DEVELOPMENT OF EPITHELIAL SODIUM CHANNEL BLOCKERS FOR CF

DESCRIPTION (provided by applicant): Our preliminary data support the hypothesis that 552-02 is a potent, selective inhibitor of epithelial sodium channels that is effective in enhancing mucociliary clearance and is well tolerated when administered as a single dose by inhalation aerosol in normal healthy adult volunteers. The general approach to be followed in the continued evaluation of 552-02 during the early phases of clinical development will focus on evaluating the safety and potential efficacy of the investigational agent when administered as an inhalation aerosol to normal healthy adult volunteers, and to adolescents and adults with the symptoms of mild to moderate cystic fibrosis (CF). In this Phase 1 portion of a Fast Track application, we propose to conduct Study 552-102, a study of the effect of inhalation of 552-02 on mucociliary clearance in healthy volunteers. As a continuation of the clinical development of 552-02, three clinical studies are proposed in Phase II of this Fast Track application. These three studies are Study 552-201, a single-dose safety and pharmacokinetic study in CF patients; Study 552-202, a single-dose study of the mucociliary clearance of 552-02 in CF patients; and Study 552-103, a study of repeated administration of 552-02 over 7 days in healthy volunteers. We will interpret data concerning the effect of treatment with a single dose of 552-02 on mucociliary clearance rates as a surrogate marker of efficacy in CF. Identification of a safe dose that stimulates mucociliary clearance (measured over the 0- to 2-hour interval following treatment) will validate our research approach and will provide the rationale for performing a second series of clearance studies in patients with CF. Demonstration of a durable effect of 552-02 on mucociliary clearance will provide the rationale for further clinical studies evaluating the safety profile of the investigational agent over a 28-day period in the target population. In Phase I of this Fast Track application, we propose to examine the effect of 552-02 administered via inhalation on mucociliary clearance in healthy volunteers. The specific aims for this Phase I proposal are as follows:  Specific Aim 1: Evaluate the safety and pharmacokinetics of 552-02 when given as a single aerosolized dose in healthy adult volunteers.  Specific Aim 2: Assess the effect of treatment of 552-02 on mucociliary clearance rates when given as a single aerosolized dose in healthy adult volunteers. 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 clinical studies in healthy volunteers and CF patients proposed in the Phase II portion of this Fast Track application. Ultimately, our goal is the full clinical development of 552-02 as a first line therapy for patients suffering from CF airways disease