Currently, several modalities are under investigation for treatments of retinal vein occlusion (RVO). These include vitrectomy with or without sheathotomy, optic nerve decompression, creation of laser or surgical anastomoses, antiaggregative and thrombolytic therapies, isovolemic hemodilution, and intravitreal and periocular steroid injection.1 Limited proof of safety and efficacy for these modalities are currently available. Intravitreal triamcinolone acetonide (IVTA) and treatment with vascular endothelial growth factor (VEGF) inhibitors are being used more frequently. Both are under phase 3 study, and results are expected to be announced later this year. Most recently, the sustained-release intravitreal dexamethasone implant (Ozurdex, Allergan, Inc.) was approved by the US Food and Drug Administration (FDA).
The FDA's approval of Ozurdex and Genentech's release of positive 6-month results from the BRAVO (A phase 3, multicenter, randomized, sham injection-controlled study of the efficacy and safety of ranibizumab injection compared with sham in patients with macular edema secondary to BRVO) and CRUISE (A phase 3, multicenter, randomized, sham injection-controlled study of the efficacy and safety of ranibizumab injection compared with sham in patients with macular edema secondary to CRVO) trials, underscores the efforts of the retina community and industry to reduce the gap in effective, and safe therapies for RVO.
OZURDEX
Ozurdex received approval for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). Ozurdex is a biodegradable implant administered by intravitreal injection that delivers dexamethasone to the vitreous cavity via Allergan's proprietary Novadur solid polymer delivery system which enables extended release and sustained effects of dexamethasone.
The approval was based on data from two multicenter, double-masked, randomized, parallel studies involving 1,300 patients. In each study, and in a pooled analysis, time to achieve an improvement of 15 or more letters (three lines) of best corrected visual acuity (BCVA) cumulative response rate curves were significantly faster for patients treated with Ozurdex compared with sham-treated patients (P<.01). Ozurdex-treated patients achieved a three-line improvement in best-corrected visual acuity earlier than sham-treated patients. The onset of effect with Ozurdex occurred within the first 2 months after implantation in approximately 20% to 30% of patients. The duration of effect persisted approximately 1 to 3 months after onset. (These data are on file with Allergan.)
BRAVO AND CRUISE AT 6 MONTHS
In July, Genentech, Inc., announced positive 6-month results from the phase 3 BRAVO and CRUISE trials. The BRAVO study showed that injections of ranibizumab (Lucentis, Genentech, Inc.) improved BCVA from baseline in patients with macular edema due to BRVO compared with sham. The CRUISE study showed early and sustained improvement in BCVA through 6 months in patients with macular edema due to CRVO receiving monthly injections of ranibizumab.
In both trials, the safety profile of ranibizumab was consistent with previous experience, and no new adverse events related to the drug were observed. Full 6-month results of BRAVO and CRUISE reportedly will be presented at the Retina Congress in New York this fall, and 12-month follow-up results will be released when available.
The Genentech-sponsored BRAVO and CRUISE trials are evaluating the safety and benefit of treating macular edema with anti-VEGF therapy vs current standard RVO therapies or observation.
The primary objectives of BRAVO and CRUISE are to evaluate the efficacy of intravitreal ranibizumab in improving BCVA in macular edema secondary to RVO at 6 months, as well as the safety and tolerability of the ranibizumab injections. Secondary endpoints include evaluating the efficacy of the treatment in improving other visual acuity measures, anatomic outcomes, and patient-reported measures of visual function.
Both 12-month studies consist of a 6-month, sham-controlled treatment period, followed by a 6-month observation period, during which all participants are eligible to receive ranibizumab as needed. During the first 6-month period, participants received monthly injections of either 0.3 mg or 0.5 mg of ranibizumab (n=265 per study) or monthly sham injections (n=132 per study). In BRAVO, patients are eligible for rescue laser therapy if criteria are met at months 3, 4, and 5. During the second 6-month period, patients are evaluated monthly and treated on an as-needed basis. Patients in the sham injection group receive 0.5 mg ranibizumab for the second 6 months. Again, rescue laser therapy is available in BRAVO at months 9, 10, and 11 if criteria are met.
ANTICIPATED PHASE 3 RESULTS
Results of the SCORE (Standard Care versus Corticosteroid for Retinal Vein Occlusion) study, sponsored by the National Eye Institute (NEI), are anticipated to become available in the fall of 2009.
SCORE consists of two multicenter, randomized, phase 3 clinical trials comparing the safety and efficacy of standard care with preservative-free IVTA in either a 1-mg or a 4-mg dose for vision loss associated with macular edema secondary to CRVO or BRVO. The primary objective of the study is to compare visual acuity outcomes among those who are randomly assigned to receive standard care and those randomly assigned to receive one of two doses of IVTA for treatment of macular edema secondary to CRVO or BRVO.
Secondary objectives include estimating the incidence of infectious endophthalmitis, noninfectious endophthalmitis, retinal detachment, vitreous hemorrhage, cataract, and elevated intraocular pressure in eyes receiving IVTA. Other secondary objectives include comparing changes in retinal thickness in participants who are randomly assigned to receive IVTA with those randomly assigned to standard care for treatment of macular edema associated with CRVO or BRVO.
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