reduced vision in
`patients with retinal vein occlusions. Due to the well-know
`antiedematous and antipermeability effects, intravitreal TA
`has been evaluated in many studies on macular edema sec-
`ondary to CRVO and BRVO. Case series have suggested that
`intravitreal injection of TA may be useful for the treatment
`of macular edema in patients with BRVO [72]. However,
`the use of this pharmacological approach was not sup-
`ported by the results presented in the Standard Care versus
`Corticosteroid for Retinal Vein Occlusion (SCORE) Study.
`In this multicenter clinical trial, 411 participants affected
`by macular edema secondary to BRVO were randomized
`to receive laser photocoagulation, 1-mg, or 4-mg doses of
`preservative-free intravitreal TA (Trivaris). After 12 months
`of follow-up, the proportion of eyes with an improvement
`in visual acuity that enabled patients to read 15 or more
`letters was similar among the three groups (27% in the
`group treated with the 4-mg dose of TA, 26% in the group
`treated with the 1-mg dose, and 29% in the control group).
`Results showed that there was no difference identified in
`visual acuity at 12 months for the laser group compared with
`the TA groups. The duration of the edema is an important
`issue to be considered. Among patients with a duration of
`macular edema that is more than 3 months, a proportion
`of 34% of eyes showed a gain of 15 letters or more in the
`4-mg TA group, versus a percentage of 15% of patients in
`the photocoagulation group. However, these findings were
`not statistically significant but indicated the importance of
`taking into account the duration of edema in data analysis
`and in clinical practice [47]. Several clinical trials have also
`published the beneficial effects of intravitreal administration
`of TA for the treatment of macular edema due to CRVO
`[73]. In a 12-month randomized clinical trial, 271 patients
`affected by macular edema secondary to nonischemic CRVO
`were randomly assigned to observation, 1-mg or 4-mg doses
`of preservative-free intravitreal TA (Trivaris). At 1 year, the
`proportion of eyes with an improvement in visual acuity of
`
`Novartis Exhibit 2303.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`The Scientific World Journal
`
`5
`
`15 or more letters was 26% in the group treated with the 4-
`mg dose of TA, 27% in the group treated with the 1-mg dose,
`and 7% in the control group (𝑃 = 0.001) [46]. Verisome
`(Icon Bioscience Inc, Sunnyvale, CA, USA) is a biodegradable
`implant designed to be injected intravitreously and release TA
`for up to one year.
`The Verisome delivery system is a sustained-release drug
`delivery system that can be injected into the eye as a liquid via
`a standard 30-gauge needle. When injected into the vitreous,
`the liquid coalesces into a single spherule. A phase I trial
`was conducted in patients with macular edema associated
`with RVO evaluating the drug delivery system at two dosing
`levels, a 25-𝜇L dose designed to last 6 months, and a 50-
`𝜇L dose designed to last one year in the vitreous cavity. The
`promising results of the clinical trial confirmed the safety and
`efficacy outcomes and the controlled-release attributes of the
`technology [74].
`
`2.3. Pseudophakic Cystoid Macular Edema. Postoperative
`cystoid macular edema may be a complication of cataract
`surgery. This condition is typically treated with topical,
`peribulbar, and systemic administration of steroids and
`nonsteroidal anti-inflammatory agents. Recently, promising
`results have been obtained using intravitreal TA for the
`treatment of this condition [50].
`
`2.4. Other Indications. Intravitreal administration of TA has
`been increasingly performed as an alternative option for
`the treatment of exudative age-related macular degeneration
`either in monotherapy or in combination with anti-VEGF
`drugs. Furthermore, TA has recently been used in combi-
`nation with pars plana vitrectomy for proliferative diabetic
`retinopathy and proliferative vitreoretinopathy. Intravitreal
`TA is also a useful surgical tool for assisting vitreoretinal
`surgery because besides visualizing the vitreous body, it
`allows a sharp contrast between the peeled and unpeeled
`retina, promoting the removal of the membranes that are
`readily visualized. TA-assisted peeling has been reported
`during macular hole and macular pucker surgery [75]. Other
`conditions that can benefit from intravitreal TA are uveitis
`and immunological disorders, cystoid macular edema after
`penetrating keratoplasty, and progressive ocular hypotony
`[76, 77].
`
`3. Dexamethasone
`Dexamethasone is a potent inhibitor of cytokines released by
`human pericytes and it has demonstrated high levels in the
`vitreous for more than 6 months in vivo. Preclinical studies
`have reported that intravitreal injection of dexamethasone
`decreases significantly Intercellular Adhesion Molecule-1
`(ICAM-1) mRNA, and protein levels, reducing leukostasis
`and BRB breakdown [78]. Dexamethasone has a relatively
`short half-life (about 3.5 hours), but is five times more potent
`than TA [79, 80]. An innovative intravitreal dexamethasone
`implant has been developed to permit a sustained and
`extended release of corticosteroids in the intravitreal cavity.
