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    What's in the pipeline for dry eye and ocular allergy?

    New therapeutics focus on causes, prevention


    Dry eye and ocular allergy are bothersome to patients and present challenges to clinicians who, until recently, had limited treatment options that were typically directed at alleviating symptoms. Now, however, new therapeutic agents in the pipeline could change all of that. Researchers have begun developing therapies for dry eye that are directed at treating the underlying causes rather than symptoms. In addition, new therapies for ocular allergy are focused on preventing the allergic reaction. This article discusses the newest agents being developed for dry eye and ocular allergy and reviews existing treatments physicians can use in the meantime.

    Dry eye

    Dry eye continues to present a unique opportunity for innovation. The majority of current dry eye therapies provide only palliative effects. Therefore, many developing therapies aim beyond symptom relief toward treating the cause(s) of the condition. Realizing that treating symptoms is not sufficient, researchers have begun to dig deeper into the causes behind the signs and symptoms of dry eye. Several classes of therapies are being explored, and some advances lie on the horizon.

    In development

    Secretagogues are one of the most prominent treatment classes for dry eye. These agents are designed to encourage mucin secretion. Tear film mucins play an important role in maintaining tear film stability and moisture on the ocular surface. An insufficient supply of mucin to the ocular surface can alter the fragile environment of the tear film. Many dry eye sufferers exhibit mucin deficiency.

    One formulation that is anticipated to combat this condition is 15(S)-hydroxyeicosatetraenoic acid (15[S]-HETE, Alcon Laboratories), which is designed to stimulate glycoprotein secretion in human ocular tissue and is known to promote production of mucin glycoprotein by airway epithelium.1 A preclinical trial found that 15(S)-HETE generates a rapid increase in the thickness of a layer of mucin-like glycoprotein on the corneal epithelium of rabbits.2 The increased thickness seen in the study implies that 15(S)-HETE could provide enhanced ocular surface protection and therefore be effective in treating mucin deficiency in dry eye.

    The P2Y2 inhibitor diquafosol tetrasodium (INS365, Inspire Pharmaceuticals) is another dry eye therapy in development. It is designed to stimulate fluid, mucin, and lipid secretion.3 A clinical trial4 evaluated ocular surface staining and other measures of 222 patients with dry eye treated with either 2% diquafosol or placebo using a controlled adverse environment ([CAE], developed by ORA Clinical Research and Development, North Andover, MA). When ocular surface staining of the central region before and after exposure to the CAE was measured, diquafosol exhibited statistically significant results against placebo (p = 0.004 and 0.007, respectively).

    A recent study using a new test to measure the degradation of visual acuity in real time between blinks (inter-blink interval visual acuity decay [IVAD]), developed and validated by ORA, showed that patients with central corneal staining could not maintain their best-corrected visual acuity for as long as patients without staining in the central cornea.5 As evidenced by those findings, the central corneal clearing data for diquafosol may indicate that the agent can improve tear film health and therefore may suggest an important clinical endpoint for visual function of patients with dry eye.

    Ecabet sodium (ISTA Pharmaceuticals), a drug approved in Japan for the treatment of gastric ulcers and gastritis, is another mucin secretagogue. Ecabet aims to increase the amount and quality of mucin in the tear film to bolster mucin's ability to provide lubrication to the tear film and slow moisture loss caused by tear evaporation.

    A phase IIb study of ecabet in the treatment of dry eye was conducted through exposure to a CAE. Study results showed statistically significant results in ocular symptom disease index (OSDI) and a positive trend in blink rate post-CAE. Results of subjective assessment of patients' most bothersome symptom in the chamber also showed a positive trend for ecabet. Phase III studies are expected to begin in 2008.6

    Rebamipide (Otsuka Pharmaceutical Co.), another secretagogue in the pipeline, is believed to stimulate mucin secretion of MUC 1, MUC 2, and MUC 5ac and to perform mucin synthesis. Pre-clinical data showed that the agent stimulates proliferation of goblet cells in rat conjunctiva7 and increases mucin content in human corneal epithelial cells in vitro.8 This mucin secretagogue holds special significance in cases of dry eye caused by mucin deficiency in the tear film.

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