EU/3/19/2224: Orphan designation for the treatment of CDKL5 deficiency disorder

CDKL5 deficiency disorder is a condition associated with problems with the brain and nervous system function (encephalopathy), resulting in seizures (fits), as well as developmental delay, abnormal muscle tone and inability to use the hands properly, and gut and breathing problems. It is caused by mutations (changes) in the gene for making a brain-cell protein called CDKL5. This gene is on the X chromosome, one of the two chromosomes (X and Y) that determine a person’s sex, and most patients with CDKL5 deficiency disorder are girls (who have two X chromosomes). When it occurs in boys (who have only one X chromosome) it is likely to be much more severe.

CDKL5 deficiency disorder is life-threatening and chronically debilitating due to early-onset seizures that do not respond to treatment, developmental delay, abnormal muscle tone and other related problems.

At the time of designation, CDKL5 deficiency disorder affected approximately less than 0.5 in 10,000 people in the European Union (EU). This was equivalent to a total of fewer than 26,000 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 28), Norway, Iceland and Liechtenstein. This represents a population of 518,400,000 (Eurostat 2019).

Although there are no specific treatments, the condition is managed with currently authorised epilepsy medicines and with a special, low-carbohydrate diet called a ketogenic diet.

The sponsor has provided sufficient information to show that the medicine might be of significant benefit for patients with CDKL5 deficiency disorder. This is because early studies in humans suggest a reduction in seizures when patients are treated with the medicine along with standard care. 

Ganaxolone mimics the action of a substance in the body called allopregnanolone. It switches on so-called GABA receptors, which reduce the electrical activity of the brain. This is expected to calm the excess activity in seizures, improving the symptoms of the disease.

The effects of ganaxolone have been evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials with ganaxolone in patients with CDKL5 deficiency disorder were ongoing.

At the time of submission, ganaxolone was not authorised anywhere in the EU for the treatment of CDKL5 deficiency disorder. Orphan designation had been granted in the United States for the treatment of this condition.

In accordance with Regulation (EC) No 141/2000, the COMP adopted a positive opinion on 10 October 2019, 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 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.