Regulatory Decision Summary for Blexten

The purpose of this Supplement to a New Drug Submission was to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, for Blexten ophthalmic solution, filed by Aralez Pharmaceuticals Canada Inc.

This Supplement was filed for Blexten (bilastine) for a new indication, a new route of administration (ophthalmic), new dosage form (ophthalmic solution), and new strength (6 milligrams per millilitre [mg/mL]). The proposed indication was for the treatment of ocular signs and symptoms of allergic conjunctivitis in adults.

Upon review of the submitted data package, Health Canada authorized Blexten with the following modification to the indication: Blexten ophthalmic solution, 6 mg/mL, is indicated for the treatment of ocular signs and symptoms of seasonal and perennial allergic conjunctivitis in adults.

The efficacy and safety of Blexten (bilastine), 6 milligrams per millilitre (mg/mL) ophthalmic solution for the treatment of seasonal and perennial allergic conjunctivitis in adults was evaluated in one Phase III study (0218) with supportive evidence from a Phase II study (0117) and a Phase III 8-week safety study (0418). The final concentration was based on the results of the dose ranging study (0117) which evaluated 2 mg/mL, 4 mg/mL, and 6 mg/mL strengths.

Study 0218 was a multi-center, double-masked, randomized, vehicle- and active-controlled study. A total of 228 male and female subjects were randomized 2:2:1 to Blexten ophthalmic solution 6 mg/mL, ketotifen ophthalmic solution 0.025% (active control) or vehicle solution. The mean age was 44 years (range 18 to 87 years), and the majority of subjects had seasonal allergic conjunctivitis (68%) and 32% had perennial allergies.

The conjunctival allergen challenge (CAC) model was used to evaluate the symptoms of conjunctivitis following treatment with the test product. The primary endpoint evaluated ocular itching at 15 minutes and 16 hours after administration of the ophthalmic solution, at three time points after the conjunctival allergen challenge. Secondary efficacy measures included conjunctival redness, ciliary redness, episcleral redness, chemosis, eyelid swelling, and tearing at the same time points.

Blexten ophthalmic solution demonstrated statistically significant improvements in ocular itching compared to the vehicle group at all time points (3, 5, and 7 min post-CAC) at 15 minutes post-treatment and 16 hours post-treatment demonstrating a fast onset of action and duration of action. The treatment differences compared to vehicle were clinically relevant and were greater than one unit at 15 minutes post-treatment and were greater than 0.5 units at 16 hours post-treatment.

Statistically significant treatment differences compared to vehicle were observed for the secondary endpoint of conjunctival redness at 15 minutes post treatment but not at 16 hours post-treatment, with smaller treatment differences than for ocular itching. Numerical improvements compared to vehicle were observed for some of the other secondary endpoints supportive of the primary endpoint.

The results for the pivotal study 0218 were supported by similar treatment differences compared to vehicle in the Phase II dose ranging study (0117) for the primary endpoint of ocular itching and secondary endpoint of conjunctival redness. In the 8-week single-center, randomized, vehicle-controlled study (0418), secondary efficacy endpoints provided supportive evidence of efficacy.

The clinical safety database included a total of 682 patients, of which 340 were treated with Blexten 6 mg/mL eye drops, and 218 were treated for up to 8 weeks. Systemic and ocular safety and tolerability were assessed. Overall, the incidence of treatment emergent adverse events (TEAEs) was balanced between groups with 9.7% of subjects in the Blexten group and 13.6% in vehicle group reporting at least 1 TEAE. The TEAEs were generally mild and there were no severe or serious adverse events (AE). The most frequently reported ocular AE reported with Blexten was visual acuity reduced in three patients in Study 0218 and two patients in Study 0117, and no reports in the other treatment groups. The most frequent non-ocular TEAE was headache. Overall, Blexten 6 mg/mL ophthalmic solution was well tolerated with no major safety concerns. There is some uncertainty regarding safety in patients aged 65 years or older due to the low number of patients in this age group. However, based on the low systemic exposure, and available safety data with oral Blexten and Blexten ophthalmic solution, no dosage adjustment was recommended.

Non-clinical studies supported the local tolerability of ocular administration of Blexten ophthalmic solution once daily.

An updated Risk Management Plan (RMP) for Blexten was reviewed by Health Canada and considered acceptable. Risks have been communicated in the approved Product Monograph and will continue to be monitored post market as outlined in the RMP, with routine and non-routine pharmacovigilance activities. The final labelling and Product Monograph were considered acceptable.

The chemistry and manufacturing information submitted for Blexten has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

Overall, the benefit-harm-uncertainty profile was favourable for Blexten ophthalmic solution, 6 mg/mL, for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance was recommended.

For further details about Blexten, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.