EU/3/07/518

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Orphan designation

On 20 December 2007, orphan designation (EU/3/07/518) was granted by the European Commission to Bayer HealthCare AG, Germany, for Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4 b]pyridine-3-yl]-5-pyrimidinyl(methyl)carbamate for the treatment of pulmonary arterial hypertension including chronic thromboembolic pulmonary hypertension.

The sponsorship was transferred to Bayer Schering Pharma AG, Germany, in April 2009. Bayer Shering Pharma AG changed its name to Bayer Pharma AG in October 2011.

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

What is pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension?

Pulmonary arterial hypertension is a rare blood vessel disorder of the lung in which the pressure in the pulmonary artery (the blood vessel that leads from the heart to the lungs) rises above normal levels. An increase of the number of smooth muscle cells in the walls of small lung arteries (a phenomenon called proliferation) that are remodelling the vessels, may lead to obstructions in the microcirculation, which will then lead to an increase in the blood pressure.

Chronic thromboembolic pulmonary hypertension is a complication representing less than 1% of all cases of acute pulmonary embolism (the sudden blocking of a lung artery by a clot or foreign material which has been brought to its site by the blood current), which directly leads to pulmonary hypertension. Pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension are chronically debilitating and life-threatening.

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

At the time of designation, pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension affected less than 2 in 10,000 people in the European Union (EU). This was equivalent to a total of fewer than 100,000 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 500,300,000 (Eurostat 2007).

What treatments are available?

Several medicinal products were authorised for the treatment of pulmonary arterial hypertension in the Community at the time of submission of the application for orphan drug designation. Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carbamate might be of potential significant benefit for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension, in particular with regards to improved efficacy based on the new mechanism of action. This benefit will have to be confirmed at the time of marketing authorisation and will be necessary to maintain the orphan status.

How is this medicine expected to work?

One of the mechanisms that contributes to pulmonary arterial hypertension is the body’s ability to increase the thickness of the pulmonary vessels. In pulmonary arterial hypertension this ability is not well regulated and the vessels become more narrow. As the inner space of the vessels becomes smaller, it is increasingly difficult for blood to go through the vessels and the disease worsens.

Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl) carbamate is expected to stimulate a protein called soluble guanylate cyclase (sGC) that is present in vascular cells and platelets. Since activation of the sGC protein may lead to dilatation of blood vessels, inhibition of cell proliferation and cell migration, a favourable effect on the condition is expected.

What is the stage of development of this medicinal product?

At the time of submission, the effects of Methyl 4, 6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3, 4-b] pyridine-3-yl]-5-pyrimidinyl (methyl) carbamate were evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials in patients with pulmonary arterial hypertension including chronic thromboembolic pulmonary hypertension were completed.

Methyl4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl) carbamate was not authorised anywhere worldwide for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension or designated as 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 8 November 2007 recommending the granting of this designation.

Update: Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carbamate (Adempas) has been authorised in the EU since 27 March 2014 for the following therapeutic indications:

Chronic thromboembolic pulmonary hypertension (CTEPH)
Adempas is indicated for the treatment of adult patients with WHO Functional Class (FC) II to III with

  • inoperable CTEPH,
  • persistent or recurrent CTEPH after surgical treatment,

to improve exercise capacity.

Pulmonary arterial hypertension (PAH)
Adempas, as monotherapy or in combination with endothelin receptor antagonists, is indicated for the treatment of adult patients with pulmonary arterial hypertension (PAH) with WHO Functional Class (FC) II to III to improve exercise capacity.

Efficacy has been shown in a PAH population including aetiologies of idiopathic or heritable PAH or PAH associated with connective tissue disease.

More information on Adempas can be found in the European public assessment report (EPAR).

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>Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carbamate</p>
Active substanceMethyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carbamate
Medicine NameAdempas
Disease/conditionTreatment of pulmonary arterial hypertension
Date of decision19/12/2007
OutcomePositive
Orphan decision numberEU/3/07/518

Review of designation

During its meeting of 4 to 6 February 2014, the Committee for Orphan Medicinal Products (COMP) reviewed the designation EU/3/07/518 for Adempas (riociguat1) as an orphan medicinal product for the treatment of pulmonary arterial hypertension including chronic thromboembolic pulmonary hypertension. 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 satisfactory methods of treatment. As other methods of treatment for patients with this condition 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.


1Previously known as methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4 b]pyridine-3-yl]-5-pyrimidinyl(methyl) carbamate.

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 Adempas for:

  • treatment of adult patients with WHO functional class II to III with inoperable chronic thromboembolic pulmonary hypertension (CTEPH), or persistent or recurrent CTEPH after surgical treatment, to improve exercise capacity.
  • treatment, as monotherapy or in combination with endothelin receptor antagonists, of adult patients with pulmonary arterial hypertension (PAH) with WHO functional class II to III, to improve exercise capacity.

This falls within the scope of the product’s designated orphan indication, which is: ‘treatment of pulmonary arterial hypertension including chronic thromboembolic pulmonary hypertension’.

The COMP concluded that there had been no change in the seriousness of the conditions since the orphan designation in 2007. PAH and CTEPH remain long-term debilitating and life threatening conditions that shorten patients’ life expectancy because they may lead to heart failure.

Prevalence of the condition

The sponsor provided updated information on the prevalence of PAH and CTEPH from the scientific literature.

On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of PAH and CTEPH 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 still estimated to be less than 2 people in 10,000. This is equivalent to a total of fewer than 102,000 people in the EU.

Existence of other satisfactory methods of treatment

At the time of the review of the orphan designation, surgery was a curative treatment for some patients with CTEPH. However, no medicines were authorised in the EU for the treatment of patients with inoperable CTEPH or those in whom CTEPH remained or returned after surgery.

For PAH, several medicines were authorised in the EU, including medicines belonging to the groups called prostanoids (such as epoprostenol, iloprost and treprostinil), PDE5 inhibitors (such as sildenafil and tadalafil), and endothelin receptor antagonists (such as bosentan and ambrisentan).

Significant benefit over existing treatments

The COMP concluded that the claim of a significant benefit of Adempas in the treatment of PAH and CTEPH is justified on the basis of data from 2 main clinical studies, one in 445 patients with PAH and the other in 262 patients with CTEPH. The study in PAH showed that Adempas significantly improved the distance patients could walk in six minutes (a valid measure of exercise capacity) when the medicine was used on its own or as an add-on to currently authorised treatments. Adempas works in a different way to currently authorised treatments, and the study with Adempas in PAH patients demonstrates the benefit of combining differently acting treatments.

Improvements in walking distance were also seen in the study in CTEPH, which included patients with inoperable disease and those in whom CTEPH remained or returned after surgery, for whom no alternative treatment is available.

Therefore, although other satisfactory methods for the treatment of PAH including CTEPH exist in the EU, the COMP concluded that Adempas is of significant benefit for patients with this condition.

Conclusions

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

Further information on the current regulatory status of Adempas can be found in the European public assessment report (EPAR) on the Agency’s website.

Related information

Sponsor’s contact details

Bayer Pharma AG
13342 Berlin
Germany
Tel. +49 2143 051348
Fax +49 2143 051603
E-mail: medical-information@bayerhealtcare.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.