EU/3/10/765

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Orphan designation

On 4 August 2010, orphan designation (EU/3/10/765) was granted by the European Commission to Novartis Europharm Limited, United Kingdom, for midostaurin for the treatment of mastocytosis.

Midostaurin for treatment of mastocytosis has been authorised in the EU as Rydapt since 18 September 2017.

What is mastocytosis?

Mastocytosis is a disorder in which there are too many mast cells in various organs in the body. Mast cells are a type of white blood cells that originate in the bone marrow and then migrate to other parts of the body such as the skin and intestine, where they take part in defending against infections and contribute to the development of allergic reactions by releasing a number of substances including histamine.

The symptoms of mastocytosis vary from patient to patient. In children, usually this disorder only affects the skin (‘cutaneous mastocytosis’) and causes a red and itchy rash, which may disappear on its own. In some patients, mainly adults, the disorder progresses into ‘systemic mastocytosis’, in which the mast cells become aggressive tumours that infiltrate organs, such as the intestine, the liver, the spleen and the bone marrow. This causes various symptoms such as palpitations and fainting, bone pain, tiredness, weight loss, diarrhoea, nausea (feeling sick), vomiting and stomach ache.

Mastocytosis is a condition that is debilitating in the long term and may be life threatening in those patients who develop the systemic form of the disorder.

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

At the time of designation, mastocytosis affected approximately 0.9 in 10,000 people in the European Union (EU). This was equivalent to a total of around 46,000 people*, and is below the threshold 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).


*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?

At the time of designation, only treatments aimed at relieving the symptoms of mastocytosis were available. They included antihistamines to block the action of histamine produced by the mast cells.

The sponsor has provided sufficient information to show that midostaurin might be of significant benefit for patients with mastocytosis because early studies indicate that it might slow down the progression of the disorder. 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?

Midostaurin is expected to work by blocking types of enzymes known as tyrosine kinases. These enzymes can be found in some receptors on the surface of mast cells, including the ‘KIT’ receptors, which are involved in stimulating the growth of mast cells in mastocytosis. By blocking these receptors, midostaurin is expected to control the growth of mast cells, slowing down the progression of mastocytosis.

What is the stage of development of this medicine?

The effects of midostaurin have been evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials with midostaurin in patients with mastocytosis were ongoing.

At the time of submission, midostaurin was not authorised anywhere in the EU for mastocytosis. Orphan designation of midostaurin had been granted in the United States of America for this condition.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 6 May 2010 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.

Name Language First published Last updated
EU/3/10/765: Public summary of opinion on orphan designation of Midostaurin for the treatment of mastocytosis (English only) 2010-08-10 2015-02-10

Key facts

Product details for <p>Midostaurin</p>
Active substanceMidostaurin
Medicine NameRydapt
Disease/conditionTreatment of mastocytosis
Date of decision04/08/2010
OutcomePositive
Orphan decision numberEU/3/10/765

Review of designation

On 25 July 2017, the Committee for Orphan Medicinal Products (COMP) completed a review of the designations EU/3/04/214 and EU/3/10/765 for Rydapt (midostaurin) as an orphan medicinal product for the treatment of acute myeloid leukaemia (AML) and mastocytosis. 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 methods of treatment are authorised in the European Union (EU), the COMP also considered whether the medicine is of significant benefit to patients with AML and mastocytosis. The COMP recommended that the orphan designations of the medicine be maintained[1].


[1] The 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 Rydapt for:

  • ‘Acute myeloid leukaemia (AML)

In combination with standard daunorubicin and cytarabine induction and high dose cytarabine consolidation chemotherapy, and for patients in complete response followed by Rydapt single agent maintenance therapy, for adult patients with newly diagnosed acute myeloid leukaemia (AML) who are FLT3 mutation positive

  • Aggressive systemic mastocytosis

As monotherapy for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated haematological neoplasm (SM AHN), or mast cell leukaemia (MCL)’

This falls within the scope of the product’s designated orphan indications, which are: ‘treatment of acute myeloid leukaemia’ and ‘treatment of mastocytosis’.

The COMP concluded that there had been no change in the seriousness of the conditions since the orphan designations in 2004 (AML) and 2010 (mastocytosis). AML and mastocytosis remain conditions that are progressive, debilitating in the long term and life threatening, particularly due to bone marrow failure.

Prevalence of the condition

The sponsor provided updated information on the prevalence of AML and mastocytosis based on data from European registries and the RARECARE database.

On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of AML 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 approximately 1 person in 10,000. This is equivalent to a total of around 52,000 people in the EU.

Similarly, the COMP also concluded that the prevalence of mastocytosis remains below the ceiling for orphan designation. At the time of the review of the orphan designation, the prevalence was estimated to be approximately 2.5 people in 10,000. This is equivalent to a total of around 129,000 people in the EU.

Existence of other methods of treatment

At the time of the review of the orphan designation, other treatments were authorised in the EU for the treatment of AML and mastocytosis. The main treatments for AML were chemotherapy (medicines to treat cancer) and haematopoietic (blood) stem-cell transplantation (a procedure where the patient’s bone marrow is cleared of cells and replaced by stem cells to form new bone marrow that produces healthy blood cells). For mastocytosis, only treatments aimed at relieving the symptoms of mastocytosis were available. They included antihistamines to block the action of histamine produced by the mast cells.

Significant benefit of Rydapt

The COMP concluded that the claim of a significant benefit of Rydapt in AML is justified on the basis of studies showing improved survival compared with placebo (a dummy treatment) when the medicine was added to standard treatment in patients whose AML showed a particular genetic change known as an FLT3 mutation. Other available treatments do not specifically target this particular group, for whom Rydapt is considered to provide a clinically relevant advantage.

The COMP also concluded that the claim of a significant benefit of Rydapt in mastocytosis is justified on the basis of improved survival in patients with advanced systemic mastocytosis. Since the existing treatments only target specific symptoms of the disease, this was also considered to be a clinically relevant advantage.

Therefore, although other methods for the treatment of these conditions have been authorised in the EU, the COMP concluded that Rydapt is of significant benefit to patients affected by AML or mastocytosis.

Conclusions

Based on the data submitted and the scientific discussion within the COMP, the COMP considered that Rydapt 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 July 2017 COMP minutes.

Sponsor’s contact details

Novartis Europharm Limited
Frimley Business Park
Camberley GU16 7SR
United Kingdom
Tel. +41 61 324 11 11 (Switzerland)
E-mail: orphan.enquiries@novartis.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.