EU/3/07/465: Orphan designation for the treatment of orthostatic hypotension in patients with pure autonomic failure

The autonomic nervous system regulates blood pressure, heart rate, sleep, and bladder function. Pure autonomic failure is a progressive disorder of the autonomic central nervous system with symptoms such as constipation, impotence in men, urinary incontinence and orthostatic (postural) hypotension. Orthostatic hypotension is an excessive drop in blood pressure when the patient stands, which causes dizziness or momentary blackouts. The condition is chronically debilitating to the patient and life-threatening due to loss of consciousness.

At the time of designation, pure autonomic failure affected less than 0.1 in 10,000 people in the European Union (EU)*. This is equivalent to a total of fewer than 5,000 people, and is below the threshold for orphan designation, which is 5 people in 10,000. This is based on the information provided by the sponsor and 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. This represents a population of 498,000,000 (Eurostat 2006).

Orthostatic hypotension in patients with pure autonomic failure can be treated by increasing water and salt intake, using compression stockings, and by the use of medication authorised for the condition in some countries in the Community at the time of submission of the application for orphan drug designation.
Satisfactory argumentation has been submitted by the sponsor to justify the assumption that the medicinal product might be of potential significant benefit for the treatment of orthostatic hypotension in patients with pure autonomic failure.
The assumption will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

When a person stands up, gravity causes blood to settle in the veins in the legs, so less blood reaches the heart for pumping, and as a result the blood pressure drops. The body normally responds automatically to the drop in blood pressure by increasing the rate at which the heart beats and by narrowing the veins to return more blood to the heart. In patients with postural hypotension, this compensating reflex fails to occur, resulting in symptomatic low blood pressure. L-threo-3,4-dihydroxyphenylserine treatment is expected to restore the normal reflex by acting on both, the heart and blood vessels.

At the time of submission of the application for orphan designation, the effects of L-threo-3,4-dihydroxyphenylserine had been evaluated in experimental models but no clinical trials in patients with pure autonomic failure had been initiated.

L-threo-3,4-dihydroxyphenylserine was not authorised anywhere worldwide for treatment of orthostatic hypotension in patients with pure autonomic failure, at the time of submission. Orphan designation of L-threo-3,4-dihydroxyphenylserine was granted in the United States for the treatment of symptomatic neurogenic orthostatic hypotension in patients with primary autonomic failure, dopamine-β-dehydroxylase deficiency or nondiabetic autonomic neuropathy.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 27 June 2007 recommending the granting of this designation.

• 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 Community) 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.