EU/3/07/524: 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. The disease 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.

At the time of designation, tuberculosis affected approximately 2 in 10,000 people in the European Union (EU). This was equivalent to a total of 101,000 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. At the time of designation, this represented a population of 502,800,000 (Eurostat 2008).

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 (R)-2-Methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole 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.

(R)-2-Methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole inhibits the production of mycolic acid, which is an exclusive component of the external wall of mycobacteria, the bacteria causing tuberculosis. The cell wall protects the bacteria from the outside and from external aggressions; its disruption can kill the bacteria.

The effects of (R)-2-Methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole were evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials in patients with tuberculosis were ongoing.

(R)-2-Methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole was not authorised anywhere worldwide for treatment of tuberculosis, at the time of submission. Orphan designation was granted in the United States for the condition.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 5 December 2007 recommending the granting of this designation.

Update: (R)-2-Methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (Deltyba) has been authorised in the EU since 28 April 2014 for use as part of an appropriate combination regimen for pulmonary multi-drug resistant tuberculosis (MDR-TB) in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability.

• 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