EU/3/01/072: Orphan designation for the treatment of off-periods in Parkinson's disease not responding to other oral treatment

Parkinson's disease is a degenerative disorder of the central nervous system. Patients with Parkinson's disease suffer from muscle rigidity, resting tremor, slowing of physical movement (bradykinesia) and, in extreme cases, complete loss of movement (akinesia). Parkinson's disease results from progressive damage to the nerves in the area of the brain responsible for controlling muscle tone and movement. Nerves that would normally produce the neurotransmitter called dopamine (chemical messenger in the brain that transmits information from one nerve cell to another) do not function properly. Patients with Parkinson's disease have depleted levels of dopamine.
Oral treatment with dopamine precursor is used in the early stages of the disease. The brain still has the ability to store the dopamine precursor and transform it into dopamine. As the disease progresses, the brain loses this ability to store or use its reserves of dopamine precursor. In practice, hours after taking the oral treatment, the characteristic symptoms such as motor fluctuations will re-appear (off periods). Therefore, as the disease progresses, the action of oral treatment with dopamine precursors will gradually shorten. Off-periods in Parkinson's disease not responding adequately to other existing therapies is a progressive and chronically debilitating condition.

At the time of designation, off-periods in Parkinson's disease not responding adequately to other existing therapies affected approximately 0.35-0.48 in 10,000 people in the European Union (EU)*. This is equivalent to a total of around 13,000-18,000 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 based on data from the European Union. This represents a population of 377,000,000 (Eurostat 2001).

At the time of submission of the application for the orphan drug designation, several medicinal products, such as levodopa and apomorphine were authorised for the treatment of Parkinson's disease. Specifically, apomorphine hydrochloride administered subcutaneously was authorised in the European Union for the treatment of refractory motor fluctuations in Parkinsons' disease. Satisfactory argumentation has been submitted by the sponsor to justify the assumption that sublingual apomorphine (administered and absorbed under the tongue) might be of potential significant benefit for the treatment of the condition, as it might be major contribution to patient care. Sublingual apomorphine could lead to a better absorption of the drug and thus provide a better control of the off-periods. The assumption will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

Apomorphine is a dopamine agonist. Dopamine agonists directly stimulate the dopamine receptors (binding site of dopamine molecule) of the nerves in the brain that normally would be stimulated by dopamine and the brain reacts as if it is receiving dopamine. In patients with off-periods, the treatment could easily be administered under the tongue (oromucosal) that would rapidly relieve off-periods, and thus help reducing the symptoms of Parkinson's disease.

At the time of submission of the application for orphan designation, clinical trials in patients with off-periods in Parkinson's disease not responding adequately to other existing therapies were ongoing.

This medicinal product was not marketed anywhere worldwide for the treatment of off-periods in Parkinson's disease not responding adequately to other existing therapies, at the time of submission. Orphan designation of apomorphine was granted in the United States for use as rescue treatment for early morning motor dysfunction in late-stage Parkinson's disease. However, the product was later withdrawn from the orphan drug registry in the United States.

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.