PHARMACOTHERAPY FOR XEROSTOMIA IN SJOGREN'S SYNDROME

DESCRIPTION (provided by applicant): Sjogren's syndrome (SS) is a slowly progressive inflammatory disorder characterized by lymphocyte-mediated destruction ofOverall, this application was found to have significant and substantial scientific merit, and is recommended with an exc exocrine glands and internal organ involvement due to autoantibody production or pre-existing connective tissue disorder. Over time, progressive infiltration of lacrimal and salivary glands by mononuclear cells leads to diminished secretions, with resultant xerostomia (dry mouth) and xeropthalmia (dry eye) being the most prevalent symptoms. Use of currently available treatments, including tear and saliva substitutes and centrally acting parasympathomimetic secretagogues such as pilocarpine and cevimeline, provide transient relief, but patients often find these remedies costly, ineffective, inconvenient, and fraught with unacceptable side effects. Studies indicate that the buccal mucosa resembles other squamous epithelia in its ability to transport sodium transepithelially. The buccal mucosa likely regulates the absorption of water through a coupled mechanism with the active absorption of sodium and passive absorption of chloride as the counter ion. The absorption of salt osmotically draws water absorption and therefore determines the status of hydration of the apical surface of the buccal mucosa. The sensitivity of this sodium transport process to inhibition by amiloride, an epithelial sodium channel (ENaC) blocker, suggests that sodium absorption by ENaC is rate limiting. Preliminary data presented in this application show that our lead compound, 552, is a potent and specific inhibitor of the epithelial sodium channel. Anecdotal evidence from our first clinical study suggests that this ENaC blocker can enhance salivary function. This clinical finding, coupled with the scientific rationale presented above, provides support for the hypothesis that topical administration of 552 will inhibit the transport of sodium through the epithelial sodium channel and at the same time decrease the rate of absorptive water loss from the oral mucosa, potentially providing relief from the sensation of dry mouth in Sjogren's syndrome patients. These observations provide the rationale for initiating the clinical testing of our lead compound, a specific, potent blocker of the epithelial sodium channel, as a therapeutic agent for the treatment of dry mouth associated with Sjogren's syndrome. In this Phase I SBIR application, we propose a clinical study of the safety and the effect of treatment with a single dose of a topical oral formulation of 552 on xerostomia in primary Sjogren's syndrome (Study 552-205S). This study is designed to fulfill the following study objectives: a. Evaluate the safety of a topical oral formulation of 552-02 administered daily for 14 days in patients with primary Sjogren's syndrome b. Evaluate the effect of daily administration of a topical oral formulation of 552-02 for 14 days on xerostomia in patients with primary Sjogren's syndrome. The proposed clinical study is a key component of the overall development program for 552-02. Results of this study will provide the basis for conducting further dose-ranging single-dose and multiple-dose clinical studies in Sjogren's patients. Ultimately, our goal is the full clinical development of 552-02 as a first-line therapy for patients suffering from xerostomia associated with Sjogren's syndrome.