Diquafosol tetrasodium (INS365)
Diquafosol tetrasodium (INS365) is a Purinergic (P2Y2) receptor agonist being developed by Inspire Pharmaceuticals. Diquafosol stimulates the eye surface cells directly to promote secretion of fluid and mucin and possibly stimulates lipid production in the meibomian glands as well. Because diquafosol stimulates fluid and mucin secretion directly on the ocular surface, it is believed to provide moisture and rehydration of the ocular surface independent of tear film secretion from the lacrimal gland.
The 6-month results of phase 3 study were recently reported (Cornea. 2004 Nov;23(8):784-92). This phase III study was evaluated the safety and efficacy of 2 dose strengths of diquafosol (1% and 2%). The study (Protocol 03-105) was performed between March and December of 2001. In this study, corneal and conjunctival staining scores in the diquafosol treatment groups were significantly lower compared with placebo as early as 2 weeks following initiation of therapy, and the benefit was maintained long-term, without any apparent loss of efficacy over time. Notably, 1 week after cessation of therapy, the beneficial effects of diquafosol with respect to corneal staining were diminished, suggesting the need for ongoing pharmacologic therapy.
Although the results of Study 105 have been reported in the November 2004 issue of Cornea, the study was completed much earlier in December 2001. Subsequent to this study 2 other studies have been performed and the results reported on the Inspire Pharmaceutical website.
The latest study results released by the company in February 2005 have been somewhat disappointing. In this study (109), diquafosol failed to demonstrate statistically significant improvement as compared to placebo for the primary endpoint of the incidence of corneal clearing (p-value = 0.369). Improvement compared to placebo (p-value less than 0.05) was achieved for a number of secondary endpoints, including mean corneal staining, mean conjunctival staining and conjunctival clearing. The positive results in mean corneal staining and mean conjunctival staining are consistent with results seen in previous Phase 3 studies of diquafosol.
"As a result of these mixed findings, we held a preliminary discussion with the Food and Drug Administration regarding next steps. Based on this discussion, we intend to file a New Drug Application (NDA) amendment for diquafosol by the end of the second quarter 2005," stated Christy L. Shaffer, Ph.D., CEO of Inspire.

Eicosanoid 15-(S)-HETE
The eicosanoid 15-(S)-HETE (hydroxyeicosatetraenoic acid) is being developed by Alcon Pharmaceuticals. This eicosanoid increases secretion of MUC1 (a form of ocular surface mucus). Topical 15-(S)-HETE may be effective in treating ocular surface mucin deficiency in dry eyes. Alcon has reported that clinical results from the latest clinical study of 15(s)HETE did not show statistical significance of the active ingredient versus the placebo. The company is evaluating clinical study designs to test the drug in specific subgroups of dry eye patients where the clinical benefit may be more evident.

Ecabet Sodium
Ecabet Sodium is being developed by Ista Pharmaceuticals. Ecabet sodium represents a new class of molecules that increases the quantity and quality of mucin produced by conjunctival goblet cells and corneal epithelia. Mucin is a glycoprotein component of tear film that lubricates while retarding moisture loss from tear evaporation. Ecabet sodium is currently marketed in Japan as an oral agent for treatment of gastric ulcers and gastritis.
June 31, 2007 Press Release: ISTA Pharmaceuticals Announces Positive Preliminary Results from Ecabet Sodium Phase IIb Study. A total of 112 patients were assigned randomly to receive either ecabet sodium or placebo four times a day for 90 days. There were four primary efficacy endpoints: two objective signs (blink rate and corneal staining) and two subjective symptoms (the patient's most bothersome symptom and the patient's response to the Ocular Surface Disease Index (OSDI)). Patients were evaluated in a controlled adverse environment ("dry eye chamber") twice during the study, once on Day 1 and once on Day 91. The objective signs were measured pre- and post-exposure to the dry eye chamber on Day 91. The subjective symptoms were measured following exposure to the dry eye chamber on both Day 1 and Day 91. Patients in the ecabet sodium group reported a strong trend in the Ocular Symptom Disease Index (OSDI) and a positive trend in the subjective assessment of patients' most bothersome symptom. 14 percent of patients in the treatment group reported increases in the quantity of tears produced, as compared to only 1.8 percent in the placebo group. Ista Pharmaceuticals anticipate beginning Phase III studies in 2008.

The 3 drugs discussed above are secretagogues i.e. agents that increase secretion of fluid from eye surface cells.

Tacrolimus (Agent FK-506)
In a July 2003 press release Sucampo Pharmaceuticals announced that it has initiated a multi-center, Phase II safety and efficacy study for the treatment of dry eye syndrome, also known as keratoconjunctivitis sicca (KCS) with agent FK-506, tacrolimus, a potent immunosuppressive agent.
FK506 (tacrolimus) is a novel macrolide immunosuppressant discovered in 1984 by the Exploratory Research Laboratories of Fujisawa Pharmaceutical Co., Ltd. (Osaka, Japan) and is now used for transplantation world-wide. Tacrolimus ointment is currently available for treatment of atopic (allergic) dermatitis in some countries, including the USA (Protopic ointment). In a recent report, Protopic ointment 0.03% was used twice daily on eyelid skin of patients with atopic dermatitis with good results (Am J Ophthalmol. 2003;135:297-302). However, Protopic ointment is not approved for ophthalmic use. We await the results of the clinical trials with tacrolimus eyedrops that will lead to the availability of an ophthalmic preparation of tacrolimus.

Androgen Eyedrops
Allergan is currently testing in clinical trials in the USA and Europe the efficacy of topical androgens for the treatment of dry eye.
Androgen deficiency may be a critical etiologic factor in the pathogenesis of aqueous-deficient and evaporative dry eye syndromes during menopause, aging and certain autoimmune diseases. The use of androgen eyedrops may correct the hormonal deficiency and thus treat dry eyes.
Androgens regulate numerous aspects of the lacrimal gland, including epithelial cell morphology, gene expression, protein synthesis, secretory processes and immune function. Women with Sjögren's syndrome have an androgen deficiency, and this hormone deficit may predispose to lacrimal gland dysfunction, decreased tear secretion and aqueous-deficient dry eye.
Meibomian glands are an androgen target organ. Androgens appear to regulate meibomian gland function, improve the quality and/or quantity of lipids produced by this tissue and promote the formation of the tear film's lipid layer. Androgen deficiency during menopause or aging is associated with meibomian gland dysfunction, tear film instability and an increase in dry eye signs and symptoms. (Reference: Arch Soc Esp Oftalmol. 2004 Feb;79(2):49-50).

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