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First Drug to Target Cause of Cystic Fibrosis Approved

Kalydeco Helps 4% of Cystic Fibrosis Patients; Future Treatment May Help Others

By Daniel J. DeNoon
WebMD Health News

Reviewed by Laura J. Martin, MD

Jan. 31, 2012 -- Kalydeco, the first drug that treats the underlying cause of cystic fibrosis (CF), today gained FDA approval.

Only 4% of CF patients -- about 1,200 people in the U.S. -- have the specific genetic defect that Kalydeco treats. However, early results from ongoing clinical studies suggest that the combination of Kalydeco with another new drug, both made by Vertex Pharmaceuticals, eventually may help 90% of people with CF.

"Kalydeco represents a major advance in the treatment of cystic fibrosis for people with a specific type of this disease," Vertex CEO Jeffrey Leiden, MD, PhD, says in a news release. "But our work isn't done. ... We're making progress toward our ultimate goal of developing additional medicines to help many more people with cystic fibrosis."

"Kalydeco is the first available treatment that targets CFTR protein, which is the underlying cause of cystic fibrosis," Janet Woodcock, MD, director of the FDA's Center for Drug Evaluation and Research, says in a news release. "This is a breakthrough therapy for the cystic fibrosis community."

It's been known since 1989 that the cause of cystic fibrosis is a defective CFTR gene. When it's working properly, CFTR controls the flow of salt and water in many tissues, including the lung, pancreas, gut, reproductive system, and sweat glands. Defects in CFTR make it impossible for the lungs to clear away thick, sticky mucus. It also keeps the pancreas and intestines from working properly.

Kalydeco Approval: Personalized Medicine for CF

More than 1,800 genetic mutations can cause cystic fibrosis. About 4% of CF patients have a mutation in the G551D gene. The mutation keeps CFTR from working properly on cell surfaces. Kalydeco is a "CFTR potentiator," improving CFTR function.

Most people with CF have a different mutation called F508del. People with this mutation make defective CFTR protein. Most of this defective protein doesn't make it to the cell surface. The little that does vanishes quickly.

An experimental Vertex drug called VX-809 is designed as a "CFTR corrector." It increases the delivery of CFTR to the cell surface. Clinical trials are exploring whether adding VX-809 to Kalydeco can help the 90% of CF patients with the F508del mutation. Very early results show some promise.

It's not yet clear how much help patients with CF lung damage can expect from Kalydeco. But last year, investigators reported that Kalydeco improved lung function by 17% in patients with the G551D mutation over 48 weeks of treatment. Since CF patients lose about 2% of lung function each year, that's a huge difference.

Moreover, patients gained more weight and had fewer symptoms than CF patients receiving placebo. (All patients continued to receive standard therapies during the study.)

Kalydeco is a pill taken twice a day. The most common side effects include upper respiratory tract infections, headache, stomachache, rash, diarrhea, and dizziness.

According to Reuters, Kalydeco will cost $294,000 per year. The company says it has assistance programs in place for eligible CF patients not covered by insurance.

Only about 30,000 Americans have cystic fibrosis. But it's likely that CFTR drugs will have uses far beyond CF. For example, the drugs may be able to help the mucus buildup that's a key factor in COPD, the fourth leading cause of death in the U.S. and in Europe. CFTR may also play a role in smoke-induced lung damage.

Vertex isn't the only company working on CFTR drugs. FoldRx Pharmaceuticals, owned by Pfizer, is working on compounds that combine the CFTR corrector and CFTR potentiator functions.

A CF drug called ataluren is under development by PTC Therapeutics. Ataluren targets CFTR mutations seen in about 10% of CF patients.

SOURCES: Dolgin, E. Nature Medicine, April 2011.Davis, P.B. The New England Journal of Medicine, Nov. 3, 2011.Ramsey, B.W. The New England Journal of Medicine, Nov. 3, 2011.Van Goor, F. Proceedings of the National Academy of Sciences, published online, Oct. 5, 2011.News release, FDA.News release, Vertex.

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