`A biodegradable dexamethasone drug delivery system (DDS)
`
`has been created by Allergan (Ozurdex, Allergan, Irvine,
`CA, USA). Ozurdex was designed to provide sustained
`distribution of 700 𝜇g of dexamethasone in the vitreous
`cavity. The implant is formed by a solid biodegradable
`polymer (NovadurTM, Allergan, Irvine, CA, USA), whose
`degradation produces lactic acid and glycolic acid, which are
`subsequently converted to and eliminated as carbon diox-
`ide and water. The dexamethasone implant is administered
`as an office-based intravitreal injection using a novel 22-
`gauge injecting applicator [81]. Recently, Chang-Lin et al.
`have published pharmacokinetics and pharmacodynamics
`data of Ozurdex. It was observed that the opaque, round
`cylindrical implant became translucent, fragmented, and
`smaller two months after implantation. The concentration
`of dexamethasone was detected in the retina and vitreous
`humor for 6 months, with peak concentrations during the
`first 2 months. Dexamethasone concentrations in the vitreous
`and in the retina were characterized by two distinct phases,
`which corresponded to the fragmentation of the implant.
`On day 60, high levels of dexamethasone were detected in
`the posterior segment, with the mean peak concentration of
`1110 ± 284 ng/g in the retina and 213 ± 49 ng/mL in the
`vitreous. Following a relatively rapid decline in concentration
`between day 60 and 90, a second steady state is reached and
`maintained through day 180 [82].
`The Ozurdex dexamethasone-sustained delivery implant
`has been approved by the United States Food and Drug
`Administration (FDA) for the treatment of macular edema
`associated with retinal vein occlusion (RVO) and for nonin-
`fectious posterior uveitis.
`
`3.1. Macular Edema Secondary to Retinal Vein Occlusion.
`FDA approval was based on the therapeutic effects of dex-
`amethasone implant investigated in a randomized, controlled
`clinical trial (the Ozurdex GENEVA study) [83]. The study
`design included two identical, randomized, prospective, mul-
`ticenter, masked, and sham-controlled parallel groups. In the
`double-masked 6-month initial treatment phase, 1.262 eyes
`were randomized to either a sham procedure (𝑛 = 426)
`or treatment with 350 𝜇g (𝑛 = 414) or 700 𝜇g (𝑛 = 427)
`dexamethasone implant. In the second open-label phase,
`all eligible eyes received a 700 𝜇g dexamethasone implant
`and were followed-up for additional 6 months. The primary
`endpoint was the time to achieve over 15-letter improvement
`(3 Snellen lines) in BCVA, and the secondary outcomes
`included BCVA over the 6-month trial period and central
`retinal thickness measured by OCT. The proportion of eyes
`that achieved an improvement in visual acuity of 15 or more
`letters was 22% in the 700 𝜇g group, 23% in the 350 𝜇g group,
`and 13% in the sham group at month 3 (𝑃 < 0.001). These data
`were no longer statistically significant at month 6. At the end
`of the follow-up, the percentage of eyes that had experienced
`a three-line gain was 41% in the 700 𝜇g group, 40% in the
`350 𝜇g group, and 23% in the sham group (𝑃 < 0.001). The
`reduction in mean central retinal thickness was greater in the
`700 𝜇g (208 ± 201 𝜇m) and 350 𝜇g (177 ± 197 𝜇m) groups than
`in the sham group (85 ± 173 𝜇m) at month 3 (𝑃 < 0.001), but
`not statistically significant at month 6. Twenty-one percent
`
`Novartis Exhibit 2303.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`6
`
`The Scientific World Journal
`
`of the eyes affected by BRVO and the 17% of eyes with CRVO
`required only a single treatment after 12 months of follow-
`up. The study was also able to show that early treatment of
`macular edema was more beneficial than delayed treatment
`in restoring VA. A post hoc analysis suggested that eyes
`treated within 90 days since the onset of cystoid macular
`edema were more likely to improve than eyes in which the
`treatment was instituted after this time point. In addition
`to being the first FDA-approved therapy for macular edema
`related to RVO, the dexamethasone DDS has been approved
`by the EMA for macular edema in eyes with RVO in all of the
`27 member states of the European Union.
`
`3.2. Pseudophakic Cystoid Macular Edema and Macular
`Edema Secondary to Uveitis. Cystoid macular edema is a con-
`dition that can cause vision impairment after cataract surgery
`or uveitis. In a randomized, prospective, single-masked,
`controlled trial, 41 eyes with persistent macular edema from
`uveitis or Irvine-Gass syndrome were randomized to