EU/3/01/066: Orphan designation for the treatment of erythema nodosum leprosum (ENL) or type II lepra reactions

Leprosy is a chronic infectious disease caused by the bacterium Mycobacterium leprae. The infection affects the skin, nerves (e.g. of the limbs) and mucous membranes (membranes that line various body cavities exposed to the external environment and internal organs). Patients develop multiple lesions accompanied by sensory loss in the affected areas that usually begins in the extremities (toes, fingertips). Erythema nodosum lepra (ENL)/ type II lepra reactions stems from a complication of the immune system that occurs in patients with leprosy. The condition may involve many parts of the body but almost always affects the skin. ENL develops rapidly over a few hours when the skin on the arms, forearms, face, trunk and thighs can be covered in painful red papules. In severe attacks the majority of the body is covered in dark papules that intensify in colour over 2-3 days before subsidising, leaving the affected area of skin darkly stained. Episodes are usually associated with fever and general malaise and sometimes other organs, such as the joints, eyes, kidneys, and lymphatics are affected. About 50% of patients with ENL develop painful neuritis (inflammation of the nerves) and increased nerve functional impairment. Painful enlargement of lymph nodes, liver and spleen may occur, as well as episcleritis (inflammation of the outer coating of the eye) and iridocyclitis (inflammation of the iris; the part of the eye with colour). ENL reactions may be of all degrees of severity being almost unnoticed in some, but in others occurring continuously, and if left untreated, may lead to gross weakness and occasionally death. The condition is chronically debilitating.

At the time of designation, erythema nodosum lepra or Type II lepra reactions affected approximately 0.02 in 10,000 people in the European Union (EU)*. This is equivalent to a total of around 750 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: The number of patients affected by the condition is estimated and assessed for the purpose of the designation, for a European Community population of 377,000,000 (Eurostat 2001) and may differ from the true number of patients affected by the condition.

Rifampicin, dapsone and clofazimin are authorised for the treatment of erythema nodosum lepra in the Community. In addition, corticosteroids and thalidomide are not authorised but are used. Thalidomide could be of potential significant benefit for the treatment of erythema nodosum lepra. The main reason for this potential is thalidomide's mechanism of action that could provide additional relief of the symptoms. This assumption will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

Although the mechanism of action of thalidomide in leprosy is not fully understood, it is thought to involve tumour necrosis factor-alpha (TNF-alpha). TNF-alpha is a molecule that controls the activation of immune system and patients with erythema nodosum lepra show high levels of it. Thalidomide is expected to alleviate the symptoms of the condition by reducing the levels of TNF-alpha.

Thalidomide was designated as orphan medicinal product in the United States for 14 indications including erythema nodosum lepra. Marketing authorisation has been granted in the United States for erythema nodosum lepra in 1998. Thalidomide was not marketed anywhere in the Community, at the time of submission.

At the time of submission for orphan drug status clinical trials in patients were completed.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 7 September 2001 recommending the granting of this designation.

• the seriousness of the condition;
• the existence of alternative methods of diagnosis, prevention or treatment;
• and either the rarity of the condition (affecting not more than five in 10,000 people in the Community) or the 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 the quality, safety and efficacy is necessary before a product can be granted a marketing authorisation.