Dry Eye Brimming With Innovation
The acceleration of research focused on dry eye over the past several decades has led to an increase in knowledge regarding the pathophysiology of the disease. The dry eye pipeline is now brimming with innovation, from investigational therapies to pioneering clinical models, study designs, and technologies.
Several new dry eye drug candidates are currently under evaluation and show great potential. SAR1118 (SARCode) is a selective small-molecule LFA-1 antagonist, inhibiting T-cell migration, proliferation, adhesion, and cytokine release thus preventing T-cell mediated chronic inflammation.1 A phase III study evaluating the efficacy of SAR 1118 (5.0%) compared with placebo in the treatment of dry eye is currently ongoing.2
As ophthalmologists wait for the approval of additional options for the treatment of dry eye, it is of utmost importance that we continue to learn more about the pathologic processes at work and strive to develop novel methods and models to understand the disease better.
Mimetogen has developed a family of smallmolecule tyrosine kinase receptor agonists that are powerful mucin secretagogues that have been shown to stimulate MUC 5AC secretion from conjunctival goblet cells. MIM-D3 is a small-molecule mimetic of nerve growth factor (NGF) and has completed a phase II study designed to compare the safety and efficacy of 1% MIM-D3 and 5% MIM-D3 with placebo for the treatment of the signs and symptoms of dry eye.3
RX-10045 (Resolvyx) is a synthetic resolvin analog formulated for topical application to treat diseases of the eye and is being investigated for the treatment of dry eye. In a phase II trial, RX- 10045 produced dose-dependent improvement in both the signs and symptoms of dry eye, and was generally shown to be safe and well tolerated.4 Last year, Resolvyx and Celtic Therapeutics announced that they would be entering into a final agreement under which Celtic had acquired and licensed rights to RX-10045.5 Also on the docket and of obvious interest is Allergan’s Restasis X, a new variation of cyclosporine, which is listed in phase II.6
At Ora, we have studied more than 10,000 patients across 150 dry eye trials. One core concept we’ve learned is that dry eye symptoms fluctuate as the seasons come and go, with many patients experiencing a worsening of signs and symptoms during heightened dry eye seasons. For example, patients living in the Northeast region of the United States may find the winter months especially challenging, because the air is drier and the humidity is decreased both indoors and outdoors. Traditionally, environmental studies investigating dry eye therapies have been conducted across many seasons, some continuing for many years.
In order to minimize the environmental influences, a clinical trial is best conducted during a single season to reduce the unpredictability of environmental factors. Trying to control for environmental factors is also challenged by numerous situational factors that may further exacerbate dry eye, such as prolonged visual tasking, ocular surgery, aging, and certain medications that cause ocular drying.
By reducing the variability caused by environmental and situational factors using an environmental model like the Controlled Adverse Environment (CAE), which was designed to exacerbate the signs and symptoms of dry eye by regulating humidity, temperature, airflow, lighting conditions, and visual tasking, we are able to study dry eye in a more controlled manner.7,8,9 The CAD model has been shown to be a valuable tool for screening and enriching patient populations in environmental trials, measuring the impact of therapeutic regimens on various subjective and objective endpoints before and after CAD exposure, and understanding of dry eye.
Using established technologies to select and diagnose patients properly can also yield better- controlled dry eye studies. These technologies have been revised and improved upon as the understanding of dry eye has increased. The work of Lemp in the 1970s brought about one of the most widely used clinical tests used to measure properties of the tear film, tear-film breakup time (TFBUT).10,11 Subsequent studies have identified improvements to the measurement of tear film stability. While the standards developed for TFBUT were >10 seconds for normal subjects and <10 seconds for subjects with dry eye, reducing the quantity of fluorescein used led to a modification of reference values to a more accurate threshold of 5 seconds. A TFBUT value less than 5 seconds is generally agreed to constitute tear-film stability consistent with dry eye.12,13
Next, because both the lids and the tear film are responsible for providing protection to the ocular surface, it became evident that TFBUT alone does not provide a complete picture of ocular health. In light of this, the ocular protection index (OPI) was developed to evaluate the interaction between blinking and TFBUT. Most recently, the development of the OPI 2.0 System allows for a measure of tear film stability under a natural blink pattern and normal visual conditions. By capturing the natural dynamics of the tear film with automated methods, studies of the interaction between blinking and TFBUT are enhanced by adding an additional component for analysis, that of tear film breakup area.14 The measure of the amount of ocular surface exposure provides a more complete picture of ocular surface health and has been previously studied.15,16
Because of the ability to automate the analysis of the tear film, the role of blink patterns has also evolved Aspects such as blink frequency, microsleeps, and fissure width will also play a pivotal role in our understanding of dry eye. Automated analysis has become useful in other diagnostic tools as well. While numerical scales have long been used to classify the extent and quality of ocular redness in patients with dry eye, automated detection of hyperemia has been utilized to provide increased repeatability and sensitivity. Because dry eye hyperemia occurs as horizontal banding over the conjunctiva, the disease is quite suitable for automated detection of redness and may be useful as a supplement to clinician grading.17
New technologies in ocular imaging techniques have also been improved. While once a challenge for ophthalmic clinicians and researches, microscopic evaluation of ocular structures has been facilitated by the use of confocal microscopy. This technology allows in vivo examination of the human cornea and conjunctiva at a cellular level.
