Ozurdex Mechanism of Action

Pharmacology: Pharmacodynamics: Dexamethasone, a potent corticosteroid, has been shown to suppress inflammation by inhibiting multiple inflammatory cytokines resulting in decreased edema, fibrin deposition, capillary leakage and phagocytic migration of inflammatory cells. Vascular endothelial growth factor (VEGF) is a cytokine which is expressed at increased concentrations in the setting of macular edema. It is a potent promoter of vascular permeability. Corticosteroids have been shown to inhibit the expression of VEGF. Additionally, corticosteroids prevent the release of prostaglandins, some of which have been identified as mediators of cystoid macular edema.
OZURDEX contains 0.7 mg micronized dexamethasone in a biodegradable polymer matrix that is injected directly into the posterior segment of the eye with an applicator. The polymer degrades into water and carbon dioxide over time, gradually releasing dexamethasone to the vitreous, allowing for sustained drug levels in the target area with a smaller total amount of drug administered than via other routes of corticosteroid administration. Furthermore, delivery of OZURDEX directly into the vitreous cavity reduces the potential for systemic effects compared to other routes of administration.
The dose of dexamethasone delivered by OZURDEX every 6 months is less than the usual single daily physiologic replacement dose (0.75 mg).
Pharmacokinetics: Plasma concentrations were obtained from 21 patients with macular edema due to branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO), and 21 patients with diabetic macular edema (DME) prior to dosing and at 4 to 5 additional post-dose timepoints on Days 1, 7, 21, 30, 45, 60, and 90 following the administration of the first intravitreal implant containing 0.7 mg dexamethasone. In RVO and DME patients, the majority of plasma dexamethasone concentrations were below the lower limit of quantitation (LLOQ=50 pg/mL). Plasma dexamethasone concentrations from 12% of the samples in the 0.7 mg dose group and from 2 of 42 samples in the 0.35 mg dose group were above the LLOQ, ranging from 52 pg/mL to 102 pg/mL. Plasma dexamethasone concentration did not appear to be related to age, body weight or sex of patients.
In an in vitro metabolism study, following the incubation of [¹⁴C]-dexamethasone with human cornea, iris-ciliary body, choroid, retina, vitreous humor and sclera tissues for 18 hours, no metabolites were observed.
These results show that systemic exposure of dexamethasone was minimal but dose dependent in patients who had received one administration of dexamethasone 0.7 mg.
Renal impairment: No formal studies have been conducted to examine the pharmacokinetics of OZURDEX in patients with renal impairment.
Hepatic impairment: No formal studies have been conducted to examine the pharmacokinetics of OZURDEX in patients with hepatic impairment.
Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: No adequate studies in animals have been conducted to determine whether OZURDEX (dexamethasone intravitreal implant) has the potential for carcinogenesis. Although no adequate studies have been conducted to determine the mutagenic potential of OZURDEX, dexamethasone has been shown to have no mutagenic effects in bacterial and mammalian cells in vitro or in the in vivo mouse micronucleus test.
Adequate fertility studies have not been conducted in animals.
Clinical Studies: Retinal Vein Occlusion: The efficacy of OZURDEX for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO) was assessed in two, multicenter, double-masked, randomized, parallel studies. Following a single injection, OZURDEX demonstrated the following clinical results for the percent of patients with ≥15 letters of improvement from baseline in best-corrected visual acuity (BCVA) (Table 1): See Table 1.

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In each individual study and in a pooled analysis, time to achieve ≥15 letters (3-line) improvement in BCVA cumulative response rate curves were significantly faster with OZURDEX compared to sham (p <0.01), with OZURDEX-treated patients achieving a 3-line improvement in BCVA earlier than sham-treated patients. The onset of a ≥15 letter (3-line) improvement in BCVA with OZURDEX occurs within the first two months after implantation in approximately 20-30% of subjects. The duration of effect persists approximately one to three months after onset of this effect.
Posterior Segment Uveitis: The efficacy of OZURDEX was assessed in a single, multicenter, masked, randomized study of 153 patients with non-infectious uveitis affecting the posterior segment of the eye.
After a single injection, the percent of patients reaching a vitreous haze score of 0 (where a score of 0 represents no inflammation) was statistically significantly greater for patients receiving OZURDEX versus sham at week 8 (primary time point) (47% versus 12%). The percent of patients achieving a 3-line improvement from baseline BCVA was 43% for patients receiving OZURDEX versus 7% for sham at week 8.
Diabetic Macular Edema: The efficacy of OZURDEX for the treatment of diabetic macular edema was assessed in two, multicenter, masked, randomized, sham-controlled studies. Subjects were to be evaluated for retreatment eligibility every three months starting from Month 6 but could only receive successive treatments at least 6 months apart. Retreatment was based on physician's discretion after examination including Optical Coherence Tomography. Patients in the OZURDEX arm received an average of 4 treatments during the 36 months.
The primary endpoint was the proportion of patients with 15 or more letters improvement in BCVA from baseline at Month 39 or final visit for subjects who exited the study at or prior to Month 36. The Month 39 extension was included to accommodate the evaluation of safety and efficacy outcomes for subjects who received re-treatment at Month 36. Only fourteen percent of the study patients completed the Month 39 visit (16.8% from OZURDEX and 12.2% from Sham). (See Table 2.)

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Visual acuity outcomes by lens status (Phakic or Pseudophakic) at different visits are presented in Figure 1 and Figure 2. The occurrence of cataracts impacted visual acuity during the study. The visual acuity improvement from baseline increases during a treatment cycle, peaks at approximately 3 Months post-treatment and diminishes thereafter. Patients who were pseudophakic at baseline achieved greater mean BCVA change from baseline at the final study visit. (See Figures 1 and 2.)

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The best corrected visual acuity outcomes for the Pseudophakic and Phakic subgroups from Studies 1 and 2 at Month 39 are presented in Table 3. (See Table 3.)

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