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EUROPEAN MEDICINES AGENCY

SCIENCE MEDICINES HEALTH

EMA/633284/2014

EMEA/H/C/002052

EPAR summary for the public

Signifor

pasireotide

This is a summary of the European public assessment report (EPAR) for Signifor. 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 Signifor.

What is Signifor?

Signifor is a medicine that contains the active substance pasireotide. It is available as a solution for injection under the skin (0.3 mg, 0.6 mg and 0.9 mg) or as a powder and solvent to make up a suspension for injection into the muscle (20 mg, 40 mg and 60 mg).

What is Signifor used for?

Signifor is used to treat adults with Cushing's disease when surgery has failed or is not an option. Signifor is also used for the treatment of adult patients with acromegaly when surgery has failed or is not an option and who are inadequately controlled with other medicines known as 'somatostatin analogues'.

Cushing's disease and acromegaly are both caused by tumours of the pituitary gland (a gland located at the base of the brain). In Cushing's disease, the tumour causes overproduction of a hormone called ACTH, which in turn stimulates the production of too much cortisol (a hormone also known as the 'stress hormone' because it is released in response to stress). In acromegaly, the tumour causes excess production of growth hormone (GH), which stimulates the production of too much IGF-1 (insulin growth factor 1).

Because the numbers of patients with these diseases are low, the diseases are considered 'rare', and Signifor was designated an 'orphan medicine' (a medicine used in rare diseases).

The medicine can only be obtained with a prescription.

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How is Signifor used?

For the treatment of Cushing's disease, Signifor is given as an injection under the skin at an initial dose of 0.6 mg twice a day in different injection sites (preferably at the top of the thigh and the abdomen). Patients should be trained on how to inject themselves. After two months, the patient's response to treatment should be evaluated, and the dose adjusted as appropriate or treatment stopped if no benefit is seen. If side effects develop the dose may need to be temporarily reduced. In patients with moderate liver problems, the starting dose should be reduced to 0.3 mg twice a day and the maximum recommended dose is 0.6 mg twice a day.

In patients with acromegaly, Signifor is given as a long-acting injection into the buttock muscle every four weeks. Treatment starts with a dose of 40 mg every four weeks, given by a trained healthcare professional. The dose may need to be adjusted according to response, or if side effects develop.

For further information, see the package leaflet.

How does Signifor work?

Pasireotide is a 'somatostatin analogue', a copy of the natural hormone somatostatin, which is known to block the release of ACTH and GH. Receptors for somatostatin can be found in high amounts on tumour cells, including tumours of the pituitary gland which cause Cushing's disease and acromegaly. Like somatostatin, pasireotide attaches to these receptors. In case of Cushing's disease this blocks the release of excessive ACTH, which in turn helps to reduce the excessive levels of cortisol in the blood, thereby relieving the symptoms of the disease. In case of acromegaly Signifor blocks the release of excessive GH as well as IGF-1, thereby relieving the symptoms of acromegaly.

How has Signifor been studied?

Signifor was studied in 165 adult patients with Cushing's disease where surgery was not appropriate. Patients were treated with Signifor at either 0.6 mg twice a day or 0.9 mg twice a day. The main measure of effectiveness was the proportion of patients whose cortisol level in the urine normalised after six months. This study also looked at the proportion of patients who partially responded to treatment and whose cortisol level in the urine decreased by at least 50% after six months.

For the treatment of acromegaly, Signifor was investigated in two main studies. One study lasting 12 months involved 358 previously untreated patients and compared Signifor with long-acting octreotide (another somatostatin analogue); the other study involved 198 patients whose disease had not been adequately controlled with surgery or other medical treatment, and compared the effect of Signifor with that of long-acting octreotide or lanreotide (a third somatostatin analogue) after 24 weeks of treatment. At the end of both studies, patients were followed in the extension phase for up to 14 months.

In both studies, the main measure of effectiveness was the proportion of patients who responded to treatment, i.e. whose GH and IGF-1 levels decreased to pre-defined values (less than 2.5 micrograms/liter for GH or within normal limits for IGF-1).

What benefit has Signifor shown during the studies?

Signifor was shown to be effective in reducing cortisol levels in patients with Cushing's disease. The study showed that 15% of patients receiving 0.6 mg Signifor (12 patients out of 82) and 26% of patients receiving 0.9 mg Signifor (21 patients out of 80) had normal urine cortisol levels within six months. In 34% of patients receiving 0.6 mg Signifor and 41% of patients receiving 0.9 mg Signifor, urine cortisol levels decreased by at least 50% within six months.

Signifor was also shown to be effective in reducing GH and IGF-1 levels in patients with acromegaly. In the first study, 31% (55 out of 176) of patients receiving Signifor responded to treatment, compared with 19% (35 out of 182) of patients receiving octreotide. In the second study, 15% (10 out of 65) of patients receiving Signifor 40 mg and 20% (13 out of 65) of patients receiving Signifor 60 mg responded to treatment, compared with none of the 68 patients given octreotide or lanreotide.

Extensions of both studies confirmed the long-term benefit of Signifor in patients with acromegaly.

What is the risk associated with Signifor?

The most common side effects with Signifor (seen in more than 1 patient in 10) in patients with Cushing's disease are hyperglycaemia (high blood sugar levels), diabetes, diarrhoea, abdominal pain (stomach ache), nausea (feeling sick), cholelithiasis (gallstones), injection site reactions, fatigue (tiredness) and increased blood levels of glycosylated haemoglobin (a substance which gives an indication of how well the blood glucose is controlled). In patients with acromegaly, the most common side effects (seen in more than 1 patient in 10) are hyperglycaemia, diabetes, diarrhoea and cholelithiasis. For the full list of all side effects reported with Signifor, see the package leaflet.

Signifor must not be used in patients with severe liver problems. For the full list of restrictions with Signifor, see the package leaflet.

Why has Signifor been approved?

The CHMP concluded that the benefits of Signifor outweigh its risks and recommended that it be granted marketing authorisation. The Committee took the view that, although the proportion of patients with Cushing's disease who responded and whose cortisol levels in the urine normalised was small, Signifor could be of benefit in patients who have failed surgery or where surgery is not an option. It also considered that a partial response may be of benefit in these patients. After two months of treatment with Signifor, it is possible to identify which patients are responding and to stop treatment in those who are not responding.

The CHMP was also of the opinion that the data provided support the use of Signifor in patients with acromegaly when surgery has failed or was not an option and for whom treatment with another somatostatin analogue did not work.

Regarding the safety of Signifor, the identified side effects were considered to be manageable. The side effects were also similar to other medicines of its class, with the exception of hyperglycaemia, which was more frequent and severe in acromegaly patients treated with Signifor. Although the Committee considered that this risk could be easily monitored and managed with standard diabetes medicines, the CHMP considered that other somatostatin analogues should be tried first in patients with acromegaly and use of Signifor should be reserved for those whose condition was not controlled by these alternative medicines.

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

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

Other information about Signifor

The European Commission granted a marketing authorisation valid throughout the European Union for Signifor on 24 April 2012.

The full EPAR for Signifor 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 Signifor, read the package leaflet (also part of the EPAR) or contact your doctor or pharmacist.

The summaries of the opinions of the Committee for Orphan Medicinal Products for Signifor can be found on the Agency's website:

•    Cushing's disease

•    Acromegaly

This summary was last updated in 11-2014.

Signifor

EMA/720175/2014

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