Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Santen Oy, Niittyhaankatu 20, 33720 Tampere, Finland
Pharmacotherapeutic group: Ophthalmologicals, other ophthalmologicals
ATC code: S01XA18
Following ocular administration, ciclosporin is passively absorbed by T-lymphocytes where its binding to cyclophilin A inactivates calcineurin, and prevents NF-AT translocation into the nucleus, thus blocking the release of pro-inflammatory cytokines such as IL-2 and hence T-lymphocyte activation. Blocking NF-AT also interferes in the allergy process. Ciclosporin inhibits histamine release from mast cells and basophils through a reduction in IL-5 production, and may reduce eosinophil recruitment and effects on the conjunctiva and cornea. Ciclosporin is also known to up-regulate the release of anti-inflammatory cytokines. All available evidence suggests that ciclosporin acts specifically and reversibly on lymphocytes and does not depress haematopoiesis or have any effect on the function of phagocytic cells.
In a 12 month double-masked, vehicle controlled, pivotal clinical trial (VEKTIS study), 169 patients with severe VKC and severe keratitis (grade 4 or 5 on the modified Oxford scale) were randomised to 4 drops of Verkazia (high dose) or 2 drops of Verkazia (low dose) and 2 drops of vehicle or 4 drops of vehicle for the first 4 months (Period 1). Patients randomised to the vehicle group were switched to Verkazia (four times or twice daily) from Month 4 to Month 12 (Period 2).
168 patients [127 children (75.6%) and 41 adolescents (24.4%)] were included in the efficacy analyses. Mean age was 9.2 years (SD: 3.3, age range: 4-17 years). There were more male [n=132 (78.6%)] than female patients [n=36 (21.4%)].
The primary efficacy endpoint which was the average penalties adjusted change of the Corneal Fluorescein Staining (CFS) score from baseline and over Period 1, considered all patients (n=168). 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 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.
Clinical relevance of the primary efficacy endpoint was however difficult to address. In that context, responder rate’s results were considered as more reliable endpoint. A responder was defined as a patient 1) with a mean CFS score over the 4 months of treatment ≤50% of baseline, 2) who did not withdraw from the study for a reason possibly due to treatment, 3) with no experience of corneal ulceration and 4) no use of rescue medicinal product in the last 4 months of treatment. There was a significantly higher number of CFS responders in both active groups as compared to vehicle (p=0.005 for the high dose group, and p=0.010 for the low dose group) with 55.4%, 50.0% and 27.6% of responders in the high dose, low dose and vehicle groups respectively. The excess rate with respect to vehicle was 27.8% for the high dose regimen and 22.4% for the low dose one.
Rescue medicinal product (topical steroids) was used more often in the vehicle than in the high dose regimen: 32.1% in the high dose group and 31.5% in the low dose group received at least one course of rescue medicinal product while they were 53.4% in the vehicle group.
All four symptoms (photophobia, tearing, itching and mucous discharge) improved over time and the difference from baseline at Month 4 for each symptom largely exceeded 10 mm.
For the average of VKC symptoms, the difference in the LS mean vs. vehicle in the high dose group was statistically significant at all time points compared to vehicle: -19.4 mm (p<0.05).
Patient quality of life (Quick questionnaire) improved significantly better in the high dose group compared to vehicle. The improvement was clinically relevant as illustrated by the effect size over 4 months (symptoms domain: 0.67 and daily activities domain: 0.44).
In Period 2, analyses demonstrated stability of improvements achieved during Period 1 for both doses regimen.
Formal pharmacokinetic studies have not been conducted in humans with Verkazia.
Blood concentrations of Verkazia were measured using a specific high-pressure liquid chromatography-mass spectrometry assay. In 166 patients at baseline from one efficacy study (55 patients in the high dose group, 53 in the low dose group and 58 in the vehicle group), plasma concentrations of ciclosporin were measured before administration and after 2, 4 and 12 months of treatment.
In the high dose group after 4 months of ocular instillation of Verkazia 4 times daily (n=50), 20 patients had values below the lower limit of detection (0.050 ng/mL) and 13 patients had values below the lower limit of quantification (0.100 ng/mL). Quantifiable values not exceeding 0.670 ng/mL were measured in 14 patients, values considered to be negligible. Ciclosporinemia was not measured for 3 patients. At Month 12, (n= 68 patients) values were below the lower limit of detection for 38 patients and below the lower limit of quantification in 10 patients. 12 patients had measurable values (maximum 0.291 ng/mL), all considered to be negligible values. Ciclosporinemia was not measured for 8 patients.
In the low dose group, after 4 months of ocular instillation of Verkazia 2 times daily (n=47 patients), 34 patients had values below the lower limit of detection (0.050 ng/mL) and 7 patients had values below the lower limit of quantification (0.100 ng/mL). Quantifiable values not exceeding 0.336 ng/mL were measured in 5 patients, values considered to be negligible. Ciclosporinemia was not measured for 1 patient. At Month 12 (n= 61 patients), values were below the lower limit of detection for 47 patients and below the lower limit of quantification in 6 patients. 5 patients had measurable values (maximum 0.300 ng/mL), all considered to be negligible values. Ciclosporinemia was not measured for 3 patients.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, phototoxicity and photoallergy, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
Effects in non-clinical studies were observed only with systemic administration or at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
