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Novel Therapy for Lung Infections in Cystic Fibrosis

Inhaled P113D for Lung Infections in Cystic Fibrosis: Product Licensing Opportunity

Cystic fibrosis (CF) is a genetic disease which affects approximately 30,000 individuals in the United States. The gene defect in CF results in altered secretions in a number of organs, including the lung. The thickened mucous in the lungs creates an ideal environment for bacterial infections, particularly of Pseudomonas aeruginosa, to take hold. It is these lung infections which lead to mortality in CF patients.

Currently, there are a limited number of products approved for the treatment of lung infections in CF patients. Pulmozyme® was approved in 1993 to help reduce the viscosity of the mucous in the lungs of CF patients. In 1997, TOBI™, tobramycin for inhalation, was approved in the US as the first inhaled antibiotic to treat CF lung infections. TOBI™ is given on a one month on/one month off cycle, primarily to minimize the development of resistant organisms. This dosing regimen and the development of strains resistant to tobramycin presents a clear need for additional inhaled antimicrobials to treat the lung infections associated with CF.

The product under development by Demegen is a novel 12 amino-acid antimicrobial peptide, P113D, that can be delivered directly to the lung by aerosolization, using a standard nebulizer. P113D is based on naturally occurring antimicrobial proteins found in human saliva called “histatins,” which play an important role in the body’s natural defense against disease in the oral cavity. This peptide has demonstrated a high level of in vitro activity against P. aeruginosa, including drug-resistant patient isolates. Because of its unique mechanism of action, this product will not contribute to drug resistance to classical antibiotics.

The Cystic Fibrosis Foundation (CFF) provided a $200,000 grant for preclinical studies. P113D is protected with composition of matter and use patents in the USA and abroad.

Safety

The amino acid sequence of P113D is derived from histatins, which are compounds found naturally in human saliva. This peptide has been modified by the incorporation of amino acids in the “D” configuration. Toxicology studies performed to date as well as experience in the clinic with P113, which is composed of amino acids in the natural “L” configuration, have shown P113 to be safe and well tolerated.

Efficacy

P113 was determined to be the smallest histatin fragment which retained antimicrobial activity equivalent to that of the parent compound. Interestingly, synthesizing P113 with D-amino acids gave rise P113D, a compound that was impervious to enzymatic degradation and maintained the antimicrobial activity of the parent compound. P113D also has very potent in vitro activity against a variety of Gram (-) and (+) bacteria including P. aeruginosa, S. aureus, H. influenzae, S. typhimurium, E. coli, S. epidermidis, S. mutans and S. sobrinus. In the case of P. aeruginosa and S. aureus, antibacterial activity has been demonstrated against a variety of CF patient clinical isolates which are resistant to traditional antibiotics. P. aeruginosa isolates that produce thick alginate secretions (mucoid phenotype) are also susceptible to killing by P113D. For both bacteria and fungi such as Candida albicans, P113D has been shown to kill cells as opposed to simply inhibiting their growth. It has been demonstrated that P113D acts by binding to the cell surface and increasing the permeability of both the outer and inner membranes of the cells of Gram (-) bacteria, killing them within seconds. 

For a compound to be effective in treating lung infections associated with CF, it must be stable and maintain activity in the altered mucous environment of the CF lung. P113D has been shown to be stable for days in sputum from CF patients and is able to significantly reduce the number of bacteria in sputum from CF patients. P113D has been shown to work in concert with Pulmozyme®, an approved drug used by ~70% of CF patients, which helps reduce the viscosity of the mucous.

Market Opportunity

Cystic fibrosis is a genetic disease which affects approximately 70,000 children and young adults worldwide. It is estimated that 60% of these individuals are infected with P. aeruginosa.