FDA Widens Use of Ivacaftor Again for Cystic Fibrosis

May 17, 2017

In what is hailed as a victory for precision medicine, the US Food and Drug Administration (FDA) today once again expanded the indication of ivacaftor (Kalydeco, Vertex Pharmaceuticals) for cystic fibrosis (CF) to cover more gene mutations that cause the life-shortening disorder.

The FDA based its decision on laboratory testing combined with evidence from earlier clinical trials instead of relying on new trials, which are not feasible for the tiny patient population involved, according to Janet Woodcock, MD, director of the agency's Center for Drug Evaluation and Research.

"This challenge led us to using an alternative approach based on precision medicine, which made it possible to identify certain gene mutations that are likely to respond to Kalydeco," Dr Woodcock said in a news release.

Patients with CF have one of many mutations in a CF transmembrane conductance regulator (CFTR) gene, which codes for a protein that helps keep mucus, sweat, and digestive juices thin and slippery. When the CFTR protein is defective because of a mutation, these secretions become sticky and thick, building up in the lungs, digestive tract, and other parts of the body and triggering a cascade of severe conditions.

Ivacaftor works by helping a defective CFTR protein better regulate secretion viscosity, which improves lung function and other aspects of CF. The drug is taken twice daily as tablets or granules, together with fat-containing food.

The drug was originally approved in January 2012 for patients with CF aged 6 years or older with the G551D mutation in the CFTR gene. At that time, 1200 people, or 4% of the about 30,000 people in the United States who have CF, were thought to harbor that mutation.

In February 2014, the drug's indication was expanded to cover eight additional CF-triggering mutations of the CFTR gene found in an estimated 150 people. The FDA added an additional mutation in 500 people to the list later that year.

Today the FDA approved ivacaftor to treat CF in individuals aged 2 years or older who have any one of 23 additional mutations of the CFTR gene, bringing the total number of covered mutations to 33. As a result, 900 more people in the United States can be treated with the drug.

All the mutations now in the drug's indication apply to nearly 2800 people, less than 10% of everyone with CF. However, the drug's manufacturer said in a news release that it will continue to peck away at more CFTR mutations to treat more patients.

The FDA based the latest expansion of the indication on laboratory tests in which gene mutations responded in vitro to the drug. Researchers extrapolated the drug's benefits from earlier clinical trials to the results from the lab, according to the FDA.

"Kalydeco serves as an example of how successful patient-focused drug development can provide greater understanding about a disease," the agency said. "For example, the Cystic Fibrosis Foundation maintains a 28,000-patient registry, including genetic data, which it makes available for research."

Headaches, upper respiratory tract infections, stomach pain, and diarrhea are some of the common adverse events seen with ivacaftor. The drug's label warns about the risk for elevated levels of liver enzymes called transaminases as well as cataracts in children.

More information about today's announcement is available on the FDA website.

Follow Robert Lowes on Twitter @LowesRobert


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