Persistence of Efficacy of 0.1% Cyclosporin A Cationic Emulsion in Subjects with Severe Keratitis Due to Dry Eye Disease: A Nonrandomized, Open-label Extension of the SANSIKA Study.

PURPOSE: Results from a 6-month double-masked and a 6-month open-label study (SANSIKA) established the efficacy and safety of once-daily 0.1% cyclosporin A cationic emulsion (CsA CE) in severe keratitis due to dry eye disease (DED). This article presents results from the Post-SANSIKA study, a 24-month extension of SANSIKA assessing the sustained efficacy of CsA CE after treatment discontinuation. METHODS: Time to relapse (corneal fluorescein staining [CFS] score ≥4 [modified Oxford scale]) was assessed after treatment discontinuation in patients from the SANSIKA study who had CFS improvement from a score of 4 to ≤2 after 6 or 12 months of treatment with CsA CE. FINDINGS: Of 62 patients who achieved a CFS score ≤2 at the end of the SANSIKA study, 38 did not relapse and 24 (39%) relapsed during the 24-month period after CsA CE discontinuation; the latter (relapse) group comprised 35% of patients initially treated with CsA CE for 12 months in SANSIKA versus 47% of those treated for 6 months only. Patients spent the most time during the extension study at CFS scores of 1 or 2 (median duration of 8.5 weeks and 14.7 weeks per year, respectively), indicating marked improvement, and less time at scores of 3, 4, or 5 (median time, 2.0 weeks, 0 weeks, and 0 weeks per year). Of 23 patients eligible for safety analysis (ie, patients who received the study treatment at least once), 12 (52.2%) reported a total of 26 ocular adverse events (AEs). Among these, 5 ocular AEs, reported in 5 patients (21.7%), were considered related to study treatment: 3 events of mild instillation site pain in 3 patients (13.0%) and eye discharge and foreign body sensation, each reported in 1 patient (4.3%). Only 1 systemic AE (nasal congestion), reported in 1 patient (4.3%), was considered related to study treatment. None of the AEs led to treatment discontinuation. IMPLICATIONS: The majority of patients who discontinued CsA CE after experiencing DED improvement in the SANSIKA study did not experience a relapse in this 24-month follow-up study; these patients spent the most time at CFS scores consistent with marked improvement. CsA CE had a favorable safety/tolerability profile over 2 years. Treatment for up to 12 months with CsA CE provides sustained improvements in patients with severe keratitis due to DED. EudraCT registration no. 2012-002066-12.

Targeting interleukin-6 in autoimmune uveitis.

Interleukin-6 (IL-6) is a key cytokine that is strongly up-regulated during infection and inflammation. Featuring pleiotropic activity, IL-6 is responsible for the induction of hepatic acute-phase proteins, trafficking of acute and chronic inflammatory cells, differentiation of adaptive T cell responses, homeostatic regulation, and tissue regeneration. Dysregulated IL-6 production has been associated with the development of a wide variety of systemic immune-mediated, chronic diseases, and even certain types of cancer. From the ocular perspective, significant elevation of IL-6 has been found in ocular fluids derived from diabetic macular edema, retinal vein occlusion, and refractory/chronic uveitis patients. During the last decade, tocilizumab, a neutralizing monoclonal antibody (mAb) that targets the IL-6 receptor (IL-6R), has been approved for the treatment of rheumatoid arthritis in >100 countries worldwide. Furthermore, it has been reported to be effective for the treatment of a number of autoimmune diseases including uveitis and its associated macular edema. Currently numerous candidate molecular strategies targeting the IL-6 signaling pathways are in progress through clinical trials in various disorders. Herein we discuss the basic biology of IL-6 and its pathological role in the development of immune-mediated conditions, particularly focusing on inflammatory eye diseases. It also provides an overview of the on-going clinical trials with the new anti-IL-6 mAbs and their potential use in the clinical practice.

One-Year Efficacy and Safety of 0.1% Cyclosporine a Cationic Emulsion in the Treatment of Severe Dry Eye Disease.

PURPOSE: The SANSIKA study evaluated the efficacy/safety of 0.1% (1 mg/mL) cyclosporine A cationic emulsion (CsA CE) for treating dry eye disease (DED) with severe keratitis. The double-masked phase demonstrated that CsA CE was effective in reducing corneal damage and ocular surface inflammation, and was well-tolerated over 6 months. Here we report efficacy and safety findings of SANSIKA's open-label extension (OLE). METHODS: In this multicenter, double-masked, phase III study, patients with severe DED (corneal fluorescein staining [CFS] grade 4, modified Oxford scale) were randomized to once-daily CsA CE (Ikervis®) or its vehicle for 6 months, followed by 6-month open-label, once-daily CsA CE (CsA CE/CsA CE and vehicle/CsA CE groups). RESULTS: A total of 177 patients completed the OLE. Efficacy results reiterated the double-masked phase: CsA CE reduced CFS score and human leukocyte antigen-antigen D related expression, improved corneal clearing, and produced continuous improvements in global symptom scores (ocular surface disease index [OSDI], visual analogue scale). The CFS-OSDI response rates (≥2 CFS points, ≥30% OSDI improvement vs baseline) at 12 vs 6 months were 39.1% vs 28.6%, respectively, for CsA CE/CsA CE and 38.0% vs 23.1% for vehicle/CsA CE. Cyclosporine A CE's safety profile was similar to the initial 6 months. The most common treatment-related treatment-emergent adverse event was instillation site pain (7.8%, CsA CE/CsA CE group; 19.0%, vehicle/CsA CE group). No unexpected safety signals were observed; systemic CsA levels were undetectable/negligible in all patients except 2 previously treated with systemic CsA. CONCLUSIONS: In this 12-month study, once-daily CsA CE was well-tolerated and showed reductions in ocular surface inflammation and improvements in signs/symptoms in DED patients with severe keratitis.