EmphyCorp has been granted Orphan Drug status by the FDA to develop N115 for the treatment of Cystic Fibrosis. Cystic Fibrosis is a genetic disease afflicting nearly 30,000 persons in the United States and Canada and nearly 250,000 worldwide. It is the most common life-shortening genetic disease in the white population, occurring in the USA in about 1/3,300 white births, in about 1/15,300 black births, and in about 1/32,000 Asian-American births.
Evidence suggests that the lungs are histologically normal at birth. Pulmonary damage is probably initiated by diffuse obstruction in the small airways due to abnormally thick mucus secretions. Bronchiolitis and mucopurulent plugging of the airways occur secondary to obstruction and infection. Bronchial changes are more common than parenchymal changes. As the pulmonary process progresses, bronchial walls thicken; the airways fill with purulent, viscid secretions; areas of atelectasis develop; and hilar lymph nodes enlarge.
Much of the pulmonary damage may be caused by immune-mediated inflammation secondary to the release of proteases by neutrophils in the airways. Glutathione is an important component of the antioxidant defense in the epithelial lung lining fluid. As a result of this decrease in transport of glutathione and other cellular antioxidant compounds into the surrounding epithelial lung lining, there is deterioration in lung function.
Fifty percent of CF patients present with pulmonary manifestations, usually chronic cough and wheezing associated with recurrent or chronic pulmonary infections. Cough is the most troublesome complaint, often accompanied by sputum, gagging, vomiting, and disturbed sleep. Intercostal retractions, use of accessory muscles of respiration, a barrel-chest deformity, digital clubbing, and cyanosis occur with disease progression.
Upper respiratory tract involvement includes nasal polyposis and chronic or recurrent sinusitis. Adolescents may have retarded growth, delayed onset of puberty, and a declining tolerance for exercise. Pulmonary complications in adolescents and adults include pneumothorax, hemoptysis, and right heart failure secondary to pulmonary hypertension. The course of the disease, largely determined by the degree of pulmonary involvement, varies greatly. However, deterioration is inevitable, leading to debilitation, respiratory failure, and eventual death.
Oral expectorants are widely used, but few data support their efficacy. Cough suppressants should be discouraged. Long-term daily aerosol administration of recombinant human deoxyribonuclease has been shown to slow the rate of decline in pulmonary function and to decrease the frequency of severe respiratory tract exacerbations. Long-term use of alternate-day corticosteroid therapy can slow the decline in pulmonary function, but because of steroid-related complications it is not recommended for routine use. The ability to up regulate the synthesis of NO is also being developed by many companies that are developing the use of arginine or arginine analogs to fight lung infections and cancers. The problem with inhaled arginine or arginine analogs has been their toxicity.
Thus, the ability of inhaled pyruvate to “up regulate” or down regulate NO levels in lungs and to protect NO from other oxygen radicals, allows NO to deactivate NF-kappa B, which, in turn, will reduce lung NO levels and reduce lung inflammation. In human clinical studies, sodium pyruvate at lower concentrations decreased hydrogen peroxide and NO levels in patients treated by inhalation therapy. Sodium pyruvate inhalation at higher concentrations increased NO levels in expired breaths, of asthmatics and moderate and severe COPD patients, that could be used to treat lung cancers, lung infections, especially in patients with cystic fibrosis. Patients with cystic fibrosis, produce very low levels of NO, that allows viral replication to occur. In HSV-1 infected cells, sodium pyruvate at the higher concentrations, reduced viral loads and in combination with antiviral agents, eliminated the virus completely from the infected cells.
Inhaled Sodium Pyruvate for the Treatment of Cystic Fibrosis
This study was completed and demonstrated the ability of inhaled Sodium Pyruvate to reduce inflammatory cytokines. No Adverse Events were reported.
It is hypothesized that the inhalation of sodium pyruvate will reduce lung damage in patients with Cystic Fibrosis (CF) by its ability to reduce levels of toxic reactive oxygen and nitrogen compounds associated with the chronic inflammatory component of the disease. The primary objective of the study is to assess the safety of inhaled sodium pyruvate in 0.9% sodium chloride (saline) solution in people with CF. Further, to determine whether inhaled sodium pyruvate will improve lung function, as determined by spirometry, or reduced inflammatory markers in induced sputum of people with CF.
Cystic fibrosis is the most common, lethal inherited disease of Caucasians. Approximately 30,000 people in the United States and 70,000 worldwide have a diagnosis of CF. It is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. The clinical manifestations characteristic of CF include progressive bronchiectatic lung disease with thick mucus production and colonization by Pseudomonas aeruginosa. The CFTR gene mutation results in altered cell transport properties, which affect both chloride and glutathione secretion. Chronic inflammation, associated with activated neutrophils and macrophages, is a common feature of CF. Highly reactive toxic oxygen (superoxide anion, free hydroxyl radical, hydrogen peroxide) and nitrogen species (NO, peroxynitrites) are abundant in the chronic inflammatory response in CF and appear to play a prominent role in the pathogenesis of this disease. These reactive oxygen and nitrogen species have been shown to be directly toxic to various mammalian tissues, including lung, via DNA damage and cell membrane lipid peroxidation. In addition, elevated levels of hydrogen peroxide and NO have been demonstrated in sputum and bronchoalveolar lavage fluid of patients with CF, asthma, and chronic obstructive pulmonary disease. Clearly reactive oxygen and nitrogen species are implicated in the pathogenesis of a variety of lung diseases including CF.
Sodium pyruvate is an antagonist to both reactive oxygen and nitrogen species. It also has the potential to increase intracellular levels of thiol compounds, major sources of intracellular anti-oxidants. Sodium pyruvate has been shown to act as an anti-inflammatory agent that can reduce the number of infiltrating neutrophils and levels of oxygen radicals at wound sites, thereby limiting the production of pro-inflammatory mediators. Thus, it is hypothesized that the inhalation of sodium pyruvate will reduce lung damage in patients with CF by its ability to reduce levels of toxic reactive oxygen and nitrogen species associated with the chronic inflammatory component of the disease.