Pre Clinical and Clinical Development of a Novel Thiol-Saccharide Mucolytic

Lee, June

Abstract

Although pathologic mucus that obstructs the airways is a major cause of symptoms and infection in cystic fibrosis (CF) and other lung diseases, mucolytic therapies are currently limited in number, efficacy, and tolerability. Recent collaborative work between UCSF and University College Dublin (UCD) has uncovered oxidative stress as a key mechanism of mucus pathology and provided rationale for thiol-based drugs as novel mucolytics. N-acetyl cysteine [NAC]) is effective as a mucolytic, but it carries significant liabilities as an inhaled therapeutic including low potency, inconvenient administration, airway irritancy, high volatility and bad odor. To overcome these problems, Dr. Oscarson at UCD has synthesized a novel class of thiol-based therapeutics by modifying saccharides with thiol functionalities to create a library of ?thiol-saccharides.? These novel compounds show significant mucolytic activity on CF sputum, fast onset of action, higher potency than NAC, and favorable processability as spray-dried powders. Importantly, we find that thiol-saccharides do not show any concerning safety signals in pilot toxicity studies in our studies on airway epithelial cells in vitro and in a mouse model in vivo. All of these data lead us to propose three Aims that will advance a drug development program for thiol-saccharides as a novel mucolytic treatment in cystic fibrosis.
In AIM 1, we will identify and optimize the preclinical candidate compound from a library of thiol-saccharides.
In AIM 2, we will conduct IND- enabling preclinical studies and prepare and file IND for clinical development of candidate thiol-saccharide in CF.
In AIM 3, on IND clearance, we plan to conduct a first-in-human Phase 1a single ascending dose study to assess initial safety of inhaled thiol-saccharide therapeutic. We will work closely with the multidisciplinary team of chemists, formulation scientists, biologists and clinicians who are a part of this Translational Program Project proposal to achieve the goal of advancing a thiol-modified carbohydrate to the clinic to improve lung health.

Public Health Relevance

Accumulation of mucus in the airways is a major cause of morbidity and mortality in cystic fibrosis and other airway diseases. Mucolytic treatments not only improve mucus clearance, they also improve lung health by decreasing lung microbial burden and reducing exacerbations. There is clear unmet need for safe, convenient, and effective mucolytic treatment in CF and a wide variety of other acute and chronic lung diseases. This project aims to develop a new mucolytic drug that is safe and can be delivered by dry powder inhaler.