Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Allergan Pharmaceuticals Ireland, Castlebar Road, Co. Mayo, Westport, Ireland
Pharmacotherapeutic group: Ophthalmologicals, antiinflammatory agents
ATC code: S01BA01
Dexamethasone, a potent corticosteroid, has been shown to suppress inflammation by inhibiting oedema, fibrin deposition, capillary leakage, and phagocytic migration of the inflammatory response. Vascular Endothelial Growth Factor (VEGF) is a cytokine which is expressed at increased concentrations in the setting of macular oedema. 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 oedema.
The efficacy of OZURDEX was assessed in two 3 year, multicentre, double-masked, randomised, sham-controlled, parallel studies of identical design which together comprised 1,048 patients (studies 206207-010 and 206207-011). A total of 351 were randomised to OZURDEX, 347 to dexamethasone 350 μg and 350 patients to sham.
Patients were eligible for retreatment based upon central subfield retinal thickness >175 microns by optical coherence tomography (OCT) or upon investigators interpretation of the OCT for any evidence of residual retinal edema consisting of intraretinal cysts or any regions of increased retinal thickening within or outside of the central subfield. Patients received up to 7 treatments at intervals no more frequently than approximately every 6 months.
Escape therapy was permitted at the investigators discretion at any stage but led to subsequent withdrawal from the studies.
A total of 36% of OZURDEX treated patients discontinued study participation for any reason during the study compared with 57% of sham patients. Discontinuation rates due to adverse events were similar across treatment and sham groups (13% vs 11%). Discontinuation due to lack of efficacy was lower in the OZURDEX group compared to sham (7% vs 24%).
The primary and key secondary endpoints for studies 206207-010 and 011 are presented in Table 2. The vision improvement in the DEX700 group was confounded by cataract formation. Vision improvement was re-established upon removal of cataract.
Table 2. Efficacy in studies 206207-010 and 206207-011 (ITT population):
| Endpoint | Study 206207-010 | Study 206207-011 | Pooled Studies 206207-010 and 206207-011 | |||
|---|---|---|---|---|---|---|
| DEX 700 N=163 | Sham N=165 | DEX 700 N=188 | Sham N=185 | DEX 700 N=351 | Sham N=350 | |
| Mean BCVA average change over 3 years, AUC approach (letters) | 4.1 | 1.9 | 2.9 | 2.0 | 3.5 | 2.0 |
| P-value | 0.016 | 0.366 | 0.023 | |||
| BCVA ≥ 15-letter improvement from baseline at Year 3/Final (%) | 22.1 | 13.3 | 22.3 | 10.8 | 22.2 | 12.0 |
| P-value | 0.038 | 0.003 | <0.001 | |||
| Mean BCVA change from baseline at year 3/final visit (letters) | 4.1 | 0.8 | 1.3 | -0.0 | 2.6 | 0.4 |
| P-value | 0.020 | 0.505 | 0.054 | |||
| OCT retinal thickness at center subfield mean average change over 3 years, AUC approach (μm) | -101.1 | -37.8 | -120.7 | -45.8 | -111.6 | -41.9 |
| P-value | <0.001 | <0.001 | <0.001 | |||
The primary and key secondary endpoints for the pooled analysis for pseudophakic patients are presented in Table 3.
Table 3. Efficacy in pseudophakic patients (pooled studies 206207-010 and 206207-011):
| Endpoint | DEX 700 N=86 | Sham N=101 | P-value |
|---|---|---|---|
| Mean BCVA average change over 3 years, AUC approach (letters) | 6.5 | 1.7 | <0.001 |
| BCVA ≥15-letter improvement from baseline at Year 3/Final visit (%) | 23.3 | 10.9 | 0.024 |
| Mean BCVA change from baseline at year 3/Final visit | 6.1 | 1.1 | 0.004 |
| OCT retinal thickness at center subfield mean average change over 3 years, AUC approach (μm) | -131.8 | -50.8 | <0.001 |
The primary and key secondary endpoints for the pooled analysis for patients with any prior treatment are presented in Table 4.
