EU/3/13/1133: Orphan designation for the treatment of cytomegalovirus disease in patients with impaired cell-mediated immunity

Cytomegalovirus is a common virus that usually only causes mild infection such as a sore throat. Most people get infected at some stage during their lifetime but are very often unaware of it. After infection, the virus usually remains in the body in a 'latent' (inactive) state and only becomes active if the body's immunity, specifically its cell-mediated immunity, is weakened.

Cell-mediated immunity is a defence mechanism where specialised cells called T lymphocytes directly neutralise viruses. In people with weakened cell-mediated immunity, such as transplant patients receiving immunosuppressant treatment (medicines that reduce the activity of the immune system), cytomegalovirus is not neutralised and cause severe infection.

Cytomegalovirus disease in patients with impaired cell-mediated immunity is long-term debilitating and life-threatening because of the complications it causes, such as inflammation of the eyes, lungs, liver and digestive tract, as well as reduced survival of transplanted organs or tissues in transplant patients.

At the time of designation, cytomegalovirus disease in patients with impaired cell-mediated immunity affected approximately 2 in 10,000 people in the European Union (EU). This was equivalent to a total of around 102,000 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 27), Norway, Iceland and Liechtenstein. This represents a population of 509,000,000 (Eurostat 2013).

At the time of designation, several antiviral medicines were authorised in the EU for the treatment of cytomegalovirus disease in patients with impaired cell-mediated immunity (cidofovir, foscarnet, ganciclovir, valaciclovir and valganciclovir).
The sponsor has provided sufficient information to show that maribavir might be of significant benefit for the treatment of cytomegalovirus disease in patients with impaired cell-mediated immunity because there is evidence that it may be effective in patients with cytomegalovirus disease resistant to existing antiviral medicines. This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.

When cytomegalovirus multiplies during an infection, its genetic material (DNA) is replicated and packaged into small protein shells, giving rise to newly formed viruses that can proceed to infect other cells. Maribavir is thought to block the action of an enzyme of the virus called UL97 kinase, which is involved in packaging the DNA in the protein shells and releasing new viruses. By blocking the enzyme, the medicine is expected to prevent viruses from reaching maturity, so that no new infectious viruses can be produced.

The effects of maribavir have been evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials with maribavir in patients with cytomegalovirus disease and impaired cellular immunity were ongoing.

At the time of submission, maribavir was not authorised anywhere in the EU for treatment of cytomegalovirus disease. Orphan designation of maribavir was previously granted in the EU for prevention of cytomegalovirus disease in patients at risk. Orphan designations had also been granted in the United States for prevention and treatment of cytomegalovirus disease in at-risk patients.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 17 April 2013 recommending the granting of this designation.

• 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.