Regulatory Decision Summary for Verkazia
The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.
Type of submission:
What was the purpose of this submission?
The purpose of this New Drug Submission (Priority Review) was to seek approval of Verkazia (Cyclosporine, 0.1% w/v, topical ophthalmic solution) for the treatment of severe keratoconjunctivitis in children from 4 years of age to adolescence.
Why was the decision issued?
One phase III study (VEKTIS) was submitted in support of this indication. The VEKTIS clinical trial was a randomised, double-masked, parallel group, vehicle controlled multinational multicentre study. Patients with severe Vernal Keratoconjunctivitis (VKS) based on validated scales (i.e., Bonini and the modified Oxford) were eligible for participation and were randomly assigned to 1 of the 3 treatment arms: Verkazia four times daily (high dose), Verkazia twice daily (low dose) or placebo (vehicle/excipient of the formulation). Patients included in VEKTIS had a severe, active, symptomatic and well-defined VKC, with corneal staining graded 4 or 5 on the modified Oxford scale, and a mean score combining four subjective symptoms ≥ 60 mm on a Visual Analogue Scale (VAS). The study population reflects the proposed VKC population with mean age of 9 years (range: 4 to 17 years); there were more males (78.6%) than females in the study.
The primary efficacy endpoint was a composite endpoint based on sign (keratitis/corneal staining), need for rescue medication (corticosteroid course) and occurrence of corneal ulceration during a 4-month period (also referred as penalty adjusted CFS score). Symptoms and quality of life were also recorded as main secondary endpoints. Efficacy was assessed every month during the 4-month treatment period and compared with baseline using a composite criterion based on keratitis assessed by the modified Oxford scale, the need for rescue medicinal product (use of topical steroids) and the occurrence of corneal ulceration. The study met its primary endpoint with both doses of Verkazia being superior to vehicle. Penalty adjusted CFS score increased from baseline to Month 4 in the two active groups, demonstrating a statistically significant improvement of VKC, most prominent in the high dose group with a difference of 0.76 versus placebo (p = 0.007).The CFS score was the main driver of the score. The magnitude of the treatment effect was similar between the two treatment groups but the commencement of the effect was faster in the high dose group. The improvement in symptoms (i.e., average of photophobia, tearing, itching and mucous discharge symptom at month 4) was significantly higher in the high dose group at all time-points (p < 0.05) when compared to the control group. In the low dose group, however, symptoms were shown to improve significantly more than in vehicle at Month 1 and Month 2. For all symptoms and in all groups, the greatest improvement took place from baseline to Month 1. The difference in the Least Square (LS) mean vs. vehicle was 0.76 (95% CI: 0.26, 1.27) for the high dose group and 0.67 (95% CI: 0.16, 1.18) for the low dose group. Both differences were statistically significant with p = 0.007 for the high dose and p = 0.010 for the low dose group. Overall, the secondary endpoints were supportive of the primary efficacy endpoint. The high Cyclosporine (CsA) dose was more effective than the low dose in improvement of photophobia, mucous discharge and quality of life. Systematic exposure was negligible in a majority of study subjects.
The safety profile was unremarkable; the majority of adverse events were ocular (related to drug administration) with instillation site pain (9.4%; 7.5% and 4.1% in the high dose, low dose and vehicle groups respectively), pruritus (5.2%; 7.5% and 3.1% in the high dose, low dose and vehicle groups respectively) and ocular hyperemia (3.1%; 2.2% and 1% in the high dose, low dose and vehicle groups respectively). The most common systemic AE was headache but frequency was very low 0.7% in the high dose group.
Of potential concern is that Verkazia might be associated with systemic and local effects as local immunosuppression could promote infection and that cyclosporine is a known carcinogen. These potential risks are mitigated in the Product Monograph labelling; Verkazia is contraindicated in patients with active or suspected ocular or peri-ocular infection and in patients with ocular malignancies or premalignant conditions.
Overall, the benefit-to-risk profile of Verkazia is favourable for the treatment of vernal keratoconjunctivitis in children from 4 years of age through adolescence.
Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.