A comparative review of Haute Autorité de Santé and National Institute for Health and Care Excellence health technology assessments of Ikervis® to treat severe keratitis in adult patients with dry eye disease which has not improved despite treatment with tear substitutes

Abstract

Background: In 2015, Ikervis® became the only EMA-approved cyclosporine A (CsA) eye-drop for the treatment of severe keratitis in adult patients with dry eye disease, which has not improved despite treatment with tear substitutes. Since the 1980s, CsA has been used empirically for ocular conditions in veterinary medicine then in humans. However, its extremely low aqueous solubility led to its administration in vegetable oils, which is characterized by low ocular availability, poor intraocular penetration, poor tolerability and short shelf-life. Concentrations from 0.05% to 2% are compounded on an industrial scale and reimbursed throughout Europe. In France, Ikervis® has been granted an ASMR score of 5 by HAS, whereas in UK NICE endorsed its use. Objective: To review the dry eye disease environment, its challenges and available treatment options, and compare the NICE and HAS assessments to question HAS’ decision to maintain full reimbursement of compounded CsA formulations in the absence of evidence, while reimbursing the EMA-approved drug at 15%. Method: extensive search on PubMED. Results: Comparator selection, composite score assessment and use of CE model are key differentiators. Conclusion: In topical formulations, improvements to the vehicle are key innovations that can bring significant benefits. After the USA, a Compounding Act is needed in Europe.

Nanocarriers for ocular drug delivery: current status and translational opportunity

“…Moreover, Ikervis® (cyclosporine A cationic nanoemulsion) has been approved for treating severe keratitis in dry eye disease patients. 141 Sun Pharmaceuticals developed Cequa® (cyclosporine A ophthalmic nano micellar solution) 0.09%, which is intended to improve drug delivery and penetration to ocular tissues. Cequa® has been investigated for efficacy and safety in treating keratoconjunctivitis sicca (dry eye).…”

Comparative analysis of 0.1% cyclosporin A cationic emulsion and 0.05% cyclosporin A emulsion in murine dry eye cases with different severities

“…A previous study reported that CsA CE is well tolerated and effectively improves the signs and symptoms in patients with moderate-to-severe DE to SDE over 6 months, in particular in patients with severe disease who are at risk of irreversible corneal damage (14). Furthermore, previous clinical studies demonstrated that 0.1% CsA CE improves the CFS, CFS OSDI response and conjunctival expression of human leukocyte antigen DR in SDE cases with keratitis and SS (12)(13)(14). Consistently with these previous reports, the results from the present study demonstrated that the application of 0.05% CsA emulsion and 0.1% CsA CE both led to improvements in the clinical parameters in EDE mice.…”

“…In previous clinical studies published over the last decade, marked improvements have been observed for subjective symptoms (i.e., based on the OSDI, Schirmer test, and CFS) in patients with severe keratoconjunctivitis, including GVHD and SS, following treatment with 0.1% CsA cationic emulsion (CsA CE; iKervis ® ; Santen Pharmaceutical Co., Ltd.) compared with 0.05% CsA emulsion (12)(13)(14). Although clinical studies have demonstrated that 0.1% CsA CE leads to an improvement in symptoms and indicators in patients following treatment for longer or shorter periods of time, to the best of our knowledge, no study has investigated the effect of 0.1% CsA CE topical application on ocular surface inflammation and damage in experimental DE (EDE).…”

Assessment and Management of Dry Eye Disease and Meibomian Gland Dysfunction: Providing a Singapore Framework

“…Cyclosporine A is an immunomodulatory drug with anti-inflammatory properties and can be used for the treatment of ocular inflammation and DED. 63 , 89 Topical cyclosporine A was approved based on an improvement in tear production, but has also been shown to reduce inflammatory markers, reduce hyperosmolarity, increase conjunctival goblet cell density, and have antiapoptotic properties. It has been shown to lead to significant improvements in symptoms, prevent disease progression, and rarely, even “cure” the disease.…”