EU/3/20/2322 - orphan designation for treatment of sickle cell disease

6-((3S,4S)-4-methyl-1-(pyrimidin-2-yl-methyl)pyrrolidin-3-yl)-3-tetrahydropyran-4-yl-7H-imidazo(1,5-a)pyrazin-8-one (Tovinontrine)

Overview

Please note that this product was withdrawn from the Union Register of orphan medicinal products in October 2022 on request of the Sponsor.

On 21 August 2020, orphan designation EU/3/20/2322 was granted by the European Commission to TMC Pharma (EU) Limited, Ireland, for 6-((3S,4S)-4-methyl-1-(pyrimidin-2-yl-methyl)pyrrolidin-3-yl)-3-tetrahydropyran-4-yl-7H-imidazo(1,5-a)pyrazin-8-one (also known IMR-687) for the treatment of sickle cell disease.

 

What is sickle cell disease?

Sickle cell disease is a genetic disease in which the red blood cells become rigid and sticky and change from being disc-shaped to being crescent-shaped (like a sickle). The change in shape is caused by the presence of an abnormal form of haemoglobin, the protein in red blood cells that carries oxygen around the body. In patients with sickle cell disease, the abnormal red blood cells attach to walls of blood vessels and block them, restricting the flow of nutrients and oxygen to the internal organs, such as the heart, the lungs, and the spleen. Episodes of such blockages (called vaso-occlusive crises) cause severe pain and damage to these organs. Since the abnormal red blood cells have a shorter life span, the disease also causes anaemia (low red blood cell counts).

Sickle cell disease is a severe disease that is long lasting and may be life threatening because of its effects on the heart and the lungs.

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

At the time of designation, sickle cell disease affected approximately 2 in 10,000 people in the European Union (EU). This was equivalent to a total of around 104,000 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).

---

*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, Iceland, Liechtenstein, Norway and the United Kingdom. This represents a population of 519,200,000 (Eurostat 2020).

What treatments are available?

At the time of designation, the medicine hydroxycarbamide was authorised in the EU for sickle cell disease. Symptoms of the condition were treated with painkillers and by increasing fluid intake. Blood transfusions were used to treat anaemia and increase the blood’s capacity to carry oxygen. Medicines called iron chelators were also used to reduce the high iron levels in the body caused by repeated blood transfusions. In some cases, patients also had haematopoietic stem cell transplantation (a procedure where the patient receives stem cells from a matched donor to help restore the bone marrow) to allow them to produce red blood cells containing normal haemoglobin.

The sponsor has provided sufficient information to show that the medicine might be of significant benefit for patients with sickle cell disease because data from early studies showed that taking the medicine in combination with hydoxycarbamide reduced vaso-occlusive crises. 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?

The medicine is thought to work by encouraging the red cells forming in the bone marrow to produce a form of haemoglobin called fetal haemoglobin. Red cells that contain this type of haemoglobin become resistant to sickling and sticking together. The medicine may also stop white blood cells from sticking to the blood vessel walls. The actions of this medicine are expected to reduce blockages in blood vessels and so reduce symptoms of sickle cell disease.

What is the stage of development of this medicine?

The effects of the medicine have been evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials with the medicine in patients with sickle cell disease were ongoing.

At the time of submission, the medicine was not authorised anywhere in the EU for the treatment of sickle cell disease. Orphan designation of the medicine had been granted in the United States for the treatment of sickle cell disease.

In accordance with Regulation (EC) No 141/2000, the COMP adopted a positive opinion on 16 July 2020, 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.

EU/3/20/2322: Public summary of opinion on orphan designation: 6-((3S,4S)-4-Methyl-1-(pyrimidin-2-yl-methyl)pyrrolidin-3-yl)-3-tetrahydropyran-4-yl-7H-imidazo(1,5-a)pyrazin-8-one for the treatment of sickle cell disease

Adopted Reference Number: EMADOC-628903358-2749

Key facts

• Active substance:
  6-((3S,4S)-4-methyl-1-(pyrimidin-2-yl-methyl)pyrrolidin-3-yl)-3-tetrahydropyran-4-yl-7H-imidazo(1,5-a)pyrazin-8-one (Tovinontrine)
• Intended use:
  Treatment of sickle cell disease
• Orphan designation status:
  Withdrawn
• EU designation number:
  EU/3/20/2322
• Date of designation:
  21/08/2020
• Sponsor:

  TMC Pharma (EU) Limited; 7A Durands Court; 45 Parnell Street; Waterford; Co. Waterford; X91 P381; Ireland; Tel. + 353766705745; E-mail: [e-mail]

Review of designation

The Committee for Orphan Medicinal Products reviews the orphan designation of a product if it is approved for marketing authorisation.