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Orphan designation

This medicine is now known as ibrutinib.

On 26 April 2012, orphan designation (EU/3/12/984) was granted by the European Commission to Nexus Oncology Ltd, United Kingdom, for 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4 d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one for the treatment of chronic lymphocytic leukaemia.

The sponsorship was transferred to Janssen-Cilag International N.V, Belgium, in January 2013.

1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4 d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one for treatment of chronic lymphocytic leukaemia has been authorised in the EU as Imbruvica since 21 October 2014.

What is chronic lymphocytic leukaemia?

Chronic lymphocytic leukaemia (CLL) is cancer of a type of white blood cell called B-lymphocytes. In this disease, the lymphocytes multiply too quickly and live for too long, so that there are too many of them circulating in the blood. The cancerous lymphocytes look normal, but they are not fully developed and do not work properly. Over a period of time, the abnormal cells replace the normal white cells, red cells and platelets (components that help the blood to clot) in the bone marrow (the spongy tissue inside the large bones in the body).

CLL is the most common type of leukaemia and mainly affects older people. It is rare in people under the age of 40 years. CLL is a long-term debilitating and life-threatening disease because some patients develop severe infections.

What is the estimated number of patients affected by the condition?

At the time of designation, CLL affected approximately 3 in 10,000 people in the European Union (EU). This was equivalent to a total of around 153,000 people*, and is below the ceiling for orphan designation, which is 5 people in 10,000. This is based on the information provided by the sponsor and the knowledge of the Committee for Orphan Medicinal Products (COMP).

*Disclaimer: For the purpose of the designation, the number of patients affected by the condition is estimated and assessed on the basis of data from the European Union (EU 27), Norway, Iceland and Liechtenstein. At the time of designation, this represented a population of 509,000,000 (Eurostat 2012).

What treatments are available?

Treatment for CLL is complex and depends on a number of factors, including the extent of the disease, whether it has been treated before, and the patient’s age, symptoms and general state of health. Patients whose CLL is not causing any symptoms or is only getting worse very slowly may not need treatment. Treatment for CLL is only started if symptoms become troublesome. At the time of designation, the main treatment for CLL was chemotherapy (medicines to treat cancer).

The sponsor has provided sufficient information to show that this medicine might be of significant benefit for patients with CLL because it works in a different way to existing treatments and early studies show that it might improve the outcome of patients whose disease has progressed or come back after previous treatment. This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.

How is this medicine expected to work?

This medicine is expected to work by blocking an enzyme called Bruton’s tyrosine kinase (Btk), which is mostly found in B-lymphocytes. Btk activates survival of B-lymphocytes and their migration to the organs where these cells normally divide. By blocking Btk, the medicine is expected to slow down the migration of B-lymphocytes in CLL and to induce cell death, thereby delaying or stopping the progression of the disease.

The medicine is expected to be taken by mouth.

What is the stage of development of this medicine?

The effects of 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4 d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one have been evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials with this medicine in patients with CLL were ongoing.

At the time of submission, this medicine was not authorised anywhere in the EU for CLL or designated as an orphan medicinal product elsewhere for this condition.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 8 March 2012 recommending the granting of this designation.

Update: 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4 d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one, ibrutinib (Imbruvica) has been authorised in the EU since 21 October 2014 for the treatment of adult patients with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy, or in first line in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo immunotherapy.

Opinions on orphan medicinal product designations are based on the following three criteria:
  •  the seriousness of the condition;
  • the existence of alternative methods of diagnosis, prevention or treatment;
  • either the rarity of the condition (affecting not more than 5 in 10,000 people in the EU) or insufficient returns on investment.

Designated orphan medicinal products are products that are still under investigation and are considered for orphan designation on the basis of potential activity. An orphan designation is not a marketing authorisation. As a consequence, demonstration of quality, safety and efficacy is necessary before a product can be granted a marketing authorisation. 