Last but not least, research to discover pertinent and clinically relevant biomarkers for dry eye, including cytokines, mucin gene expression levels, and tear osmolarity, is also of interest to the industry. These biomarkers may serve as important determinants of disease risk, prognosis, or even response to a treatment.
As we wait with bated breath for the approval of additional options for the treatment of dry eye, it is of utmost importance that we continue to learn more about the pathological processes at work and strive to develop novel methods and models to understand the disease better.OT References
George W. Ousler III is Vice President of dry eye at Ora Inc., Andover, MA.
- 1. Murphy CJ, Bentley E, Miller PE, et al. The pharmacologic assessment of a novel lymphocyte function-associated antigen-1 antagonist (SAR 1118) for the treatment of keratoconjunctivitis sicca in dogs. Invest Ophthalmol Vis Sci. 2011;52:3174-3180.
- 2. Safety and Efficacy Study of SAR 1118 to Treat Dry Eye (OPUS-1). http://clinicaltrials.gov/ct2/show/ NCT01421498. Accessed April 04, 2012.
- 3. Safety and Efficacy Study of MIM-D3 Ophthalmic Solution for the Treatment of Dry Eye. http://clinicaltrials. gov/ct2/show/NCT01257607. Accessed April 04, 2012.
- 4. Resolvyx Announces Positive Data from Phase 2 Clinical Trial of the Resolvin RX-10045 in Patients with Dry Eye Syndrome. http://www.resolvyx.com/news-pubs/ releases/082409.asp. Accessed April 04, 2012.
- 5. Resolvyx Pharmaceuticals and Celtic Therapeutics Enter Final Agreement in Ophthalmology. http://www.resolvyx. com/news-pubs/releases/011011.asp. Accessed April 04, 2012.
- 6. Allergan: Pipeline. http://www.allergan.com/research_ and_development/pipeline.htm. Accessed April 06, 2012.
- 7. Ousler GW, Gomes PJ, Welch D, Abelson MB. Methodologies for the study of ocular surface disease. Ocul Surf. 2005;3:143-154.
- 8. Ousler G, Johnston P, Welch DKL, Abelson M. Validation of the Enhanced Controlled Adverse Environment II. TFOS Poster Presentation. 2010.
- 9. Patane MA, Cohen A, From S, Torkildsen G, Welch D, Ousler GW 3rd. Ocular iontophoresis of EGP-437 (dexamethasone phosphate) in dry eye patients: results of a randomized clinical trial. Clin Ophthalmol. 2011;5:633-643.
- 10. Lemp MA, Holly FJ, Iwata S, Dohlman CH. The precorneal tear film. I. Factors in spreading and maintaining a continuous tear film over the corneal surface. Arch Ophthalmol. 1970;83:89-94.
- 11. Lemp MA, Hamill JR Jr. Factors affecting tear film breakup in normal eyes. Arch Ophthalmol. 1973;89:103-105.
- 12. Lemp MA. Report of the National Eye Institute/Industry workshop on Clinical Trials in Dry Eyes. CLAO J. 1995;21:221-232.
- 13. Abelson MB, Ousler GW 3rd, Nally LA, Welch D, Krenzer K. Alternative reference values for tear film break up time in normal and dry eye populations. Adv Exp Med Biol. 2002;506(Pt B):1121-1125.
- 14. Abelson RLK, Rodriguez J, Johnston P, Angjeli E, Ousler G, Montgomery D. Validation and verification of the OPI 2.0 System. In Press: Clin Ophthalmol. 2012, 6.
- 15. Begley CG, Himebaugh N, Renner D, et al. Tear breakup dynamics: a technique for quantifying tear film instability. Optom Vis Sci. 2006;83:15-21.
- 16. Harrison WW, Begley CG, Liu H, Chen M, Garcia M, Smith JA. Menisci and fullness of the blink in dry eye. Optom Vis Sci. 2008;85:706-714.
- 17. Gomes PLK, Abelson MB, Rodriguez J, Angjeli E. Clinical Evaluation of Automated Detection and Grading of Conjunctival Hyperemia in Dry Eye and Allergic Conjunctivitis Patients. TFOS Asia. Kamakura, Japan; 2012.