EU/3/14/1264

On 29 April 2014, orphan designation (EU/3/14/1264) was granted by the European Commission to Janssen-Cilag International N.V., Belgium, for ibrutinib for the treatment of lymphoplasmacytic lymphoma.

Update: ibrutinib (Imbruvica) has been authorised in the EU since 21 October 2015 for treatment of adult patients with Waldenström’s macroglobulinaemia (WM) who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy.

What is lymphoplasmacytic lymphoma?

Lymphoplasmacytic lymphoma is a cancer of a type of white blood cell called B lymphocytes or B cells. In lymphoplasmacytic lymphoma, the B cells multiply too quickly and live for too long, so there are too many of them in places like the bone marrow, lymph nodes or spleen. The first signs of the disease are usually weakness and tiredness. In many patients with lymphoplasmacytic lymphoma, the abnormal B cells produce too much of a type of blood protein called immunoglobulin-type-M paraprotein (IgM paraprotein), which makes the blood too viscous (thick) and can lead to symptoms such as eye problems, heart failure, haemolytic anaemia (destruction of red blood cells) and effects on the nervous system.

Lymphoplasmacytic lymphoma is a life-threatening and long-term debilitating disease due to damage to the bone marrow and other organs.

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

At the time of designation, lymphoplasmacytic lymphoma affected less than 0.1 in 10,000 people in the European Union (EU). This was equivalent to a total of fewer than 5,000 people*, and is below the ceiling for orphan designation, which is 5 people in 10,000. This isbased on the information provided by the sponsor and the knowledge of the Committee for Orphan Medicinal Products (COMP).

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*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 28), Norway, Iceland and Liechtenstein. This represents a population of 511,100,000 (Eurostat 2014).

What treatments are available?

At the time of designation, the main treatments for diseases such as lymphoplasmacytic lymphoma available in the EU included immunotherapy (medicines that stimulate the body’s own immune system to kill the cancer cells), and combinations of immunotherapy with chemotherapy (cancer medicines intended to kill the cancer cells). Medicines designed to attach to the cancer cells and kill them with radiation (radioimmunotherapy) were also sometimes used.

The sponsor has provided sufficient information to show that ibrutinib might be of significant benefit for patients with lymphoplasmacytic lymphoma, because early studies in patients with lymphoplasmacytic lymphoma that was resistant to or had come back after existing treatments showed that some of these patients responded to ibrutinib. 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?

Ibrutinib is expected to work in patients with lymphoplasmocytic lymphoma by blocking the action of an enzyme known as Bruton’s tyrosine kinase (BTK). BTK is important for the growth of B cells, including the abnormal B cells of the cancer. By blocking the action of BTK, it is expected that the medicine will slow the progression of the disease.

What is the stage of development of this medicine?

The effects of ibrutinib have been evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials with ibrutinib in patients with lymphoplasmacytic lymphoma were ongoing.

At the time of submission, ibrutinib was not authorised anywhere in the EU for lymphoplasmacytic lymphoma 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 12 March 2014 recommending the granting of this designation.

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.

During its meeting of 16 to 18 June 2015, the Committee for Orphan Medicinal Products (COMP) reviewed the designation EU/3/14/1264 for Imbruvica (ibrutinib)as an orphan medicinal product for the treatment of lymphoplasmacytic lymphoma (also known as Waldenström’s macroglobulinaemia). The COMP assessed whether, at the time of addition of a new indication to the marketing authorisation, the medicinal product still met the criteria for orphan designation. The Committee looked at the seriousness 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 lymphoplasmacytic lymphoma. The COMP recommended that the orphan designation of the medicine be maintained¹.

¹The 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 extending the approved therapeutic indication for Imbruvica to include the following indication:

'treatment of adult patients with Waldenström’s macroglobulinaemia who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy'.

This falls within the scope of the product’s designated orphan indication, which is: 'lymphoplasmacytic lymphoma'.

The COMP concluded that there had been no change in the seriousness of the condition since the orphan designation in 2014. Lymphoplasmacytic lymphoma remains a long-term debilitating and life-threatening condition due to damage to the bone marrow and other organs.

Prevalence of the condition

The sponsor provided updated information on the prevalence of lymphoplasmacytic lymphoma based on data from the Globocan 2012 database.

On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of lymphoplasmacytic lymphoma 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 less than 0.1 people in 10,000. This is equivalent to a total of fewer than 5,000 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 treatments for lymphoplasmacytic lymphoma included immunotherapy (medicines that stimulate the body’s own immune system to kill the cancer cells), and combinations of immunotherapy (such as rituximab) with chemotherapy (cancer medicines intended to kill the cancer cells).

Significant benefit of Imbruvica

The COMP concluded that the claim of a significant benefit of Imbruvica for patients with lymphoplasmacytic lymphoma is justified. Imbruvica was shown to improve outcomes in patients whose disease had come back after, or had not responded to, previous treatments. This is based on a main study of previously treated patients which showed that around 87% (55 out of 63) of patients responded to treatment with Imbruvica.

Furthermore, Imbruvica could also be of benefit to previously untreated patients who cannot receive chemo-immunotherapy. No satisfactory treatments are currently available to these patients.

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 for patients affected by lymphoplasmacytic lymphoma.

Conclusions

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.