A Fatal Genetic Disease

Cystic Fibrosis (CF) affects about 30,000 children and adults in the United States and 70,000 worldwide. Approximately 2,500 babies are born with each year, with more than 70% of CF patients diagnosed by the age of two.

In CF patients, the CFTR gene is defective, resulting in a missing or malfunctioning CFTR protein on the surface of their cells. Without adequate CFTR function, chloride ion transport is decreased. The result: abnormally thick mucus in the lungs and a decrease in pancreatic function, which can lead to both serious lung infections and serious digestive complications. Today, the predicted median survival age for people with CF is about 37 years.

Cause Known but Breakthrough Treatments Elusive

The defective gene that results in CF was first identified in 1989. Now, 18 years later, despite significant research efforts, there are still no treatments that address the root cause of the disease. For example, gene therapy approaches, which attempt to introduce “normal” CFTR genes (using viruses to carry them) to CF patients, emerged in the 1990s as a promising avenue for development. However, it has proved difficult to get these viruses through the epithelial lining in the airways of CF patients.

Treatment regimens for CF patients can be onerous. Each morning, a CF patient may have to spend an hour or more in physical therapy and taking inhaled therapies in order to thin the mucous and help clear out their lungs. CF patients may also be hospitalized once or twice a year to help protect against the establishment of dangerous bacterial infections.

Despite advances in symptomatic approaches to therapy, the median survival age of CF patients remains unacceptably low. Most CF patients experience a gradual decline in lung function over time. Treatments to address the root cause of CF, which restore the function of CFTR, may be required to enable CF patients to live a normal lifespan. However, a drug that restores the function of a misfolded, defective protein is unprecedented in medicine.

Suggested Reading: Cystic Fibrosis

Breathing Easier
Mary Ellen Egan
Forbes Magazine, 18 September 2006

Cystic Fibrosis Foundation Therapeutics Pipeline

Mucus Clearance and Lung Function in Cystic Fibrosis Patients with Hypertonic Saline
Scott Dondalson, William Bennett, Kirby Zeman, Michael Knowles, Robert Tarran, Richard Boucher New England Journal of Medicine, Vol 354, No 3, 19 January 2006, pp 241-250

Rescue of F508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules
Frederick Van Goor, Kimberly S. Straley, Dong Cao, Jesus Gonzalez, Sabine Hadida, Anna Hazelwood, John Joubran, Tom Knapp, Lewis R. Makings, Mark Miller, Timothy Neuberger, Eric Olson, Victor Panchenko, James Rader, Ashvani Singh, Jeffrey H. Stack, Roger Tung, Peter D.J. Grootenhuis and Paul Negulescu American Journal of Physiology, Lung Cellular and Molecular Physiology, Vol 290, No 6, 27 January 2006, pp L1117-L1130

Holding CF in Check

Despite the challenges, there is reason for optimism in the future treatment of CF. Complications of the disease are now well understood, and a host of new therapies have emerged to help patients manage their disease. Some therapies focus on clearing out the lungs and others on eliminating infection. Mucolytics, such as pulmozyme, are inhaled in order to thin mucus, facilitating a patient’s ability to cough up the mucus more easily. Hypertonic saline (an extra salty, sterile mist) draws more water into the airways, which also helps to clear out the lungs. Antibiotics like tobramycin — whether taken orally, inhaled in an aerosol or mist, or administered intravenously — help CF patients fight common respiratory infections associated with the disease.

Forward-Thinking Legislation

The U.S. Government has enacted two important laws which are spurring industry investment in CF drug development:

The Orphan Drug Act
Passed in 1982, the Orphan Drug Act has given generous incentives to companies willing to take on rare diseases like CF and bring treatments to market. Critical CF drugs, such as tobramycin, found their way to patients in need in part because of this transformative piece of legislation; 182 orphan products — addressing a range of diseases — have been approved since its signing into law.

Fast-Track Designation
Enacted in 1997, Fast Track designation is designed to accelerate the approval process for life-saving drugs, including therapies for CF. The Fast Track designation applies to product candidates that have the potential to address an unmet medical need for serious or life-threatening diseases.

A Non-Profit Pioneer

The Cystic Fibrosis Foundation has pioneered a new model in drug development. The CF Foundation directly supports a large number of research and development projects, including those in development at Vertex, aimed at bringing new treatments to patients with CF.

More than two dozen potential CF therapies are in various stages of development at companies and institutions receiving support from the CF Foundation. These include gene therapy, anti-inflammatory and anti-infective drugs, and therapies directed at protein assist/repair. This is in addition to four relatively new therapies, developed with CF Foundation support, that are currently used by patients worldwide.

Supported by the CF Foundation, Vertex is conducting clinical development of VX-770, to determine if this compound can enhance the function of defective CFTR in certain CF patients. Vertex is also collaborating with the CF Foundation to develop a class of molecules, called correctors, which may increase the concentration of CFTR proteins on the cell surface.

With support from the CF Foundation, incentives for R&D investment, and significant advances in the understanding of CF disease, a new wave of compounds are under investigation.