Table 4. Efficacy in patients with any prior treatment (pooled studies 206207-010 and 206207-011):
| Endpoint | DEX 700 N=247 | Sham N=261 | P-value |
|---|---|---|---|
| Mean BCVA average change over 3 years, AUC approach (letters) | 3.2 | 1.5 | 0.024 |
| BCVA ≥15-letter improvement from baseline at Year 3/Final visit (%) | 21.5 | 11.1 | 0.002 |
| Mean BCVA change from baseline at year 3/Final visit | 2.7 | 0.1 | 0.055 |
| OCT retinal thickness at center subfield mean average change over 3 years, AUC approach (μm) | -126.1 | -39.0 | <0.001 |
The efficacy of OZURDEX was assessed in two multicentre, double-masked, randomised, sham-controlled, parallel studies of identical design which together comprised 1,267 patients who were randomized to receive treatment with dexamethasone 350 μg or 700 μg implants or sham (studies 206207-008 and 206207-009). A total of 427 were randomised to OZURDEX, 414 to dexamethasone 350 μg and 426 patients to sham.
Based on the pooled analysis results, treatment with OZURDEX implants showed statistically significantly greater incidence of responders, defined as patients achieving a ≥15 letter improvement from baseline in Best Corrected Visual Acuity (BCVA) at 90 days following injection of a single implant, when compared with sham (p<0.001).
The proportion of patients achieving the primary efficacy measure of ≥15 letter improvement from baseline in BCVA following injection of a single implant is shown in Table 5. A treatment effect was seen at the first observation time point of day 30. The maximum treatment effect was observed at day 60 and the difference in the incidence of responders was statistically significant favouring OZURDEX compared with sham at all time points to day 90 following injection. There continued to be a numerically greater proportion of responders for a ≥15 letter improvement from baseline in BCVA in patients treated with OZURDEX compared with sham at day 180.
Table 5. Proportion of patients with ≥15 letters improvement from baseline best corrected visual acuity in the study eye (pooled, ITT population):
| Visit | OZURDEX N=427 | Sham N=426 |
|---|---|---|
| Day 30 | 21.3%a | 7.5% |
| Day 60 | 29.3%a | 11.3% |
| Day 90 | 21.8%a | 13.1% |
| Day 180 | 21.5% | 17.6% |
a Proportion significantly higher with OZURDEX compared to sham (p<0.001)
The mean change from baseline BCVA was significantly greater with OZURDEX compared to sham at all time points.
In each Phase III study and the pooled analysis, the time to achieve ≥ 15 letters (3-line) improvement in BCVA cumulative response curves were significantly different with OZURDEX compared to sham (p<0.001) with OZURDEX treated patients achieving a 3-line improvement in BCVA earlier than sham treated patients.
OZURDEX was numerically superior to sham in preventing vision loss as shown by a lower of proportion of patients experiencing deterioration of vision of ≥15 letters in the OZURDEX group throughout the 6-month assessment period.
In each of the phase III studies and the pooled analysis, mean retinal thickness was significantly less, and the mean reduction from baseline was significantly greater, with OZURDEX (-207.9 microns) compared to sham (-95.0 microns) at day 90 (p<0.001, pooled data). The treatment effect as assessed by BCVA at day 90 was thus supported by this anatomical finding. By Day 180 the mean retinal thickness reduction (-119.3 microns) compared with sham was not significant.
Patients who had a BCVA score of <84 OR retinal thickness >250 microns by optical coherence tomography OCT and in the investigator’s opinion treatment would not put the patient at risk; were eligible to receive an OZURDEX treatment in an open label extension. Of the patients who were treated in the open label phase, 98% received an OZURDEX injection between 5 and 7 months after the initial treatment.
As for the initial treatment, peak response was seen at Day 60 in the open label phase. The cumulative response rates were higher throughout the open label phase in those patients receiving two consecutive OZURDEX injections compared with those patients who had not received an OZURDEX injection in the initial phase.
The proportion of responders at each time point was always greater after the second treatment compared with the first treatment. Whereas, delaying treatment for 6 months results in a lower proportion of responders at all time points in the open label phase when compared with those receiving a second OZURDEX injection.
The clinical efficacy of OZURDEX has been assessed in a single, multicentre, masked, randomised study for the treatment of non-infectious ocular inflammation of the posterior segment in patients with uveitis.
A total of 229 patients were randomised to receive dexamethasone 350 μg or 700 μg implants or sham. Of these, a total of 77 were randomised to receive OZURDEX, 76 to dexamethasone 350 μg and 76 to sham. A total of 95% of patients completed the 26-week study.
The proportion of patients with vitreous haze score of 0 in the study eye at week 8 (primary endpoint) was 4-fold higher with OZURDEX (46.8%) compared to Sham (11.8%), p<0.001. Statistical superiority was maintained up to and including week 26 (p≤0.014) as shown in Table 6.
