Source: European Medicines Agency (EU) Revision Year: 2017 Publisher: SANTEN Oy, Niittyhaankatu 20, 33720, Tampere, Finland
Pharmacotherapeutic group: Ophthalmologicals, other ophthalmologicals
ATC code: S01XA18
Ciclosporin (also known as ciclosporin A) is a cyclic polypeptide immunomodulator with immunosuppressant properties. It has been shown to prolong survival of allogeneic transplants in animals and significantly improved graft survival in all types of solid organ transplantation in man.
Ciclosporin has also been shown to have an anti-inflammatory effect. Studies in animals suggest that ciclosporin inhibits the development of cell-mediated reactions. Ciclosporin has been shown to inhibit the production and/or release of pro-inflammatory cytokines, including interleukin 2 (IL-2) or T-cell growth factor (TCGF). It is also known to up-regulate the release of anti-inflammatory cytokines.
Ciclosporin appears to block the resting lymphocytes in the G0 or G1 phase of the cell cycle. All available evidence suggests that ciclosporin acts specifically and reversibly on lymphocytes and does not depress haematopoiesis or has any effect on the function of phagocytic cells..
In patients with dry eye disease, a condition that may be considered to have an inflammatory immunological mechanism, following ocular administration, ciclosporin is passively absorbed into T- lymphocyte infiltrates in the cornea and conjunctiva and inactivates calcineurin phosphatase.
Ciclosporin-induced inactivation of calcineurin inhibits the dephosphorylation of the transcription factor NF-AT and prevents NF-AT translocation into the nucleus, thus blocking the release of pro- inflammatory cytokines such as IL-2.
The efficacy and safety of IKERVIS were evaluated in two randomised, double-masked, vehicle-controlled clinical studies in adult patients with dry eye disease (keratoconjunctivitis sicca) who met the International Dry Eye Workshop (DEWS) criteria.
In the 12 month, double-masked, vehicle controlled, pivotal clinical trial (SANSIKA study), 246 Dry Eye Disease (DED) patients with severe keratitis (defined as a corneal fluorescein staining (CFS) score of 4 on the modified Oxford scale) were randomised to one drop of IKERVIS or vehicle daily at bedtime for 6 months. Patients randomised to the vehicle group were switched to IKERVIS after 6 months. The primary endpoint was the proportion of patients achieving by Month 6 at least a two-grade improvement in keratitis (CFS) and a 30% improvement in symptoms, measured with the Ocular Surface Disease Index (OSDI). The proportion of responders in the IKERVIS group was 28.6%, compared to 23.1% in the vehicle group. The difference was not statistically significant (p=0.326).
The severity of keratitis, assessed using CFS, improved significantly from baseline at Month 6 with IKERVIS compared to vehicle (mean change from baseline was -1.764 with IKERVIS vs. -1.418 with vehicle, p=0.037). The proportion of IKERVIS-treated patients with a 3-grade improvement in CFS score at Month 6 (from 4 to 1) was 28.8%, compared to 9.6% of vehicle-treated subjects, but this was a post-hoc analysis, which limits the robustness of this outcome. The beneficial effect on keratitis was maintained in the open phase of the study, from Month 6 and up to Month 12.
The mean change from baseline in the 100-point OSDI score was -13.6 with IKERVIS and -14.1 with vehicle at Month 6 (p=0.858). In addition, no improvement was observed for IKERVIS compared to vehicle at Month 6 for other secondary endpoints, including ocular discomfort score, Schirmer test, use of concomitant artificial tears, investigator’s global evaluation of efficacy, tear break-up time, lissamine green staining, quality of life score, and tear osmolarity. A reduction in the ocular surface inflammation assessed with Human Leukocyte Antigen-DR (HLA-DR) expression (an exploratory endpoint), was observed at Month 6 in favour of IKERVIS (p=0.021).
