Cystic fibrosis - denufosol tetrasodium
Cystic fibrosis is an inherited condition that affects the mucus glands in the lungs, causing them to produce thick mucus and resulting in frequent lung infections. It also causes reduced secretion of pancreatic enzymes, which causes poor growth, malnutrition and a deficiency in fat soluble vitamins; patients can also develop liver disease, pancreatitis, gallstones and diabetes, among numerous other life affecting problems. There is no cure, and most who develop the disease die young, but as new treatments reach patients, life expectancy is increasing.
Cystic fibrosis is an inherited condition that affects the mucus glands in the lungs, causing them to produce thick mucus and resulting in frequent lung infections. It also causes reduced secretion of pancreatic enzymes, which causes poor growth, malnutrition and a deficiency in fat soluble vitamins; patients can also develop liver disease, pancreatitis, gallstones and diabetes, among numerous other life affecting problems. There is no cure, and most who develop the disease die young, but as new treatments reach patients, life expectancy is increasing.
Correcting the ion transport defects in the airways may improve the prognosis of CF patients. This could lead to normal mucus secretions from the lungs, and thus prevent chronic lung infections and damage to the lungs. One way of doing this is activating the P2Y2 receptors on the epithelial surface of the airways. Uridine 5'-triphosphate has been shown to have this effect, but it is not very metabolically stable and has only a short half-life when given by inhalation. A dinucleotide compound, denufosol, has been developed by Inspire Pharmaceuticals, which has the effect on the P2Y2 receptor but is more metabolically stable.1
In a Phase II trial in 89 patients with mild CF were given 20, 40 or 60mg doses of the drug via nebuliser three times a day for 28 days, or placebo.2 It was well tolerated with no dose-related adverse events, and it also improved air flow in the lungs compared with placebo. The overall improvement was modest, but this may have been a result of the patients having only mild lung impairment.
It has also been investigated in a Phase III trial, again in patients with a mild form of the disease. A total of 352 were given denufosol or placebo for 24 weeks, followed by an open label safety assessment. The treatment effect of the drug increased over time, and those given the drug continued to improve over the open label extension period. Again, it was well tolerated, and trials are continuing, including studies in patients with more serious forms of the disease.3