o

EUROPEAN MEDICINES AGENCY

SCIENCE MEDICINES HEALTH

EMA/770843/2015

EMEA/H/C/003954

EPAR summary for the public

Orkambi

lumacaftor / ivacaftor

This is a summary of the European public assessment report (EPAR) for Orkambi. It explains how the Agency assessed the medicine to recommend its authorisation in the EU and its conditions of use. It is not intended to provide practical advice on how to use Orkambi.

For practical information about using Orkambi, patients should read the package leaflet or contact their doctor or pharmacist.

What is Orkambi and what is it used for?

Orkambi is a medicine used to treat cystic fibrosis in patients aged 12 years and above who have a genetic mutation called the F508del mutation. This mutation affects the gene for a protein called cystic fibrosis transmembrane conductance regulator (CFTR) which is involved in regulating the production of mucus and digestive juices. Orkambi is used in patients who have inherited the mutation from both parents and therefore have the mutation in both copies of the CFTR gene.

Cystic fibrosis is an inherited disease that has severe effects on the lungs and the digestive system. It affects the cells that produce mucus and digestive juices. In cystic fibrosis, the secretions become thick and cause blockage. Build-up of thick and sticky secretions in the lungs causes inflammation and longterm infection. In the gut, blockage of the tubes from the pancreas slows down the digestion of food and causes poor growth.

Orkambi contains the active substances lumacaftor and ivacaftor.

How is Orkambi used?

Orkambi can only be prescribed by a doctor with experience in the treatment of cystic fibrosis. It should be prescribed only to patients aged 12 years and above confirmed to have the F508del mutation in both copies of the CFTR gene.

30 Churchill Place • Canary Wharf • London E14 5EU • United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact

© European Medicines Agency, 2015. Reproduction is authorised provided the source is acknowledged.

Orkambi is available as tablets containing 200 mg lumacaftor and 125 mg ivacaftor. The recommended dose of Orkambi is two tablets twice a day, taken 12 hours apart with fat-containing foods, such as meals prepared with butter or oils or foods containing eggs, cheese, nuts, whole milk or meats.

The dose of Orkambi may have to be reduced in patients with liver problems and in patients taking certain medicines called strong CYP3A4 inhibitors.

How does Orkambi work?

Cystic fibrosis is caused by mutations of the CFTR gene. This gene makes a protein called 'cystic-fibrosis transmembrane conductance regulator' (CFTR), which is involved in regulating the production of mucus and digestive juices. These mutations reduce the number of CFTR protein channels on the cell surface or affect the way they work. These channels are used for the transport of ions (charged atoms and molecules) in and out of cells. When the channels are defective, mucus and digestive juices can become abnormally thick and sticky.

One of the active substances in Orkambi, lumacaftor, increases the number of CFTR proteins on the cell surface and the other, ivacaftor, increases the activity of the defective CFTR protein. This normalises the transport of ions through channels making the secretions less thick.

What benefits of Orkambi have been shown in studies?

Orkambi was shown to be effective at improving lung function in two main studies involving 1,108 cystic fibrosis patients aged 12 years and above who had the F508del mutation in both copies of the CFTR gene. In the studies, Orkambi was compared with placebo (a dummy treatment), both added to patients' usual therapy. The main measure of effectiveness was based on improvement in patients' percent of predicted FEV₁ which is a measure of how well the lungs work.

Results from the first study showed that after 24 weeks of treatment patients who took Orkambi had an average improvement in FEV₁ of 2.41 percentage points more than those who took placebo, whereas this figure was 2.65 in the second study.

Treatment with Orkambi also led to a reduction in the number of exacerbations (flares-up) requiring hospital admission or antibiotic therapy. Overall the number of exacerbations was reduced by 39% when compared with placebo.

What are the risks associated with Orkambi?

The most common side effects with Orkambi (which may affect more than 1 in 10 people) are dyspnoea (shortness of breath), diarrhoea and nausea (feeling sick). Serious side effects included liver problems such as raised liver enzymes, cholestatic hepatitis (build-up of bile leading to inflammation of the liver) and hepatic encephalopathy (a brain disease caused by liver problems). In total, these serious side effects occurred in more than 1 in 200 people during the clinical studies.

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

Why is Orkambi approved?

The Agency's Committee for Medicinal Products for Human Use (CHMP) decided that Orkambi's benefits are greater than its risks and recommended that it be approved for use in the EU.

Although the beneficial effects of Orkambi were consistent across studies and similar to medicines that treat symptoms of cystic fibrosis they were smaller than expected for a medicine that treats the mechanism of the disease rather than its symptoms. However, as cystic fibrosis caused by F508del

Orkambi

EMA/770843/2015    Page 2/3

mutation is particularly severe the CHMP considered that the observed effects seen were clinically relevant for patients with no other alternative options. In addition the committee noted that the benefits of Orkambi were maintained for the duration of treatment of 48 weeks. Orkambi's side effects mainly affected the gut and breathing and were generally considered mild to moderate and manageable.

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

A risk management plan has been developed to ensure that Orkambi 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 Orkambi, including the appropriate precautions to be followed by healthcare professionals and patients.

Further information can be found in the summary of the risk management plan.

Other information about Orkambi

The European Commission granted a marketing authorisation valid throughout the European Union for Orkambi on 19 November 2015.

The full EPAR and risk management plan summary for Orkambi 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 Orkambi, read the package leaflet (also part of the EPAR) or contact your doctor or pharmacist.

This summary was last updated in 11-2015.

Orkambi

EMA/770843/2015