EU/3/07/524

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Orphan designation

On 1 February 2008, orphan designation (EU/3/07/524) was granted by the European Commission to Otsuka Pharmaceutical Europe Ltd, United Kingdom, for (R)-2-Methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole for the treatment of tuberculosis.

The sponsorship was transferred to Otsuka Novel Products GmbH, Germanz, in September 2011.

For a list of the administrative updates to this public summary of opinion please refer to the PDF document below.

What is 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.

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

t 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 isbased 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).

What treatments are available?

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.

How is this medicine expected to work?

(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.

What is the stage of development of this medicine?

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.

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

Key facts

Product details for <p>(R)-2-Methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole</p>
Active substance(R)-2-Methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole
Medicine NameDeltyba
Disease/conditionTreatment of tuberculosis
Date of decision01/02/2008
OutcomePositive
Orphan decision numberEU/3/07/524

Review of designation

During its meeting of 11 to 12 March 2014, the Committee for Orphan Medicinal Products (COMP) reviewed the designation EU/3/07/524 for Deltyba (delamanid)1 as an orphan medicinal product for the treatment of tuberculosis. 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 methods of treatment. As other methods of treatment for patients with tuberculosis 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 Deltyba be maintained2.


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

2 The 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.

Life-threatening or chronically debilitating nature of the condition

The Committee for Medicinal Products for Human Use (CHMP) recommended the authorisation of Deltyba for:

‘use as part of an appropriate combination regimen for pulmonary multi-drug resistant tuberculosis in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability.’

This falls within the scope of the product’s designated orphan indication, which is: ‘treatment of tuberculosis.’

The COMP concluded that there had been no change in the seriousness of the condition since the orphan designation in 2008. Tuberculosis remains a condition that is debilitating in the long term or life threatening, particularly due to irreversible lung damage and the presence of drug resistant tuberculosis bacteria.

Prevalence of the condition

The sponsor provided updated information on the prevalence of tuberculosis based on data from the World Health Organization (WHO) and the United Nations.

On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of tuberculosis in the EU remains below the ceiling for orphan designation, which is 5 people in 10,000. At the time of the review of the orphan designation, the prevalence in the EU was still estimated to be approximately 2 people in 10,000. This is equivalent to a total of around 102,000 people in the EU.

Existence of other satisfactory methods of treatment

At the time of the review of the orphan designation, several other products were authorised in the EU for the treatment of tuberculosis either as combinations (e.g. ethambutol/isoniazid, isoniazide/rifampin and isoniazide/rifampin/pyrazinamide) or as products containing only one active substance (e.g. ethambutol, isoniazide, rifampin, pyrazinamide and streptomycin).

Significant benefit over existing treatments

The COMP was of the opinion that the data provided sufficiently demonstrate that Deltyba is of significant benefit to patients affected by multi-drug resistant tuberculosis when added to a standard background treatment. The main study showed that adding Deltyba to standard treatment shortened the time needed for the tuberculosis bacteria to clear from the patients’ sputum after two months of treatment. The COMP considered that these effects are likely to be sustained if Deltyba is used for the full treatment duration of six months therefore resulting in better survival and lower rates of relapse. This was supported by additional data from multi-drug resistant tuberculosis patients who continued to receive Deltyba for up to six months and who showed sustained negative sputum results after 24 months and better survival rates compared with patients who did not receive six months treatment with Deltyba. Therefore, although other methods for the treatment of this condition have been authorised in the EU, the COMP concluded that Deltyba is of significant benefit for patients affected by multi-drug resistant tuberculosis.

Conclusions

Based on the data submitted and the scientific discussion within the COMP, the COMP considered that Deltyba still meets the criteria for designation as an orphan medicinal product and that it should remain in the Community Register of Orphan Medicinal Products.

Related information

Sponsor’s contact details

Otsuka Novel Products GmbH
Erika-Mann-Strasse 21
80636 Muenchen
Germany

Patients' organisations

For contact details of patients’ organisations whose activities are targeted at rare diseases, see:

  • Orphanet, a database containing information on rare diseases which includes a directory of patients’ organisations registered in Europe.
  • European Organisation for Rare Diseases (EURORDIS), a non-governmental alliance of patient organisations and individuals active in the field of rare diseases.