EU/3/19/2239: Orphan designation for the treatment of cystinuria

Cystinuria is an inherited condition caused by a mutation (change) in the genes that produce the protein rBAT, which transports the amino acid cystine out of the urine and gut. Because the mutation means that rBAT does not work properly, people with the condition develop high concentrations of cystine in their urine. As cystine is poorly soluble, it crystallises in the urine inside the kidney, forming kidney stones that can damage the kidneys and block passage of urine. The condition is long-term debilitating due to the pain, bleeding, obstruction and risk of infection and kidney damage caused by the stones.

At the time of designation, cystinuria affected approximately 1 in 10,000 people in the European Union (EU). This was equivalent to a total of around 52,000 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).

At the time of designation, patients were managed with increased fluid intake, restriction of sodium and protein in the diet, and with substances such as potassium citrate to make the urine more alkaline and so improve the amount of cystine it can dissolve, reducing the risk of stones. In some EU countries the medicines penicillamine and tiopronin were authorised for treatment in patients who could not be managed with other measures.

The sponsor has provided sufficient information to show that the medicine might be of significant benefit for patients with cystinuria. Early data in patients showed that the medicine kept the urine more alkaline throughout the night and for longer than other medicines that work in the same way. This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.

The medicine contains tripotassium citrate monohydrate and potassium hydrogen carbonate, which are substances that can make urine more alkaline, allowing cysteine to be dissolved and preventing stone formation. The substances are included in granules designed to slow down the release of the substances over several hours. After the medicine is taken by mouth, the slow release of the substances in the body is expected to maintain the medicine’s effect throughout the day and especially during the night. 

The effects of the medicine have been evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials with the medicine in patients with cystinuria were ongoing.

At the time of submission, the medicine was not authorised anywhere in the EU for the treatment of cystinuria or designated as an orphan medicinal product elsewhere for this condition.

In accordance with Regulation (EC) No 141/2000, the COMP adopted a positive opinion on 5 December 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.