EU/3/11/899

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Orphan designation

On 27 September 2011, orphan designation (EU/3/11/899) was granted by the European Commission to Takeda Global Research and Development Centre (Europe) Ltd., United Kingdom, for 2,2'-{2-[(1R)-1-({[(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid (also known as ixazomib citrate) for the treatment of multiple myeloma.

In November 2013, Takeda Global Research and Development Centre (Europe) Ltd changed name to Takeda Development Centre Europe Ltd.

The sponsorship was transferred to Takeda Pharma A/S, Denmark, in March 2015.

2,2'-{2-[(1R)-1-({[(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid has been authorised in the EU as Ninlaro since 21 November 2016.

What is multiple myeloma?

Multiple myeloma is a cancer of a type of white blood cell called plasma cells. Plasma cells are found in the bone marrow, the spongy tissue inside the large bones in the body. In multiple myeloma, the division of plasma cells becomes out of control, resulting in abnormal, immature plasma cells multiplying and filling up the bone marrow. This interferes with production of normal white blood cells, red blood cells and platelets (components that help the blood to clot), leading to complications such as anaemia (low red blood cell counts), bone pain and fractures, raised blood calcium levels and kidney disease.

Multiple myeloma is a debilitating and life-threatening disease that is associated with poor long-term survival.

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

At the time of designation, multiple myeloma affected approximately 2.4 in 10,000 people in the European Union (EU). This was equivalent to a total of around 122,000 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 507,700,000 (Eurostat 2011).

What treatments are available?

At the time of designation, several medicines were authorised for multiple myeloma in the EU. The main treatment for multiple myeloma was chemotherapy (medicines to treat cancer) usually combined with steroids to reduce the activity of the immune system, the body’s natural defences. Where chemotherapy did not work, some patients received an allogenic stem-cell transplant (a complex procedure where the patient receives stem cells from a matched donor to help restore the bone marrow). Radiotherapy (treatment with radiation) was used in treating pain and weakened bones. Interferon alfa, a protein normally produced by the body during viral infections, was sometimes used in combination with chemotherapy.

The sponsor has provided sufficient information to show that this medicine might be of significant benefit for patients with multiple myeloma because it may improve the outcome of patients, particularly if used in combination with other treatments in patients whose cancer is otherwise not responsive to treatment or has come back. 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 a proteasome inhibitor. It blocks the proteasome, which is an enzyme complex within the cells that breaks down proteins when they are no longer needed. When the proteins in the cancer cells are not broken down, including the proteins that control cell growth, the cancer cells are damaged and to eventually die. The medicine is expected to be taken by mouth.

What is the stage of development of this medicine?

The effects of this medicine 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 multiple myeloma were ongoing.

At the time of submission, this medicine was not authorised anywhere in the EU for multiple myeloma. Orphan designation had been granted in the United States for the treatment of multiple myeloma.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 8 July 2011 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.

Key facts

Product details for <p>2,2'-{2-[(1R)-1-({[(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid</p>
Active substance2,2'-{2-[(1R)-1-({[(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid
Medicine NameNinlaro
Disease/conditionTreatment of multiple myeloma
Date of decision27/09/2011
OutcomePositive
Orphan decision numberEU/3/11/899

Review of designation

During its meeting of 4 to 6 October 2016, the Committee for Orphan Medicinal Products (COMP) reviewed the designation EU/3/11/899 for Ninlaro (ixazomib1)as an orphan medicinal product for the treatment of multiple myeloma. 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 multiple myeloma. The COMP recommended that the orphan designation of the medicine be maintained2.


1Previously known as 2,2'-{2-[(1R)-1-({[(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid.

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 the same 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 Ninlaro in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.

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

The COMP concluded that there had been no change in the seriousness of the condition since the orphan designation in 2011. Multiple myeloma remains a debilitating and life-threatening disease because it disrupts the normal functioning of the bone marrow, damages the bones and causes kidney failure.

Prevalence of the condition

The sponsor provided updated information on the prevalence of multiple myeloma based on data from the scientific literature and 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 multiple myeloma 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 estimated to be less than 4 people in 10,000. This is equivalent to a total of fewer than 205,000 people in the EU.

Existence of other methods of treatment

At the time of the review of the orphan designation, bortezomib, carfilzomib, doxorubicin, elotuzumab and lenalidomide were authorised in the EU for the treatment of multiple myeloma in patients who had received a previous treatment (‘second-line therapy’).

Significant benefit of Ninlaro

The COMP concluded that the claim of a significant benefit of Ninlaro in multiple myeloma is justified because it is taken by mouth together with two other oral medicines, lenalidomide and dexamethasone, meaning that patients who received a previous treatment and require triple therapy can conveniently take their medicines at home. In addition, Ninlaro is well tolerated by patients, and does not seem to significantly increase the frequency of serious side effects when added to lenalidomide and dexamethasone.

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

Conclusions

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

More information on the COMP assessment can be found in the October 2016 COMP minutes.

Further information on Ninlaro can be found in the European public assessment report (EPAR) on the Agency’s website.

Related information

Sponsor’s contact details

Takeda Pharma A/S
Dybendal Alle 10
2630 Taastrup
Denmark
Tel. +45 4677 1111
Fax +45 4675 6640
http://www.takeda.dk/kontakt/

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.