Combination OZURDEX® & EyLea® vs. OZURDEX® Monotherapy in IncompLete-Responders wIth Diabetic Macular Edema (COLLIDE)

Diabetic macular edema (DME) is a common cause of vision loss in patients with diabetes. The pathophysiology of DME is complex and likely multifactorial, where some of the most important features include the accumulation of advanced glycation end products, reactive oxygen species, protein kinase C and diacylglyceride activation, up-regulation of the renin-angiotensin-aldosterone system and up-regulation of vascular endothelial growth factor (VEGF). Additionally, inflammation has also been identified as an important etiological factor because breakdown of the retinal pigment epithelium - a physiologic barrier to fluid flow from the choriocapillaris and active retinal fluid pump, has been linked to increased levels of pro-inflammatory mediators including VEGF and processes that support leukostasis.

In Canada, LUCENTIS® (0.5 mg ranibizumab or RBZ, an anti-neovascular VEGF-A inhibitor, Novartis Pharmaceuticals Canada Inc.) was the first approved medical treatment for DME. Health Canada's decision for regulatory approval of RBZ (0.5 mg) for treatment of DME was based on 12-month results from the RESOLVE (Phase II trial investigating RBZ (0.3 mg or 0.5 mg) vs. sham injection) and RESTORE (Phase IIIb trial investigating RBZ (0.5 mg) + sham laser or RBZ (0.5 mg) + laser vs. laser + sham injection) trials. In the RESOLVE trial, pooled RBZ treatment arms resulted in significant and continuous improvement compared to sham treatment in both BCVA (mean improvement of 7.8 letters with RBZ treatment compared to a mean decline of 0.1 letters with sham treatment) and CRT (mean reduction of -194.2 µm with RBZ treatment vs. -48.4±153.4 µm with sham treatment). Similarly in the RESTORE trial, RBZ monotherapy and RBZ treatment with adjunctive laser yielded a statistically significantly greater mean average change in BCVA letter score compared to laser monotherapy through 12-months of study (+6.1 and +5.9 vs. +0.8 BCVA letters, respectively) along with a significantly greater improvement in CRT change from baseline vs. laser (-118.7 µm and -128.3 µm vs. -61.3 µm, respectively). Additionally, RBZ treatment arms in both RESOLVE and RESTORE demonstrated comparable safety with controls permitting conclusions that RBZ 0.5 mg is well-tolerated in the management of DME.

Diabetic Retinopathy Clinical Research Network (DRCR.net) published in 2015 their Protocol T: Comparison of RBZ with Eylea (Aflibercept or AFL, Regeneron Pharmaceuticals) and Avastin (Bevacizumab or BCZ, Roche) in DME. At 1 year, the patients treated with AFL had a statistically improved visual acuity of 13.3 letters as compared to BCZ (9.7 letters) and RBZ (11.2 letters). The same cohort of AFL treated DME had greater improvement on Ocular Coherence Tomography central subfield thickness with 169 micron change vs 101 um with BCZ and 147 um with RBZ. However, in all treatment arms, a large number of patients 46% required rescue laser therapy as per study protocol.

While anti-VEGF agents are a mainstay for the management of DME, a subgroup of eyes having partial or incomplete response to AVASTIN® (bevacizumab or BCZ), EYLEA® (intravitreal aflibercept injection or AFL) and RBZ exist.

RISE and RIDE, two phase III trials for registration of RBZ in the USA randomized DME patients on a basis of 1:1:1 to receive monthly 0.3 mg or 0.5 mg RBZ intravitreal treatments or sham injections over 24 months. Upon completion of the 24-month study (time point for primary efficacy outcome, namely the proportion of patients gaining ≥ 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in BCVA from baseline), patients within the sham arm were eligible to receive delayed monthly 0.5 mg RBZ treatments over the next 12 months. Although strong vision gains were observed in patients originally randomized to RBZ arms at month 24 and sustained through month 36, sham controls receiving delayed RBZ treatment had vision improvements to a lesser extent than those receiving continuous RBZ treatment throughout the 36 month study, thereby suggesting benefits with initiation of DME treatment early in the course of DME management.