The cumulative response rate curves (time to vitreous haze score of 0) were significantly different for the OZURDEX group compared to the Sham group (p<0.001), with patients receiving dexamethasone showing an earlier onset and greater treatment response.
The reduction in vitreous haze was accompanied by an improvement in visual acuity. The proportion of patients with at least 15 letters improvement from baseline BCVA in the study eye at week 8 was more than 6-fold higher with OZURDEX (42.9%) compared to Sham (6.6%), p<0.001. Statistical superiority was achieved at week 3 and maintained up to and including week 26 (p<0.001) as shown in Table 6.
The percent of patients requiring escape medications from baseline to week 8 was nearly 3-fold less with OZURDEX (7.8%) compared to Sham (22.4%), p=0.012.
Table 6. Proportion of patients with vitreous haze score of zero and ≥15 letters improvement from baseline best corrected visual acuity in the study eye (ITT population):
| Visit | Vitreous Haze Score of Zero | BCVA improvement from baseline of ≥15 letters | ||
|---|---|---|---|---|
| DEX 700 N=77 | Sham N=76 | DEX 700 N=77 | Sham N=76 | |
| Week 3 | 23.4% | 11.8% | 32.5%a | 3.9% |
| Week 6 | 42.9%a | 9.2% | 41.6%a | 7.9% |
| Week 8 | 46.8%a | 11.8% | 42.9%a | 6.6% |
| Week 12 | 45.5%a | 13.2% | 41.6%a | 13.2% |
| Week 16 | 40.3%b | 21.1% | 39.0%a | 13.2% |
| Week 20 | 39.0%c | 19.7% | 40.3%a | 13.2% |
| Week 26 | 31.2%d | 14.5% | 37.7%a | 13.2% |
a p<0.001; bp=0.010; cp=0.009; dp=0.014
The European Medicines Agency has waived the obligation to submit the results of studies with OZURDEX in all subsets of the paediatric population for retinal vascular occlusion and also for diabetic macular oedema (see section 4.2 for information on paediatric use).
Plasma concentrations were obtained from a subset of 21 patients in the two RVO, 6-month efficacy studies prior to dosing and on days 7, 30, 60 and 90 following intravitreal injection of a single intravitreal implant containing 350 μg or 700 μg dexamethasone. Ninety-five percent of the plasma dexamethasone concentration values for the 350 μg dose group and 86% for the 700 μg dose group were below the lower limit of quantitation (0.05 ng/mL). The highest plasma concentration value of 0.094 ng/mL was observed in one subject from the 700 μg group. Plasma dexamethasone concentration did not appear to be related to age, body weight, or sex of patients.
Plasma concentrations were obtained from a subgroup of patients in the two DME pivotal studies prior to dosing and on days 1, 7, and 21, and months 1.5 and 3 following intravitreal injection of a single intravitreal implant containing 350 μg or 700 μg dexamethasone. One hundred percent of the plasma dexamethasone concentration values for the 350 μg dose group and 90% for the 700 μg dose group were below the lower limit of quantitation (0.05 ng/mL). The highest plasma concentration value of 0.102 ng/mL was observed in 1 subject from the 700 μg group. Plasma dexamethasone concentration did not appear to be related to age, body weight, or sex of patients.
In a 6-month monkey study following a single intravitreal injection of OZURDEX the dexamethasone vitreous humour Cmax was 100 ng/mL at day 42 post-injection and 5.57 ng/mL at day 91. Dexamethasone remained detectable in the vitreous at 6 months post-injection. The rank order of dexamethasone concentration was retina > iris > ciliary body > vitreous humour > aqueous humour > plasma. In an in vitro metabolism study, following the incubation of [14C]-dexamethasone with human cornea, iris-ciliary body, choroid, retina, vitreous humour, and sclera tissues for 18 hours, no metabolites were observed. This is consistent with results from rabbit and monkey ocular metabolism studies.
Dexamethasone is ultimately metabolised to lipid and water soluble metabolites that can be excreted in bile and urine.
The OZURDEX matrix slowly degrades to lactic acid and glycolic acid through simple hydrolysis, then further degrades into carbon dioxide and water.
Effects in non-clinical studies were observed only at doses considered sufficiently in excess of the maximum dose for human indicating little relevance to clinical use.
No mutagenicity, carcinogenicity, reproductive or developmental toxicity data are available for OZURDEX. Dexamethasone has been shown to be teratogenic in mice and rabbits following topical ophthalmic application.
Dexamethasone exposure to the healthy/untreated eye via contralateral diffusion has been observed in rabbits following delivery of the implant to the posterior segment of the eye.
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