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EUROPEAN MEDICINES AGENCY

SCIENCE MEDICINES HEALTH

EMA/674901/2015

EMEA/H/C/002494

EPAR summary for the public

Kalydeco

ivacaftor

This is a summary of the European public assessment report (EPAR) for Kalydeco. It explains how the Committee for Medicinal Products for Human Use (CHMP) assessed the medicine to reach its opinion in favour of granting a marketing authorisation and its recommendations on the conditions of use for Kalydeco.

What is Kalydeco?

Kalydeco is a medicine that contains the active substance ivacaftor. It is available as tablets (150 mg) and as granules (50 mg and 75 mg) in a sachet.

What is Kalydeco used for?

Kalydeco is used to treat cystic fibrosis in patients aged 2 years and above who have one of nine mutations in the gene for the protein called 'cystic fibrosis transmembrane conductance regulator' (CFTR). The mutations are: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N and S549R (also known as gating mutations).

Kalydeco is also used to treat patients with cystic fibrosis aged 18 years and above who have the R117H mutation in the CFTR gene.

Cystic fibrosis is an inherited disease that mainly affects the cells that secrete mucus in the lungs, and the cells that secrete digestive juices from the glands in the gut and pancreas. In cystic fibrosis these secretions become thick and cause blockage. Build-up of thick and sticky secretions in the lungs causes inflammation and long-term infection. In the gut, blockage of the tubes from the pancreas and the liver as well as the production of abnormal digestive juices slows down the digestion of food and causes poor growth.

Because the number of patients with cystic fibrosis is low, the disease is considered 'rare', and Kalydeco was designated an 'orphan medicine' (a medicine used in rare diseases) on 8 July 2008.

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The medicine can only be obtained with a prescription.

How is Kalydeco used?

Kalydeco should only be prescribed by doctors with experience in the treatment of cystic fibrosis, and only patients confirmed to have one of the ten mutations mentioned above should be prescribed the medicine.

For children aged 2 years and above and weighing less than 25 kg the granules should be used. They should be mixed with 5 ml of soft food or liquid to make a suspension to be taken by mouth. For children weighing between 14 and 25 kg the recommended dose is 75 mg twice a day. For children weighing less than 14 kg the recommended dose is 50 mg twice a day.

The tablets are used in children aged 6 years and above and weighing 25 kg or more. The recommended dose is one 150 mg tablet twice a day.

The tablets or the granules should be taken at 12-hour intervals with fat-containing foods, such as meals prepared with butter or oils or foods containing eggs, cheese, nuts, whole milk or meat.

Food containing grapefruit or Seville oranges should be avoided during treatment with Kalydeco as they may affect the way the medicine is absorbed and broken down in the body.

Blood tests to check liver function should be performed before starting Kalydeco and regularly during treatment. In patients with severely reduced liver function Kalydeco should only be started if the benefits outweigh the risks. These patients should be started at a lower dose which should be given every other day. The dosing regimen of Kalydeco may need to be adjusted in patients taking certain types of medicines.

For more information, see the summary of product characteristics (also part of the EPAR).

How does Kalydeco work?

Cystic fibrosis is caused by mutations in the CFTR gene. The mutation causes problems with protein channels involved in the production of secretions such as mucus and digestive juices. These channels are used for the transport of ions (charged atoms and molecules) in and out of the secretion-producing cells. When the channels are defective, secretions can become abnormally thick.

The active substance in Kalydeco, ivacaftor, increases the activity of the defective channels in patients with the mutations G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R or R117H. This normalises the transport of ions through channels, making the secretions less thick and thereby relieving symptoms of the disease.

How has Kalydeco been studied?

Kalydeco was compared with placebo in two main studies involving 219 patients with cystic fibrosis who had the G551D mutation. One of the studies was in patients aged over 12 years, while the other involved patients aged between six and 12 years.

A third study investigated the effectiveness of Kalydeco in patients with cystic fibrosis due to several mutations other than G551D. The study involved 39 patients over 6 years of age and compared Kalydeco with placebo.

A fourth study investigated the effectiveness of Kalydeco in patients with cystic fibrosis who had the R117H mutation. The study included 69 patients aged 6 years and above.

