EU/3/09/716

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Orphan designation

On 2 February 2010, orphan designation (EU/3/09/716) was granted by the European Commission to Ariad Pharma Ltd, United Kingdom, for benzamide, 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] for the treatment of chronic myeloid leukaemia.

For a list of the administrative updates to this public summary of opinion please refer to the PDF document below.

What is chronic myeloid leukaemia?

Chronic myeloid leukaemia (CML) is a cancer of the white blood cells (cells that fight against infections). In patients with CML, the bone marrow (the spongy tissue inside the large bones) produces large numbers of abnormal, immature white blood cells called ‘blasts’, so there are too many of them circulating in the blood. These blast cells are not fully developed and do not work properly. Over a period of time, they replace the normal white blood cells, red blood cells and platelets in the bone marrow.

CML is most common in adults and older people, but children may also be affected. The disease usually develops very slowly, which is why it is called ‘chronic’. However, when it progresses, CML is a severe and life-threatening disease that is associated with poor overall survival.

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

At the time of designation, CML affected approximately 0.8 in 10,000 people in the European Union (EU). This was equivalent to a total of around 41,000 people*, and is below the threshold for orphan designation, which is 5 people in 10,000. This is based on the information provided by the sponsor and 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 506,300,000 (Eurostat 2010).

What treatments are available?

Treatment for CML 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. At the time of designation, the main treatments for CML were chemotherapy (medicines to treat cancer) and bone-marrow transplantation (a complex procedure where the bone marrow of the patient is destroyed and replaced with healthy bone marrow from a matched donor).

The sponsor has provided sufficient information to show that benzamide, 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] might be of significant benefit for patients with CML because it may represent an alternative treatment for patients with this condition, and because early studies indicate that it might be used in patients who do not respond to existing treatments. These assumptions 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?

Benzamide, 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] belongs to a group of medicines called ‘protein-tyrosine-kinase inhibitors’. These medicines work by blocking enzymes known as protein kinases. This medicine is expected to work mainly by blocking the protein kinase called ‘BCR-ABL’ kinase. This enzyme is produced by leukaemia cells, and causes them to multiply uncontrollably. By blocking BCR-ABL kinase, as well as other kinases, the medicine is expected to help to control the spread of leukaemia cells.

What is the stage of development of this medicine?

The effects of benzamide, 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] have been evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials with the designated product in patients with CML were ongoing.

At the time of submission, this medicine was not authorised anywhere in the EU for CML 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 3 December 2009 recommending the granting of this designation.

Update: Benzamide, 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] (Iclusig) was authorised in the EU on 1 July 2013. Iclusig is indicated in adult patients with chronic-phase, accelerated-phase or blast-phase chronic myeloid leukaemia (CML) who are resistant to dasatinib or nilotinib, who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation; 

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 Community) 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>Benzamide, 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]</p>
Active substanceBenzamide, 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]
Medicine NameIclusig
Disease/conditionTreatment of chronic myeloid leukaemia
Date of decision02/02/2010
OutcomePositive
Orphan decision numberEU/3/09/716

Review of designation

During its meeting of 16-17 April 2013, the Committee for Orphan Medicinal Products (COMP) reviewed the designations EU/3/09/715 and EU/3/09/716 for Iclusig (ponatinib1) as an orphan medicinal product for the treatment of acute lymphoblastic leukaemia and of chronic myeloid leukaemia. 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 conditions, and the existence of other methods of treatment. As other satisfactory methods of treatment for patients with these conditions are authorised in the European Union (EU), the COMP also looked at the significant benefit of the product over existing treatments. The COMP recommended that the orphan designations of the medicine be maintained2.


1Previously known as benzamide, 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]. 
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 Iclusig for the treatment of adult patients with:

  • chronic-phase, accelerated-phase or blast-phase chronic myeloid leukaemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation;
  • Philadelphia-chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) who are resistant to dasatinib; who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation.

This falls within the scope of the product’s designated orphan conditions, which are treatment of ALL and CML.

The COMP concluded that there had been no change in the seriousness of the conditions since the orphan designation in 2010. Despite the available treatments, ALL and CML remained long-term debilitating and life-threatening conditions.

Prevalence of the condition

The sponsor provided updated information on the prevalence of ALL and CML based on recent scientific literature and data from the Globocan 2008 database (which contains prevalence data for all types of leukaemia combined).

On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of ALL and CML remained 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 estimated to be approximately 1 in 10,000 people for ALL and 0.8 in 10,000 people for CML. In the EU, this is equivalent to a total of around 51,000 people for ALL and around 41,000 people for CML.

Existence of other satisfactory methods of treatment

At the time of the review of the orphan designation, several medicines were authorised in the EU for the treatment of ALL and CML, including imatinib, nilotinib and dasatinib, which are orphan medicines with a similar mechanism of action to Iclusig, known as ‘tyrosine-kinase inhibitors’ (TKIs). In addition, bosutinib, another TKI orphan medicine, had been authorised in March 2013 for the treatment of CML in patients for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options. Haematopoietic-stem-cell transplantation (a complex procedure where the patient receives stem cells from a matched donor to help restore the bone marrow) was used in some patients.

Significant benefit over existing treatments

The COMP concluded that the claim of a significant benefit of Iclusig in the treatment of ALL and CML was justified because this medicine represents a valuable treatment option for those patients who are intolerant or resistant to treatment with currently approved TKIs. This is based on a study involving 449 patients with CML or Ph+ ALL who were intolerant or resistant to treatment with dasatinib or nilotinib. A subgroup of patients who were resistant to bosutinib were also included in the study. The study showed that treatment with Iclusig led to clinically relevant responses in all groups of patients. In addition, Iclusig was shown effective in patients who have the T315I mutation, for which treatment with currently available TKIs including bosutinib does not work.

Therefore, although other satisfactory methods for the treatment of this condition have been authorised in the EU, the COMP concluded that Iclusig is of significant benefit for patients affected by ALL or CML.

Conclusions

Based on the data submitted and the scientific discussion within the COMP, the COMP considered that Iclusig still met the criteria for designation as an orphan medicinal product and that Iclusig should remain in the Community register of orphan medicinal products.

Sponsor’s contact details

Ariad Pharma Ltd
1 Northumberland Avenue
Trafalgar Square
London
WC2N 5BW
United Kingdom
Tel. +44 (0)20 7872 5869
Fax +44 (0)20 7872 5611
E-mail: christine.regan@ariad.com

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.