EU/3/09/620

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Orphan designation

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

On 3 April 2009, orphan designation (EU/3/09/620) was granted by the European Commission to Incyte Corporation Ltd, United Kingdom, for (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate for the treatment of myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia.

The sponsorship was transferred to Novartis Europharm Limited, United Kingdom, in September 2010.

What is myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia?

Myelofibrosis is a disease in which the bone marrow (the spongy tissue inside the large bones in the body) becomes very dense and rigid, and produces abnormal and immature blood cells that replace the normal blood cells. It can develop as a reaction to polycythaemia vera (overproduction of red blood cells) or essential thrombocythaemia (overproduction of platelets, components that help the blood to clot). ‘Essential’ means that the thrombocythaemia is not caused by any known condition.

In myelofibrosis, some immature blood cells migrate from the bone marrow to other organs, such as the spleen and liver, where they mature. This causes the organs to become enlarged. Patients with myelofibrosis can develop several symptoms, including pain in the bones, tiredness, weakness, infections and bleeding.

Myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia is a debilitating disease that is long-lasting and may be life-threatening because it can lead to severe anaemia (low red-blood-cell counts) and infections, and can result in leukaemia (cancer of the white blood cells).

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

At the time of designation, myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia affected approximately 0.01 in 10,000 people in the European Union (EU). This was equivalent to a total of around 500 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 502,800,000 (Eurostat 2008).

What treatments are available?

At the time of designation, although hydroxyurea was authorised in the EU for idiopathic myelofibrosis (myelofibrosis of unknown cause), it was not authorised for myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia.

Treatments for this condition were aimed at relieving the symptoms of the disease, and included androgens (male hormones), glucocorticoids (a type of steroid) and erythropoietin (a hormone that stimulates the production of red blood cells) to treat anaemia, and surgery to remove the enlarged spleen. In some patients, bone-marrow transplantation was used. This is a complex procedure where the bone marrow of the patient is destroyed and replaced with bone marrow from a matched donor.

How is this medicine expected to work?

This medicine is thought to work by blocking some enzymes known as Janus kinases (JAKs). These enzymes can be found in some receptors on the surface of cells and are involved in the reproduction and growth of blood cells. In myelofibrosis, JAKs are overactivated. By blocking the enzymes, this medicine is expected to slow down the abnormal growth of blood cells, reducing the symptoms of the disease.

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 in patients with myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia were ongoing.

At the time of submission, this medicine was not authorised anywhere in the EU for myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia. Orphan designation of this medicine had been granted in the EU for chronic idiopathic myelofibrosis and in the United States for myelofibrosis.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 9 February 2009 recommending the granting of this designation.

Update: (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate (Jakavi) was authorised in the EU on 23 August 2012 for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythaemia-vera myelofibrosis or post-essential-thrombocythaemia myelofibrosis.

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 European Union) 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>(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate</p>
Active substance(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate
Medicine NameJakavi
Disease/conditionTreatment of myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia
Date of decision03/04/2009
OutcomePositive
Orphan decision numberEU/3/09/620

Review of designation

During its meeting of 10-11 May 2012, the Committee for Orphan Medicinal Products (COMP) reviewed the designations EU/3/08/572 and EU/3/09/620 for Jakavi (ruxolitinib1) as an orphan medicinal product for the treatment of chronic idiopathic myelofibrosis and myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia. 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 satisfactory methods of treatment. As other satisfactory methods of treatment for patients with chronic idiopathic myelofibrosis 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 designation of the medicine be maintained2.


1At time of orphan designation ruxolitinib was known as (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate.
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 Jakavi for 'the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythaemia-vera myelofibrosis or post-essential-thrombocythaemia myelofibrosis’.

This falls within the scope of the product’s designated orphan conditions, which are ‘chronic idiopathic myelofibrosis’, and ‘myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia’.

The COMP concluded that there had been no change in the seriousness of the conditions since the orphan designations in 2008 and 2009. Chronic idiopathic myelofibrosis and myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia are conditions that are debilitating in the long term and life-threatening, particularly due to the development of pancytopenia (low blood cell count), splenomegaly (enlarged spleen), hepatomegaly (enlarged liver) and leukaemia.

Prevalence of the condition

The sponsor provided recent scientific literature on the prevalence of chronic idiopathic myelofibrosis and myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia in the EU. On the basis of this information and the knowledge of the COMP, the COMP concluded that the prevalence of these conditions 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 for chronic idiopathic myelofibrosis was estimated to be approximately 0.3 people in 10,000, and for myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia it was estimated to be less than 0.3 people in 10,000. This is equivalent to a total of around, or fewer than, 15,000 people in the EU for each condition, respectively.

Existence of other satisfactory methods of treatment

At the time of the review of the orphan designation, hydroxycarbamide and busulfan were authorised in the EU for chronic idiopathic myelofibrosis, but there were no treatments authorised specifically for myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia. Medicines were authorised to treat the symptoms of these diseases, including erythropoietin to treat anaemia, and surgery or radiation were used to remove or shrink the enlarged spleen.

Significant benefit over existing treatments

The COMP noted that, for myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia, no justification of significant benefit over existing treatments was needed as no alternative treatments were authorised in the EU at time of the review.

Regarding the treatment of chronic idiopathic myelofibrosis, the COMP noted that Jakavi works in a different way to authorised treatments, inhibiting enzymes known as Janus kinases (JAKs) 1 and 2, which are known to be overactivated in patients with this condition. More importantly, the COMP noted that in two main phase-III studies, the medicine significantly reduced the spleen volume and improved the symptoms of the disease compared with placebo or best available treatment. In the first study, which compared Jakavi with placebo, the significant benefit of the medicine was demonstrated by its efficacy in patients who could not be treated or did not respond to other available treatments. The second study showed improved efficacy of Jakavi as compared with best available treatments. In particular, 29% of patients receiving Jakavi experienced a reduction in spleen size by at least 35% following 48 weeks of treatment, compared with zero patients receiving best available treatment.

Therefore, although other satisfactory methods for the treatment of chronic idiopathic myelofibrosis have been authorised in the EU, the COMP concluded that Jakavi is of significant benefit for patients affected by this condition.

Conclusions

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

Sponsor’s contact details

Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex
RH12 5AB
United Kingdom
Tel. +44 (0)1403 272827
Fax +44 (0)1403 323060
E-mail: carol.beauchamp@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.