EU/3/04/192

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Orphan designation

On 8 March 2004, orphan designation (EU/3/04/192) was granted by the European Commission to Gregory Fryer Associates Limited, United Kingdom, for 3-(4'aminoisoindoline-1'-one)-1-piperidine-2,6-dione for the treatment of myelodysplastic syndromes. 

The sponsorship was transferred to Celgene Europe Limited in July 2005.

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

What are myelodysplastic syndromes?

Myelodysplastic syndromes are a distinct group of disorders in which the production of blood cells by the bone marrow is abnormal. The bone marrow is the spongy tissue found in the large bones. It has the function of producing red cells (which are the main carriers of oxygen to body tissues), white blood cells (which fight infection), and platelets (which make the blood clot). In myelodysplastic syndromes these cells do not grow and mature normally. Consequently, several symptoms can develop: fatigue or weakness (due to anaemia, red-cell deficit), infections (due to an decrease in white blood cells) or easy bruising or abnormal bleeding (platelet deficit). Myelodysplastic syndromes are life-threatening because they can result in severe anaemia, infections or haemorrhage and they can progress to acute leukaemia.

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

At the time of designation, myelodysplastic syndromes affected between 1 and 3 in 10,000 people in the European Union (EU). This was equivalent to a total of around 46,000 to 139,000 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 25), Norway, Iceland and Liechtenstein. At the time of designation, this represented a population of 464,200,000 (Eurostat 2004).

What treatments are available?

At the time of submission of the application for orphan-drug designation, there were no treatments authorised in the European Union. Available therapeutic options for myelodysplastic syndromes included supportive care methods (e.g. antibiotics to treat infections, blood or platelet transfusions for anaemia or bleeding respectively), the use of products such as erythropoietin (a substance that stimulates the bone marrow to produce red cells), chemotherapy (using drugs that can kill the abnormal cells), and bone-marrow transplantation.

How is this medicine expected to work?

3-(4'Aminoisoindoline-1'-one)-1-piperidine-2,6-dione mechanism of action is quite complex and only partly understood.

This substance acts at different levels: by modulating the immune system activity, by stimulating the growth of red blood cells (thus reducing the anaemia), and by inhibiting the growth of new blood vessels.

What is the stage of development of this medicine?

The effects of 3-(4'aminoisoindoline-1'-one)-1-piperidine-2,6-dione have been evaluated in experimental models.

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

The medicinal product was not marketed anywhere worldwide for myelodysplastic syndromes designated as an orphan medicinal product elsewhere for this condition, at the time of submission.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 5 February 2004 recommending the granting of this designation.

Update: 3-(4'aminoisoindoline-1'-one)-1-piperidine-2,6-dione (Revlimid) was authorised in the EU on 13 June 2013 for the treatment of patients with transfusion-dependent anaemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.

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>3-(4'Aminoisoindoline-1'-one)-1-piperidine-2,6-dione</p>
Active substance3-(4'Aminoisoindoline-1'-one)-1-piperidine-2,6-dione
Medicine Name
Disease/conditionTreatment of myelodysplastic syndromes
Date of decision07/03/2004
OutcomePositive
Orphan decision numberEU/3/04/192

Review of designation

During its meeting of 14-15 May 2013, the Committee for Orphan Medicinal Products (COMP) reviewed the designation EMA/OD/083/03 for Revlimid (lenalidomide, previously known as 3-(4'aminoisoindoline-1'-one)-1-piperidine-2,6-dione) as an orphan medicinal product for the treatment of myelodysplastic syndromes. 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 and prevalence of the conditions, and the existence of other satisfactory methods of treatment. As other methods of treatment for patients with myelodysplastic syndromes 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 maintained1.


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 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 Revlimid to include the following indication:

Treatment of patients with transfusion-dependent anaemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.

This falls within the scope of the product’s designated orphan condition, which is ‘treatment of myelodysplastic syndromes’.

The COMP concluded that there had been no change in the seriousness of the conditions since the orphan designation in 2004. Myelodysplastic syndromes remain long-term debilitating and life-threatening diseases because of the need of frequent blood transfusions and the risk of infections and bleeding.

Prevalence of the condition

The sponsor provided a review of recent scientific literature on the prevalence of myelodysplastic syndromes. On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of myelodysplastic syndromes 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 3 people in 10,000. This is equivalent to a total of fewer than 153,000 people in the EU.

Existence of other satisfactory methods of treatment

At the time of the review of the orphan designation, Vidaza (azacitidine) and Glivec (imatinib) were authorised in the EU for the treatment of myelodysplastic syndromes. However, Vidaza was only authorised for use in patients with higher-risk myelodysplastic syndromes, and Glivec was for use in patients with myelodysplastic / myeloproliferative syndromes associated with platelet-derived-growth-factor (PDGFR) gene re-arrangements, which represents a small minority of the myelodysplastic-syndrome patient population.

Haematopoietic (blood) stem-cell transplantation (a complex procedure where the patient receives stem cells from a matched donor to help restore the bone marrow) was the only potentially curative treatment for myelodysplastic syndromes, but because of its risks and the lack of suitable donors it was only considered in younger patients with high-risk disease.

Significant benefit over existing treatments

The COMP concluded that the claim of a significant benefit of Revlimid in myelodysplastic syndromes is justified because of its effectiveness in a sub-group of patients with lower risk myelodysplastic syndromes, for whom no authorised treatments are available. This is based on the results of a main study in 205 patients with lower risk myelodysplastic syndromes, which showed that 55% of patients treated with Revlimid did not need blood transfusions for at least six months, compared with 6% of patients who received placebo (a dummy treatment). In addition, patients treated with Revlimid had a clinically relevant increase in haemoglobin (the protein found in red blood cells that carries oxygen around the body).

Therefore, although other methods for treating some patients with myelodysplastic syndromes have been authorised in the EU, the COMP concluded that Revlimid is of significant benefit in myelodysplastic-syndrome therapy.

Conclusions

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

Sponsor’s contact details

Celgene Europe Limited
1 Longwalk Road
Stockley Park
Uxbridge
Middlesex
UB11 1DB
United Kingdom
Tel. +44 (0)20 8831 8300
Fax +44 (0)20 8831 8301
E-mail: medinfo.uk.ire@celgene.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.