EU/3/07/518 - orphan designation for treatment of pulmonary arterial hypertension

Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carbamate (riociguat)  

Overview

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.

The sponsorship was transferred to Bayer AG, Germany, in August 2017.

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

This medicine is now known as riociguat.

Please note that this product was withdrawn from the Community Register of designated orphan medicinal products in June 2022 upon request of the marketing authorisation holder.

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).

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*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.

EU/3/07/518: Public summary of positive opinion for orphan designation of 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 arteria...

AdoptedReference Number: EMEA/COMP/35953/2008 Rev.3

Key facts

• Active substance:
  Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carbamate (riociguat)
• Medicine name:
  Adempas
• Intended use:
  Treatment of pulmonary arterial hypertension
• Orphan designation status:
  Withdrawn
• EU designation number:
  EU/3/07/518
• Date of designation:
  20/12/2007
• Sponsor:

  Bayer AG; 51368 Leverkusen; Germany; Tel. [phone]; E-mail: [e-mail]

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.

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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.