Key facts

Product details for <p>1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4 d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one (ibrutinib)</p>
Active substance1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4 d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one (ibrutinib)
Medicine NameImbruvica
Disease/conditionTreatment of chronic lymphocytic leukaemia
Date of decision26/04/2012
Orphan decision numberEU/3/12/984

Review of designation

During its meeting of 2 to 4 September 2014, the Committee for Orphan Medicinal Products (COMP) reviewed the designation EU/3/12/984 for Imbruvica (ibrutinib1) as an orphan medicinal product for the treatment of chronic lymphocytic leukaemia (CLL). The COMP assessed whether, at the time of marketing authorisation, the medicinal product still met the criteria for orphan designation. The Committee looked at the seriousness and prevalence of the condition, and the existence of other methods of treatment. As other methods of treatment are authorised in the European Union (EU), the COMP also considered whether the medicine is of significant benefit to patients with CLL. The COMP recommended that the orphan designation of the medicine be maintained2

1Previously known as 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo [3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one.
2The maintenance of the orphan designation at time of marketing authorisation would, except in specific situations, give an orphan medicinal product 10 years of market exclusivity in the EU. This means that in the 10 years after its authorisation similar products with a comparable therapeutic indication cannot be placed on the market.

Life-threatening or long-term debilitating nature of the condition

The Committee for Medicinal Products for Human Use (CHMP) recommended the authorisation of Imbruvica for:

‘treatment of adult patients with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy, or in first line in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo‑immunotherapy’.

This falls within the scope of the product’s designated orphan indication, which is: ‘treatment of CLL’.

The COMP concluded that there had been no change in the seriousness of the condition since the orphan designation in 2012. CLL remains a condition that is debilitating in the long term and life threatening because patients may develop disease-related complications including severe infections.

Prevalence of the condition

The sponsor provided updated information on the prevalence of CLL based on data from RARECARE and the GLOBOCAN 2008 database.

On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of CLL remains below the ceiling for orphan designation, which is 5 people in 10,000. At the time of the review of the orphan designation, the prevalence was still estimated to be approximately 3 people in 10,000. This is equivalent to a total of around 153,000 people in the EU.

Existence of other methods of treatment

The COMP noted that, at the time of the review of the orphan designation, the main treatment for CLL was chemotherapy (medicines to treat cancer), which might include chlorambucil or fludarabine-based therapy. In patients with CLL that did not respond to or had come back after previous treatment, subsequent treatments included ofatumumab and the combination of rituximab with chemotherapy medicines.

Significant benefit of Imbruvica

The COMP concluded that the claim of a significant benefit of Imbruvica in CLL is justified by data showing that treatment with Imbruvica improved patient’s overall survival (how long they lived) and progression-free survival (how long they lived without their disease getting worse) compared with existing treatments. Imbruvica was also shown to be effective in patients with those mutations (17p deletion or TP53 mutation) that confer a poor prognosis. In addition, the COMP noted that Imbruvica has the advantage of being available as capsules that can be taken by mouth at home unlike current treatments that are given by injection in hospital.

Therefore, although other methods for the treatment of this condition have been authorised in the EU, the COMP concluded that Imbruvica is of significant benefit to patients affected by CLL.


Based on the data submitted and the scientific discussion within the COMP, the COMP considered that Imbruvica still meets the criteria for designation as an orphan medicinal product and that it should remain in the Community Register of Orphan Medicinal Products.

Further information on the current regulatory status of Imbruvica can be found in the European public assessment report (EPAR).

Sponsor’s contact details

Janssen-Cilag International N.V.
Turnhoutseweg, 30
2340 Beerse
Tel. +32 14 60 31 89
Fax +32 14 60 55 33

Patients' organisations

For contact details of patients’ organisations whose activities are targeted at rare diseases, see:

  • Orphanet, a database containing information on rare diseases, which includes a directory of patients’ organisations registered in Europe;
  • European Organisation for Rare Diseases (EURORDIS), a non-governmental alliance of patient organisations and individuals active in the field of rare diseases.