After years of fits and starts, the often stalled but always prodigious machinery of the dry-eye pipeline appears to be moving forward. Thanks to improvements in designing clinical trials, monitoring patients’ signs and symptoms and evaluating the performance of therapeutic agents, a number of drugs are making their way through the clinical trial process. These agents include new mucomimetics, receptor inhibitors and anti-inflammatories. Here’s a comprehensive look at the dry-eye drugs you may be using in the coming years.
Many different therapeutic entities are under investigation for the treatment of dry eye. Besides the continued efforts to improve polymers, more targeted mechanisms are also coming into focus, from secretagogues and mucomimetics to anti-evaporatives and hormonal and nutritional supplements. Here are the different classes of drugs being investigated.
• Hyaluronic acid. Hyaluronic acid has been intensely studied in the realm of artificial tears, primarily in Europe: 0.1% solutions in saline;
Efforts to modify HA to increase its residence time on the ocular surface have provided us with improved compounds. A thiolated, carboxymethyl hyaluronic acid (CMHA-S) has been synthesized to form covalent disulfi de cross-links, thus modulating the gelation of the formulation to enhance dwell time on the ocular surface. A similar formulation is already marketed worldwide for veterinary use (ReMend),
Yet another tear solution containing CMC, the osmoprotective erythritol L-carnitine and glycerin, was compared to a standard HA formulation in a Phase III non-inferiority study in Europe. Compared to HA, the osmoprotective CMC-containing tear was preferred by patients, and was noninferior in terms of efficacy and safety.
• Mucomimetic/mucogenic agents. Tamarind seed polysaccharide is a mucomimetic, mucoadhesive pseudoplastic with a structure similar to mucin 1, a transmembrane glycoprotein thought to play an essential role in ocular surface wetting. This has been evaluated alone and with HA in Europe, and is a component of Visine Intensiv 1% EDO eyedrops, available commercially in Europe.
Ways to Streamline the Pipeline
What’s behind the current number of advances in the pipeline of dry-eye therapy? It turns out that several enhancements to trial design are making it possible to guide a drug through the process more effectively than ever before.
First, there are without a doubt improvements in clinical trial execution within the fi eld of dry eye. At our research firm, Ora, the pitfalls of conducting dry-eye trials have been well-defi ned over the past 10 years. Recognition of the seasonality of dry eye and the importance of conducting a study in as short a period as possible rather than a four- or sixseason period, was critical. Seasonal and geographic constraints add a layer of complexity to conducting a dry-eye trial that makes it best to complete the trial within one season.1-4
Another challenge to running a successful dry-eye trial is the placebo effect. Any placebo vehicle solution will ameliorate a desiccated ocular surface, and this benefi t will narrow the differences between the study treatment and the placebo. Most of our clinical trials involve prescreening subjects with placebo and eliminating anyone who responds to its lubricating effects. Thus, the population that remains will more effectively reveal any drug effect.1
In addition, we now have tools that screen for a greater likelihood of response, such as a significant increase in staining with the controlled adverse environment challenge or other more subtle matching of sign/symptom characteristics with the mechanism of action of the drug. By selecting patients based on their response to an artificial challenge [controlled adverse environment (CAE)], and not based on a potentially anomalous threshold level of naturally presenting signs and symptoms, regression to the mean should be minimized. Even though fi nding the right patient might result in a higher rate of non-eligibility, the considerably smaller pool of subjects is more homogeneous and provides cost-containment and greater statistical power.
The trial endpoints themselves have also benefi ted from improvements. The most critical areas of the cornea have been redefi ned to home in on dry eye, the techniques for conducting tear-fi lm breakup time and staining have been recalibrated and precise scales for assessments of staining and discomfort have been developed. Similarly, calibration, both initially and continuously through the education of investigators, minimizes “investigatordrift,” and tightens the dataset across sites. Educating dry-eye investigators and patients about how to use the sign and symptom scales is vital for maintaining data consistency.1 In terms of future modifications to clinical trials, there’s been some consideration of looking for sign efficacy and symptom efficacy in separate trials. The published literature might corroborate this approach, since signs and symptoms of dry eye have often been shown to have no correlation.5
- Ousler GW, Gomes PJ, Welch D, Abelson MB. Methodologies for the study of ocular surface disease. Ocul Surf 2005;3:3:143-154.
- Davis J, Ousler GW, Langelier NA, Schindelar MR, Abelson R, Abelson MB. Seasonal changes in dry eye symptomatology. Invest Ophthalmol Vis Sci 2006;47:13:280.
- Ousler GW, Watson M, Bateman K, Lane KJ, Welch D. Longitudinal evaluation of seasonal differences in patient-reported dry eye symptoms. Invest Ophthalmol Vis Sci 2015;56:7:4462.
