EU/3/07/513: Orphan designation for the treatment of tuberculosis

Tuberculosis is an infection caused by a group of bacteria called Mycobacterium. It spreads from person-to-person by inhaling the infected airborne droplets generated by sneezing and coughing. The manifestation of the disease is variable and not all patients who are infected will develop the disease. Tuberculosis is characterised by fever, cough and breathing difficulties. The infection by the tuberculosis bacteria induces formation of granulomas, which are accumulations of large numbers of cells leading to chronic inflammatory lesions. Granulomas can develop in any tissue, but occur most often in the lungs (pulmonary tuberculosis). Tuberculosis can also affect the central nervous system (meningitis), lymphatic system, genitourinary system, bones and joints. Tuberculosis is a life-threatening condition.

The treatment of tuberculosis consists of the administration of a combination of antibiotics for long periods of time. Several medicinal products were authorised for the condition in the Community, at the time of submission of the application for orphan designation. Satisfactory argumentation has been submitted by the sponsor to justify the assumption that (S)-2-nitro-6-(4-trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo[2,1-b] [1,3] oxazine might be of potential significant benefit for the treatment of tuberculosis, mainly because it might improve the long-term outcome of the patients. The assumption of benefit will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

Based on the information provided by the sponsor and previous knowledge of the Committee, tuberculosis was considered to affect approximately 2 in 10,000 persons in the European Union, which, at the time of designation, corresponded to about 100,000 persons in total.

*Disclaimer: For the purpose of the designation, the number of patients affected by the condition is estimated and assessed based on data from the European Union (EU 27), Norway, Iceland and Lichtenstein. This represents a population of 498,000,000 (Eurostat 2006). This estimate is based on available information and calculations presented by the sponsor at the time of the application.

(S)-2-nitro-6-(4-trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo[2,1-b] [1,3] oxazine is considered as a potential anti-mycobacterial agent. It acts by inhibiting (blocking) the building of the mycobacterial cell wall components. The cell wall protects the microorganism from the outside and from external aggressions; its disruption can kill the microorganism.

The effects of (S)-2-nitro-6-(4-trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo[2,1-b] [1,3] oxazine have been evaluated in experimental models.

At the time of submission of the application for orphan designation, no clinical trials in patients with tuberculosis had been initiated.

(S)-2-nitro-6-(4-trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo[2,1-b] [1,3] oxazine had not been authorised anywhere worldwide for tuberculosis, at the time of submission. Orphan designation of the (S)-2-nitro-6-(4-trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo[2,1-b] [1,3] oxazine had been granted in the United States for the treatment of tuberculosis.

According to Regulation (EC) No 141/2000 of 16 December 1999, the Committee for Orphan Medicinal Products (COMP) adopted on 10 October 2007 a positive opinion recommending the grant of the above-mentioned designation.

• the seriousness of the condition,
• the existence or not of alternative methods of diagnosis, prevention or treatment and
• either the rarity of the condition (considered to affect not more than five in ten thousand persons in the Community) or the insufficient return of development investments.

Designated orphan medicinal products are still investigational products which were considered for designation on the basis of potential activity. An orphan designation is not a marketing authorisation. As a consequence, demonstration of the quality, safety and efficacy will be necessary before this product can be granted a marketing authorisation.