For more than a decade, there has only been one approved pharmacologic treatment for dry eye—Allergan’s Restasis (topical cyclosporine 0.05%). This in a market estimated to be worth more than $2.4 billion, one that affects up to 100 million people worldwide, and one that is expected to grow by almost 3% yearly.
Dry eye products have particularly difficult hurdles to U.S. regulatory approval—they must show improvement in both signs and symptoms of the disorder. Restasis was approved based solely on its statistically significant improvement in the clinical signs of dry eye; it did not show a significant improvement in symptoms.
With a market as lucrative as dry eye, numerous manufacturers are continuing to develop compounds to treat the chronic disorder. The furthest one along so far is Lexington, Mass.-based Shire. Last month the company submitted lifitegrast to U.S. regulators for the treatment of signs and symptoms of dry eye disease. Shire picked up the compound in the acquisition of SARcode Bioscience in 2013. At the time investors were skeptical if the drug would move forward.
One reason for the skepticism, while the Phase 3 study on lifitegrast met its co-primary endpoint of relieving dry eye symptoms it missed the other endpoint for improving corneal staining. At the time, John Sheppard, MD, suggested investigators had chosen the wrong endpoint—improvement on the Ocular Surface Disease Index. He suggested the data indicated that lifitegrast was a much more viable compound than the OSDI would indicate.
Shire forged ahead, using compiled data from more than 1,800 patients enrolled in four clinical trials, including one Phase 2 study, two Phase 3 efficacy and safety studies, and one long-term Phase 3 safety study.
Dry eye-associated inflammation is typically mediated by T-cells that feature increased expression of intracellular adhesion molecule-1 (ICAM-1). Lifitegrast binds to integrin lymphocyte function-associated antigen-1 (LFA-1) and blocks the interaction of LFA-1 with ICAM-1 (that interaction results in T-cell activation and migration to the target tissues).
Comparatively, Restasis only works on newly formed T-cells, and since those cells can live for about 3.5 months, patients get frustrated quickly when the medication “doesn’t work” after two or three weeks, experts say. Some specialists have combined lodeprednol (a “soft” steroid) to provide patient relief while Restasis is building up in their systems.
Some clinicians have predicted lifitegrast would be best used in conjunction with Restasis as lifitegrast has a much quicker onset of action. If approved, analysts predict lifitegrast could see sales of $60 million in 2016, and upwards of $348 million in 2018.
Here, a brief rundown of the others (in alphabetical order):
1. EBI 005 by Eleven Biotherapeutics is a topical, novel interleukin-1 (IL-1) receptor blocker. Enrollment in pivotal Phase 3 study was completed late last year, with top-line results expected during Q2 2015.
2. EGP-437 from EyeGate Pharmaceuticals is a dexamethasone formulation tailored for iontopheresis that has completed Phase 3 studies. Results demonstrated statistically significant improvements in dry eye signs and symptoms relative to the placebo group in controlled adverse environment (CAE) challenge, CAE recovery, and environmental conditions.
3. KP-121 by Kala Pharmaceuticals is a loteprednol etabonate mucus-penetrating particle (MPP) drug product that in Phase 2 trials that enrolled 150 patients. Top-line results indicate KP-121 achieved statistical significance for the primary sign endpoint of bulbar conjunctival hyperemia, and promising trends were observed for key symptom endpoints.
4. MIM-D3 from Mimetogen Pharmaceuticals has completed a Phase 3 trial. Top-line data suggests MIM-D3 demonstrated significant improvements in signs and symptoms with 1% MIM-D3 versus placebo, along with excellent safety, comfort and tolerability profiles.
5. OTX-DP by Ocular Therapeutix is sustained-release dexamethasone that is administered as a one-time absorbable intracanalicular plug, designed with a four-week tapered release. The Phase 3a study, which enrolled 247 patients, met both primary efficacy measures, achieving a statistically significant improvement in the reduction of inflammatory cells and pain. The company plans to file for regulatory approval in 2Q 2015.
6. Published study results on 2% rebamipide ophthalmic suspension (OPC-12759, Otsuka Pharmaceuticals) found it effective in improving both the objective signs and subjective symptoms of dry eye patients for at least 52 weeks.
7. RU-101 by R-Tech Ueno is an ophthalmic solution containing recombinant human serum albumin. A Phase 2 study found RU-101 significantly improved the corneal staining score time-dependently and statistically for 4, 8, and 12 weeks after starting instillation, but did not reach statistical significance when compared to placebo.