In the 6 month, double-masked, vehicle controlled, supportive clinical trial (SICCANOVE study), 492 DED patients with moderate to severe keratitis (defined as a CFS score of 2 to 4) were also randomised to IKERVIS or vehicle daily at bedtime for 6 months. The co-primary endpoints were the change in CFS score, and the change in global score of ocular discomfort unrelated to study medication instillation, both measured at Month 6. A small but statistically significant difference in CFS improvement was observed between the treatment groups at Month 6 in favour of IKERVIS (mean change from baseline in CFS -1.05 with IKERVIS and -0.82 with vehicle, p=0.009).
The mean change from baseline in ocular discomfort score (assessed using a Visual Analogic Scale) was -12.82 with IKERVIS and -11.21 with vehicle (p=0.808).
In both studies, no significant improvement of symptoms was observed for IKERVIS compared to vehicle after 6 months of treatment, whether using a visual analogue scale or the OSDI.
In both studies one third of the patients in average had Sjögren’s syndrome; as for the overall population, a statistically significant improvement in CFS in favour of IKERVIS was observed in this subgroup of patients.
At completion of the SANSIKA study (12 month study), patients were asked to enter the Post SANSIKA study. This study was an open-label, non-randomized, one-arm, 24-month study extension of the Sansika Study. In Post SANSIKA study patients alternatively received IKERVIS treatment or no treatment depending on CFS score (patients received IKERVIS when there was a worsening of keratitis).
This study was designed to monitor the long-term efficacy and relapse rates in patients who have previously received IKERVIS.
The primary objective of the study was to assess the duration of the improvement following IKERVIS treatment discontinuation once the patient was improved with respect to the baseline of the SANSIKA study (i.e. at least 2 grade improvement on the modified Oxford scale). 67 patients were enrolled (37.9% of the 177 patients having ended Sansika). After the 24-month period, 61.3% of 62 patients included in the primary efficacy population did not experience a relapse based on CFS scores. Percentage of patients who experienced a severe keratitis recurrence was 35% and 48% in patients treated 12 months and 6 months with IKERVIS respectively in the SANSIKA study.
Based on the first quartile (the median could not be estimated due to the small number of relapses), time to relapse (back to CFS grade 4) was ≤224 days and ≤175 days in patients previously treated 12 months and 6 months with IKERVIS, respectively. Patients spent more time on CFS grade 2 (Median 12.7 weeks/year) and grade 1 (Median 6.6 weeks/year) than CFS grade 3 (Median 2.4 weeks/year), CFS grades 4 and 5 (Median time 0 week/year). Assessment of DED symptoms by VAS showed a worsening of patient’s discomfort from the time treatment was first stopped to the time it was restarted except pain which remained relatively low and stable. The median global VAS score increased from the time treatment was first stopped (23.3%) to the time treatment was restarted (45.1%).
No significant changes have been observed in the other secondary endpoints (TBUT, lissamine green staining and Schirmer test, NEI-VFQ and EQ-5D) over the course of the extension study.
The European Medicines Agency has waived the obligation to submit the results of studies with IKERVIS in all subsets of the paediatric population for dry eye disease (see section 4.2 for information on paediatric use).
Formal pharmacokinetic studies have not been conducted in humans with IKERVIS.
Blood concentrations of IKERVIS were measured using a specific high-pressure liquid chromatography-mass spectrometry assay. In 374 patients from the two efficacy studies, plasma concentrations of ciclosporin were measured before administration and after 6 months (SICCANOVE study and SANSIKA study) and 12 months of treatment (SANSIKA study). After 6 months of ocular instillation of IKERVIS once per day, 327 patients had values below the lower limit of detection (0.050 ng/mL) and 35 patients were below the lower limit of quantification (0.100 ng/mL).
Measurable values not exceeding 0.206 ng/mL were measured in eight patients, values considered to be negligible. Three patients had values above the upper limit of quantification (5 ng/mL) however they were already taking oral ciclosporin at a stable dose, which was allowed by the studies' protocol.
After 12 months of treatment, values were below the low limit of detection for 56 patients and below the low limit of quantification in 19 patients. Seven patients had measurable values (from 0.105 to 1.27 ng/mL), all considered to be negligible values. Two patients had values above the upper limit of quantification, however they were also on oral ciclosporin at a stable dose since their inclusion in the study.
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.
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