The main measure of effectiveness in these studies was based on improvements in patients' percent of predicted forced expiratory volume in one second (FEV₁), adjusted for the patient's age, height and sex. FEV₁ is the maximum amount of air a person can breathe out in one second and is a measure of how well the lungs work.

A fifth study investigated the safety of Kalydeco granules in 34 patients aged between 2 and 5 years of age who had cystic fibrosis due to a G551D or S549N mutation. The study looked at bodyweight and the amount of chloride in sweat, both of which are reduced in patients with cystic fibrosis.

What benefit has Kalydeco shown during the studies?

Kalydeco was shown to be effective at improving lung function in patients with cystic fibrosis who had the G551D mutation. After 24 weeks of treatment, patients aged 12 years and older who took Kalydeco had an average improvement in percent of predicted FEV1 of 10.6 percentage points more than those who took placebo. Similar results were seen in patients aged between 6 and 11 years, where Kalydeco treatment led to an improvement of 12.5 percentage points more than with placebo.

Kalydeco was also effective in patients with mutations other than G551D. In the third study, after 8 weeks of treatment patients who took Kalydeco had an average improvement of 10.7 percentage points more than those who took placebo. In the fourth study in patients with the R117H mutation, no difference was seen between placebo and Kalydeco for children aged 6 years and above. However, when analysing the subset of patients aged 18 years and above alone, an average improvement of around 5.0 percentage points was seen in patients who took Kalydeco compared with patients who took placebo.

In the study in children aged 2 to 5 years, Kalydeco granules had a positive effect on bodyweight and the amount of chloride contained in sweat.

What is the risk associated with Kalydeco?

The most common side effects with Kalydeco seen in patients aged 6 years and above are headache (23.9%), sore throat (22.0%), upper respiratory tract infection (colds, 22.0%), nasal congestion (20.2%), abdominal (belly) pain (15.6%), nasopharyngitis (inflammation of the nose and throat, 14.7%), diarrhoea (12.8%), dizziness (9.2%), rash (12.8%), bacteria in sputum (12.8%) and an increase in certain liver enzymes (12.8%).

In children aged 2 to 5 years the most common side effects are nasal congestion (26.5 %), upper respiratory tract infection (23.5 %), increase in liver enzymes (14.7 %), rash (11.8 %) and bacteria in sputum (11.8 %).

For the full list of all side effects and restrictions with Kalydeco, see the package leaflet.

Why has Kalydeco been approved?

Kalydeco has been shown to improve lung function in patients aged six years and above who had one of nine CFTR gating mutationsandin patients aged 18 years and above who had an R117H mutation. Additional data also supports effectiveness of Kalydeco in children aged 2 to 5 years of age with a G551D or S549N mutation. The medicine was also shown to have an acceptable safety profile. The CHMP concluded that the benefits of Kalydeco are greater than its risks and recommended that it be given marketing authorisation. The CHMP also noted, however, that there were limited data on the longer-term effects of the medicine and that further data should be provided by the company.

What measures are being taken to ensure the safe and effective use of Kalydeco?

A risk management plan has been developed to ensure that Kalydeco is used as safely as possible. Based on this plan, safety information has been included in the summary of product characteristics and the package leaflet for Kalydeco, including the appropriate precautions to be followed by healthcare professionals and patients.

In addition, the company is conducting a five-year observational study to assess the longer-term effects of the medicine as well as a six-year observational study in children who were aged 2 to 5 years at the time of treatment start to assess long-term effects of early treatment.

Other information about Kalydeco

The European Commission granted a marketing authorisation valid throughout the European Union for Kalydeco on 23 July 2012.

The full EPAR for Kalydeco can be found on the Agency's website: ema.europa.eu/Find medicine/Human medicines/European public assessment reports. For more information about treatment with Kalydeco read the package leaflet (also part of the EPAR) or contact your doctor or pharmacist.

The summary of the opinion of the Committee for Orphan Medicinal Products for Kalydeco can be found on the Agency's website: ema.europa.eu/Find medicine/Human medicines/Rare disease designation.

This summary was last updated in 11-2015.

Kalydeco

EMA/674901/2015

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