FDA Advisory Committee Gives Cystic Fibrosis Drug Kalydeco (ivacaftor) Thumbs-Up for Patients Six And Up With R117H Mutation

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by Charles Moore |

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Vertex Pharmaceuticals Incorporated announced Tuesday that the U.S. Food and Drug Administration’s Pulmonary Allergy Drugs Advisory Committee (PADAC) voted 13-2 to recommend approval of Kalydeco (ivacaftor) in people with cystic fibrosis (CF) ages six and older who have the R117H mutation in the cystic fibrosis transmembrane regulatory (CFTR) gene, which is the indication being reviewed by the FDA.

chodakewitzJ“Today’s recommendation is a positive and important step toward making ivacaftor available for people ages 6 and older with the R117H mutation,” said Vertex Senior Vice President and Chief Medical Officer M.D. Jeffrey Chodakewitz, in a release.

Advisory committees provide the FDA with independent scientific and medical advice on safety, effectiveness and appropriate use of potential new medicines. The FDA is not bound by the committee’s recommendation, but often follows its advice. The FDA is expected to make a decision on the approval of ivacaftor by December 30, 2014 under the Prescription Drug User Fee Act (PDUFA).

Cystic Fibrosis (CF), a devastating genetic disease most common in individuals of European descent, and the most common fatal genetic disease affecting North American children and young adults, affects approximately 75,000 people in North America, Europe and Australia, about 50,000 of whom are in the U.S. Currently, the median predicted age of survival for a person with CF is between 34 and 47 years, although the median age of death remains in the mid-20s. There is currently no cure.

CF is caused by a defective or missing transmembrane conductane regulator (CFTR) proteins resulting from mutations in the CFTR gene. Children must inherit two defective CFTR genes — one from each parent — to develop CF. There are more than 1,900 known mutations in the CFTR gene. Some of these mutations, which can be determined by a genetic, or genotyping test, lead to CF by creating non-working or too few CFTR proteins at the cell surface. The defective function or absence of CFTR proteins in people with CF results in poor flow of salt and water into and out of the cell in a number of organs, including the lungs. This leads to the buildup of abnormally thick, sticky mucus that can cause chronic lung infections and progressive lung damage.

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Kalydeco (ivacaftor)

Kalydeco (ivacaftor) is the first medicine to treat the underlying cause of CF in people with specific mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Known as a CFTR potentiator, Kalydeco is an oral medicine designed to keep CFTR proteins at the cell surface open longer to improve the transport of salt and water across the cell membrane, which helps hydrate and clear mucus from the airways. Vertex retains worldwide rights to develop and commercialize Kalydeco.

shutterstock_168767156Vertex’s Kalydeco (Ivacaftor, 150 mg tablets) is indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who have a G551D mutation in the CFTR gene, and is currently approved to treat more than 2,600 people ages 6 and older in North America, Europe and Australia who have specific mutations in the CFTR gene. In the United States, these mutations include G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P and G1349D. In people with the R117H mutation, the CFTR protein reaches the cell surface but does not function properly. Approximately 500 people ages 6 and older have this mutation in the United States.

According to the advocacy organization Cystic Fibrosis Canada (CFC), one of the world’s top three charitable organizations committed to finding a cure for cystic fibrosis, CF is the most common fatal genetic disease among Canadian children and young adults, affecting some 4,000 individuals directly. It is estimated that about 100 CF patients in Canada carry the specific G551D mutation of the CFTR gene that makes CF treatable with Kalydeco, according to the Canadian CF Registry. When taken twice a day with fat-containing food, Kalydeco helps the protein made by the CFTR gene function better, improving lung function and weight gain. As about 118 Canadians would be eligible for Kalydeco treatment if it was covered by provincial health insurance plans. Both the governments and the manufacturer want patients to have access to Kalydeco.

In June, Canada’s CTV News reported that the province of Alberta’s health minister has successfully negotiated a tentative deal that will allow Canadian provinces to cover the cost to their provincial pharmacare plans of the multiple sclerosis (MS) drug Kalydeco, used for treatment of cystic fibrosis (CF) in patients aged six years and older who have one of the following specific CF gene mutations cited above.

In people with the G551D mutation of CF ages six and older, Kalydeco helps improve lung function and lower sweat chloride levels and helps patients gain weight — all key indicators that the drug is working. In people with this mutation, the defective protein moves to the right place at the surface of the cell but does not function correctly. Instead, it acts like a locked gate, preventing the proper flow of salt and fluids in and out of the cell. Kalydeco helps unlock that gate and restore the CFTR protein’s function. This allows for a proper flow of salt and fluids on the surface of the lungs. This helps to thin the thick, sticky mucus caused by CF that builds up in the lungs.

In the United States, Kalydeco is also indicated for the treatment of CF in patients age 6 and older who have one of the following mutations in the CFTR gene: G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R. In Canada, ivacaftor is indicated for these same mutations and additionally for G970R.

The company notes that Ivacaftor is not effective in patients with CF with 2 copies of the F508del mutation (F508del/F508del) in the CFTR gene. The safety and efficacy of ivacaftor in children with CF younger than 6 years of age have not been established.

Side Effects:

Elevated liver enzymes (transaminases; ALT and AST) have been reported in patients receiving ivacaftor. Vertex recommends that ALT and AST be assessed prior to initiating ivacaftor, every 3 months during the first year of treatment, and annually thereafter. Patients who develop increased transaminase levels should be closely monitored until the abnormalities resolve. Dosing should be interrupted in patients with ALT or AST of greater than 5 times the upper limit of normal. Following resolution of transaminase elevations, consider the benefits and risks of resuming ivacaftor dosing.

Use of ivacaftor with medicines that are strong CYP3A inducers, such as the antibiotics rifampin and rifabutin; seizure medications (phenobarbital, carbamazepine, or phenytoin); and the herbal supplement St. John’s Wort, substantially decreases exposure of ivacaftor and may diminish effectiveness. Therefore, co-administration is not recommended.

The ivacaftor dose must be adjusted when used concomitantly with strong and moderate CYP3A inhibitors or when used in patients with moderate or severe hepatic disease.

Ivacaftor can cause serious adverse reactions including abdominal pain and high liver enzymes in the blood. The most common side effects associated with ivacaftor include headache; upper respiratory tract infection (the common cold), including sore throat, nasal or sinus congestion, and runny nose; stomach (abdominal) pain; diarrhea; rash; and dizziness. These are not all the possible side effects of ivacaftor. A list of the adverse reactions can be found in the product labeling for each country where ivacaftor is approved. Patients should tell their healthcare providers about any side effect that bothers them or does not go away.

Founded in 1989 in Cambridge, Mass., Vertex today has research and development sites and commercial offices in the United States, Europe, Canada and Australia. For five years in a row, Science magazine has named Vertex one of its Top Employers in the life sciences.

Vertex initiated its CF research program in 1998 as part of a collaboration with Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT) — the nonprofit drug discovery and development affiliate of the Cystic Fibrosis Foundation. This collaboration was expanded to support the accelerated discovery and development of Vertex’s CFTR modulators. The CF Foundation is a donor-supported nonprofit organization. For more information, visit:

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