- Teson M, Lopez-Miguel A, Neves H, et al. Infl uence of climate on clinical diagnostic dry eye tests: Pilot study. Optom Vis Sci 2015 Jul 22 (Ahead of print).
- Nichols KK, Nichols JJ, Mitchell GL. The lack of association between signs and symptoms inpatients with dry eye disease. Cornea 2004;23:8:762-70.
Mucomimetic agents continue to be developed in Japan, but the programs are stalled in the United States. The compounds approved in Japan are rebamipide (Otsuka/ Acucela), a quinolone that enhances mucosal defense and scavenges free radicals,
Diquafasol 3%, approved in Japan in 2010, was also shown to be noninferior to HA in a similar trial run in Japan, and was superior to HA for rose bengal staining.
• Autologous serum. Eyedrops composed of autologous serum are being tested on a regular basis, and publications in the past 15 years have been numerous.
• Antioxidant therapy. Scavenging free radicals is the role of every antioxidant, and these molecules are in high demand in all avenues of medicine and nutriceuticals. One promising antioxidant with a somewhat different mechanism is SkQ1, a mitochondria-specific plastoquinone- containing reactive oxygen species scavenger. In Phase II testing of 91 dry-eye subjects exposed to a controlled adverse environment challenge, improvements in central fl uorescein and lissamine green staining, lid margin redness and the symptoms of discomfort, dryness and grittiness were all significant after one month of treatment with SkQ1.
• Receptor inhibition. Mimetogen is developing a dry-eye therapeutic, MIM-D3, that has an innovative mechanism of action. Conjunctival mucin gene expression and secretion, as well as goblet cell differentiation, are stimulated by nerve growth factor action at the tyrosine kinase A receptor. MIM-D3 is a partial TRKA receptor agonist that demonstrates activities similar to NGF, and also acts by potentiating suboptimal concentrations of NGF. Although it didn’t meet its pre-specifi ed primary endpoints, after four weeks of treatment in a Phase II trial, MIM-D3 signifi – cantly improved total corneal fluorescein staining when assessed as the change from pre- to post-exposure in the CAE chamber.
A thymosin beta-4 antagonist has completed Phase II development with publication of results in the CAE model. As frequently occurs, neither of the primary endpoints showed a significant difference between treatment and placebo groups; however, a number of secondary endpoints demonstrated significant treatment benefi ts. In a single-center study of 72 subjects treated with RGN-259 (0.1% Tβ4) for 28 days, discomfort scores in the CAE were significantly improved, as were central and superior corneal fluorescein staining. 21
• Oculeve tear stimulator. An innovative intranasal device from Oculeve that stimulates tearing will continue clinical testing this year.
Treating inflammation has always been a mainstay for dry-eye therapy, with cyclosporin A (Restasis, Allergan) leading the way, and several other promising agents coming up fast. Here’s a look at what’s making its way to the clinic.
• Lifitegrast. In the lead in the race to approval is Shire’s lifi tegrast, the lymphocyte function antigen-1 (LFA-1) antagonist and a first-inclass integrin anti-inflammatory agent specifically engineered for ophthalmic indications. Activation and homing of lymphocytes to the ocular surface is central to the chronic dry-eye process and under the control of T-cell activators like LFA-1, which binds to intercellular adhesions molecule-1 (ICAM-1) expressed on the cell surface of the inflamed epithelium. Lifi tegrast acts as an ICAM decoy, preventing binding of LFA-1 to ICAM.
Lifitegrast has been the subject of three clinical trials involving b.i.d. treatment for 84 days. The first dose-response Phase II trial in 230 subjects used the CAE challenge to enrich the study population with subjects who had a modifiable, moderate degree of inferior corneal staining. Mean change from baseline to day 84 in inferior corneal staining was statistically significant (p=0.0208). Furthermore, the proportion of patients with an increase in inferior staining greater than one at day 84 compared to baseline was 16.1 percent for placebo, 3.6 percent for 1% and zero for 5% lifitegrast. The Ocular Surface Disease Index and the vision-related OSDI showed significant improvements, as did Ora scale-measured ocular discomfort (p=0.0442) in the per-protocol population. Improvements in tear production (p=0.0392) and symptoms were also seen as early as day 14. A reduction in burning/ stinging was also found after 84 days of treatment when assessed as change from baseline (p=0.0496).
The first Phase III study of lifitegrast was conducted with the same study design but with greater power due to an increased number of subjects. Again, mean change from baseline in inferior corneal staining as measured by the Ora scale was highly significant, this time with the p-value going from p=0.0208 to p=0.0007. It also significantly reduced superior and total fl uorescein staining, as well as conjunctival lissamine green staining. The co-primary endpoint of OSDI symptoms wasn’t met. Secondary symptom scores for Ora-scale measured discomfort (p=0.0273) and dryness (p=0.0291) were significant, however.
