These days, it seems that there is such a heavy emphasis on drug delivery systems that many of our current ophthalmic pharmaceuticals are simply being reformulated as “novel” therapies, rather than replaced entirely.¹ Because the shortcomings of topical drops are well-known, these delivery systems are aimed at eliminating variability in drug concentration with each dose to decrease dose frequency and increase absorption.²

First Out
One such drug is CyclASol (Novaliq), which incorporates EyeSol, an ophthalmic drug delivery technology based on semi-fluorinated alkanes (SFAs).³ SFAs have been used for over a decade in the management of retinal detachments and overall have been well-tolerated by patients. They are physically, chemically and physiologically inert and stable as well as water insoluble.^4-7 Research shows the EyeSol preparation does not require preservatives, so a multidose bottle can be prepared without concern for contamination. Droplet size of SFAs is only 15µl compared with the 40µl or 50µl size of aqueous drops. SFAs also exhibit low viscosity and low surface tension, making them less likely to cause blurry vision and allowing for better wettability.³ 

Viscous vehicles like polyethylene glycol and hyaluronic acid currently used for ophthalmic solutions can effectively solubilize hydrophilic drugs. However, drugs that are lipophilic (i.e., hydrophobic) like cyclosporin A are more challenging; as such, SFAs are effective solvents for these medications.^5,6 CyclASol contains cyclosporin A in combination with perfluorobutylpentane, a unique formulation with an SFA.

What’s In a Name? Cyclosporine was initially developed to suppress the immune response and prevent organ rejection in transplant patients. It was later brought to market in 1983 for oral and parenteral administrations; however, the drug exhibited poor solubility and had widely variable bioavailability, so it was then formulated as a microemulsion in 1995 to address some of the malabsorption concerns. The drug is referred to by at least three nonproprietary names: cyclosporine by the United States Adopted Names Council, cyclosporin by the British Pharmacopoeia and ciclosporin as the drug’s international non-proproprietary name designed by the World Health Organization.15 It is also commonly referred to as cyclosporin A, as an alternative to cyclosporine, in some applications.

Earlier this year, 207 patients were enrolled in a Phase II clinical trial of CyclASol’s safety, tolerability and efficacy in treating moderate to severe dry eye disease. Patients were randomized into one of four treatment groups, including two CyclAsol groups (each containing a different concentration of cyclosporin A), a vehicle control group and an open-label cyclosporin A 0.05% ophthalmic emulsion (Restasis) group. Patients were directed to use the study medication twice a day for four months; researchers will then evaluate the primary outcome measure of corneal fluorescein staining. Results are expected by the end of 2016.⁸

Other research has already demonstrated the drug’s absorption profile. In a pharmacokinetic study involving rabbits, CyclASol penetrated the lacrimal gland significantly better (14-fold increase) than an oil-in-water emulsion.⁵ Additionally, results from a Phase I trial of healthy volunteers who received CyclASol eye drops or a placebo and then switched to the alternate option in the second phase of the study found the drug offered excellent tolerability and safety.²

Second One in the Running
Another drug under consideration is Seciera (Auven Therapeutics), a nanomicellar formulation of cyclosporine previously known as OTX-101. Nanomicelles are tiny particles comprised of a hydrophobic core surrounded by a hydrophilic shell that measure 10nm to 100nm large. They are used to solubilize hydrophobic drugs and are believed to increase ocular bioavailability, minimize degradation and improve penetration of the drug—all of which make them an excellent drug delivery method. Use of nanomicelles allows for cyclosporine to be formulated in a clear, preservative-free, isotonic aqueous solution.^9,10 

In a Phase IIB/III clinical trial, 455 patients in a randomized, double-masked study at 28 sites received either 0.05% cyclosporine, 0.09% cyclosporine or the vehicle as the control. All drops were administered twice a day for 84 days. Co-primary outcome measures consisted of changes in both conjunctival staining and global symptom scores from baseline. Results indicated both concentrations of Seciera were statistically superior to the placebo on both co-primary endpoints. Additionally, the 0.09% concentration also demonstrated an improvement in tear production and corneal staining.

Ultimately, however, the 0.09% concentration was superior to the 0.05% and so will be used in an additional Phase III trial to reconfirm some of the earlier findings.^8,11 This study will enroll 700 patients at 50 sites who will be randomized to receive either cyclosporine 0.09% or the vehicle (control) for 12 weeks. Researchers will look for the number of subjects with a clinically significant increase in Schirmer’s score as compared with baseline. Secondary measures include lissamine green conjunctival staining, fluorescein corneal staining and changes in symptom score. Enrollment for this study began in February 2016. It is expected to conclude by the end of the year.⁸ Reports suggest a long-term safety study is also planned for 2016 that, if successful, may yield a new drug application for Seciera in 2017.¹¹ 

