Regulatory Decision Summary for Cequa

Health Canada considers that the benefit-harm-uncertainty profile of CEQUA (cyclosporine ophthalmic solution, 0.09% w/v) is favourable to increase tear production in patients with moderate to severe keratoconjunctivitis sicca (dry eye).

The indication is supported by the results of two multi-centre, randomized, double-masked, vehicle-controlled trials of similar design in patients with moderate to severe KCS (i.e., OTX-101-2016-001 and OTX-101-2014-001). Study OTX-101-2016-001, which was considered by Health Canada to be the pivotal Phase 3 trial, was conducted in the United States in 744 patients with KCS. In this study, 371 patients were treated with Cequa and 373 patients were treated with the vehicle. The primary efficacy endpoint was a clinically meaningful improvement in tear production using Schirmers test at day 84 of the study in both eyes. The percentage of eyes in the group of patients treated with Cequa with a clinically meaningful increase in tear production (≥ 10 mm from baseline) at day 84 was statistically significantly greater than that in the vehicle group (Cequa: 16.6%; Vehicle: 9.2%; p < 0.0001). Study OTX-101-2014-001, which was considered by Health Canada as a supportive Phase 2b/3 trial, was conducted in 455 patients with KCS. In this study, 152 patients were treated with Cequa at the proposed dosage of 0.09% w/v, 151 patients were treated with the same formulation but at 0.05% w/v, and 152 patients were treated with the vehicle. The co-primary efficacy endpoints were the mean change from baseline at day 84 based on data for one eye for total conjunctival staining score in the designated study eye and for the SANDE (Symptom Assessment iN Dry Eye) global symptom score. This study failed to meet the co-primary efficacy endpoint of mean change from baseline in the global symptom score at day 84. Based on the (Food and Drug Administrations (FDA) advice, the data collected to determine the clinically meaningful improvement in tear production using Schirmers test (a secondary endpoint in this study) from this study was re-analyzed using the statistical methods of Study OTX-101-2016-001. This post-hoc analysis showed that the group of patients treated with Cequa (0.09% w/v) had a statistically significantly greater, clinically meaningful increase in tear production compared to that in the vehicle group (Cequa 0.09% w/v: 16.8%; Vehicle: 8.6%; p=0.0113). Health Canada deemed this approach to be exploratory in nature but acceptable as supportive of the results reported in Study OTX-101-2016-001. The combined results from the two studies supported the approved indication to increase tear production in patients with moderate to severe KCS.

Cyclosporine has a long history of ocular and systemic use and therefore has a well-established and well-understood safety profile. Cequa was well-tolerated in the submitted studies. In the submitted clinical trials, 524 subjects received at least 1 dose of Cequa (cyclosporine ophthalmic solution, 0.09% w/v). The most commonly identified adverse events were pain on instillation of drops and conjunctival hyperemia. These adverse events were mild and transient in nature, and are commonly reported adverse events with topical eye drops. Evaluation of a battery of ophthalmic safety tests did not trigger any safety concerns. The Sponsor submitted a long-term safety extension study of Study OTX-101-2016-001 wherein patients had a combined total exposure of ≥ 6 months. The safety results from this study were consistent with the safety results from the pivotal Phase 3 and supportive Phase 2b/3 studies and did not raise any additional safety concerns. Overall, the risks associated with Cequa are considered to be manageable through the inclusion of appropriate warnings and cautionary statements in the Product Monograph and through the Risk Management Plan.

Overall, the anticipated benefits of Cequa are expected to outweigh its risks under the conditions of use recommended in the Cequa (cyclosporine ophthalmic solution, 0.09% w/v) Product Monograph at this time.