The OPUS-2 study has been completed in 718 subjects, and the company has announced success with symptom endpoints. While this study failed in the co-primary corneal fluorescein staining endpoint, symptoms won big across the board in primary (p=0.001), secondary and tertiary symptom outcomes.
• Cyclosporine A derivatives. In recent years, researchers have attempted various changes in the formulation of cyclosporine in order to facilitate manufacturing and improve tolerability. Aqueous solutions of cyclosporine at 1% were shown to be superior to 0.5% in improving the major signs of dry-eye disease as early as 21 days after initiation of treatment.
A unique 0.1% unpreserved cyclosporine cationic emulsion (Cyclokat) is in Phase III development by Santen, and has now been recommended for approval by the European Medicines Agency. In Europe, a six-month study showed statistically significant improvements in fluorescein and lissamine green staining at months one, three and six. Post-hoc analyses revealed better outcomes in groups with higher staining scores (~3) at baseline; however, for complete corneal clearing of staining, Cyclokat was superior in patients with grade 2 staining at baseline. This higher concentration appears to be focusing on severe keratitis associated with dry eye. It will be interesting to see if Santen attempts to bring Cyclokat across the ocean.
Novaliq in Germany is also developing a novel formulation of cyclosporine (CyclASol) that’s entering Phase II development. CyclASol is a novel, patented, non-aqueous and preservative-free formulation of cyclosporine. EyeSol is Novaliq’s proprietary drug delivery technology based on the chemically and biologically inert semi-fl uorinated alkanes. These compounds have extraordinary spreading properties that optimize drug distribution on the corneal surface, and aid in the solubility of poorly water-soluble compounds such as cyclosporine. As such, CyclASol is the fi rst clear, non-emulsion, multidose, preservative-free solution of this immunosuppressive, promising greater tolerability, less stinging and superior pharmacokinetics. Phase I results were positive and the Phase II program is under way.
• Steroids and NSAIDs. Antiinflammatories don’t end with cyclosporine. Steroid use has been studied, both alone and as an adjunct to cyclosporine. Ocular Therapeutix has a slow-release, biodegradable dexamethasone punctal plug that’s being investigated for both allergy and dry eye. 34
In another recent report, researchers studied the effect of loteprednol etabonate 0.5% administered two weeks before initiation of cyclosporine in 118 patients. When compared to subjects treated with cyclosporine alone, the steroid group had significantly less cyclosporineinduced stinging, and more importantly, loteprednol-treated subjects had significantly better OSDI scores and Schirmer’s test scores, as well as fluorescein and lissamine staining.
In China, investigators compared the nonsteroidal anti-inflammatory 0.1% pranoprofen in a sodium hyaluronate drop to viscoelastic alone in 115 patients. Gradual improvements in symptom scores, fl uorescein staining and TFBUT were shown, with statistical significance for the latter two at day 14. This anti-inflammatory was well-tolerated with 28 days of dosing.
Another anti-inflammatory on the horizon for dry eye has a unique mechanism and origin. Cis-urocanic acid is an endogenous small molecule component of human and animal skin. It’s formed in the upper layers of the skin, and is constantly present in the human body at micromolar levels, and in millimolar levels in the epidermis after exposure to sunlight. This molecule has anti-inflammatory effects due to inhibition of c-Jun N-terminal kinase (JNK) signaling; a notable effect is that activation of the mitogen-activated protein kinase (MAPK) cascade is thought to be central to dry-eye inflammatory events. The Phase I safety and pharmacokinetics of 0.5% and 2.5% cis-UCA eyedrops were recently published.
IL-1 is a key inflammatory and immune mediator in many inflammatory diseases, and Eleven Biotherapeutics is developing an IL-1 antagonist (EBI-005) for treatment of ocular allergy and/or dry eye. The fate of Eleven’s research programs is not yet clear, but both Phase II and Phase III studies are listed on clinicaltrials. gov, and the company has completed a Phase III study in 669 patients at more than 40 clinical sites. In a press release, the dry-eye study results were described as failing to show significant efficacy in any primary or secondary endpoints, so the second Phase III study was shelved.
Potentially effective therapeutic agents deserve a rigorous clinical study program based on an understanding of corneal physiology, disease pathology and epidemiology, as well as pharmacology and pharmacokinetics. Having spent more than 20 years refi ning the precise operational execution of dry-eye clinical trials, and having had the opportunity to work with many therapeutic agents, it’s gratifying to the clinical achievements that fi nally hold the promise of greater choice for treating our dryeye patients.
Dr. Abelson is a clinical professor of ophthalmology at Harvard Medical School, and emeritus surgeon at the Massachusetts Eye and Ear Infi rmary. Mr. Ousler is vice president of dry eye at Ora Inc. Ms. Smith is a medical writer at Ora Inc.