Kicking Keratitis to the Curb
Ikervis (Santen Pharmaceutical) was approved last year as the first ophthalmic drug to treat severe keratitis in adults with dry eye in Europe. Ikervis contains 1mg/mL of cyclosporin A and is formulated as a cationic oil-in-water emulsion. Drug retention time was improved using a cationic nanoemulsion platform technology (i.e., Novasorb). The drug is formulated as a series of nano-sized droplets, which increase the surface area-to-volume ratio and improve ocular surface exposure to the drug, allowing Ikervis to be given to the patient just once a day.^12,13 

Also, Santen recently completed a Phase III study, Vektis, evaluating a 1mg/mL formulation of cyclosporin A for the treatment of severe active vernal keratoconjunctivitis (VKC) in Europe. The drug—tentatively named Vekacia—met its primary and key secondary endpoints in a multicenter, randomized, placebo-controlled study of patients ranging in age from four to 18 years old. 

Cyclosporine Reborn
Allergan announced last fall it had submitted a supplemental document to the FDA for approval of a multi-dose preservative-free bottle of cyclosporin A 0.05%.¹⁴ The bottle will contain the equivalent amount of 60 single-unit vials and is a first-of-its-kind product with a unidirectional valve and air filter technology designed to prevent the need for a preservative to be included. The FDA did request more chemistry, manufacturing and control (CMC) information regarding the bottle.

Monitoring clinical trial outcomes of these drugs will surely be an interesting process. Restasis may soon have to share the limelight with more cyclosporine-based cousins.  

1. Novack GD. Eyes on new product development. J Ocul Pharmacol Ther. 2016 Mar;32(2):65-6.
2. Drug Development & Delivery. EyeSol: a novel topical ocular drug delivery system for poorly soluble drugs. Available at: www.specialtypharma.com/Main/Back-Issues/EyeSol-a-Novel-Topical-Ocular-Drug-Delivery-System-137.aspx. Accessed Mar 1, 2016.
3. ONdrugDelivery. An integrated pipeline of ophthalmic products based on eyeSol delivery technology. Available at: www.ondrugdelivery.com/publications/54/Novaliq.pdf. Accessed Mar 1, 2016.
4. Meinert H, Roy T. Seminfluorinated alkanes – a new class of compounds with outstanding properties for use in ophthalmology. Eur J Ophthalmol. 2000 Jul-Sep,10(3):189-97.
5. Steven P, Scherer D, Krosser S, et al. Semifluorinated alkane eye drops for treatment of dry eye disease – a prospective, multicenter noninterventional study J Ocul Pharmacol Ther. 2015 Oct;31(8):498-503.
6. Dutescu R, Panfil C, Merkel O, Schrage N. Semifluorinated alkanes as a liquid drug carrier system for topical ocular drug delivery. Eur J Pharm Biopharm. 2014 Sep;88(1):123-8.
7. Broniatowski M, Dynarowicz-Latka P. Semifluorinated alkanes – primitive surfactants of fascinating properties. Adv Colloid Interface Sci. 2008 May 19;138(2):62-83.
8. Novaliq. Novaliq announces last patient enrolled in phase 2 clinical trial of cyclasol for the treatment of moderate to severe dry eye disease. Available at: www.novaliq.de/en/news/press-releases/. Accessed May 15, 2016.
9. Vadlapudi AD, Mitra AK. Nanomicelles: an emerging platform for drug delivery to the eye. Ther Deliv. 2013 Jan;4(1):1-3
10. Guo C, Zhang Y, Yang Z, et al. Nanomicelle formulation for topical delivery of cyclosporine A into the cornea: in vitro mechanism and in vivo permeation evaluation. Nature. 2015;Aug:1-14. 
11. Auven Therapeutics. Auven Therapeutics announces positive results from pivotal clinical trial of seciera (OTX-101) in dry eye disease. Available at: www.auventherapeutics.com/pr/Seciera%20P3%20Results%20Release.pdf. Accessed: Mar 1, 2016.
12. Santen. Santen announces approval of Ikervis for EU marketing authorization. Available at: www.santen.com/en/news/20150325.pdf. Accessed: May 15,2016.
13. The Ophthalmologist. Introducing Ikervis. Available at: theophthalmologist.com/issues/0615/introducing-ikervis/. Accessed: May 15, 2016. 
14. EyeWireToday. In complete response letter, FDA requests more information from Allergan for multi-dose preservative-free restasis. Available at: eyewiretoday.com/2016/03/11/allergan-receives-complete-response-letter-from-fda-for-prior-approval-supplement-for-restasis-cyclosporine-ophthalmic-emulsion-005-multi-dose-preserv. Accessed: May 15, 2016.
15. David Moore’s World of Fungi. Origin of drugs in current use: the cyclosporine story. Available at: www.davidmoore.org.uk/Sec04_01.htm. Accessed May 26, 2016.