EU/3/18/2019: Orphan designation for the treatment of Alport syndrome

Alport syndrome is an inherited condition caused by a mutation (change) in one of a group of genes responsible for producing type IV collagen, a fibrous protein needed to form the membranes that separate and support cells in organs such as the kidney, ear and eye. In patients with Alport syndrome, these membranes have an abnormal structure, so the organs cannot develop and function properly. Patients therefore experience internal scarring and inflammation of the kidney and gradually worsening kidney function that eventually results in kidney failure. Patients also suffer hearing loss and may develop cataracts and visual impairment.

Alport syndrome is a long-term debilitating disease due to the progressive kidney damage and impaired hearing and vision; it is potentially life threatening because it results in kidney failure that requires dialysis or transplantation.

At the time of designation, Alport syndrome affected approximately 2 in 10,000 people in the European Union (EU). This was equivalent to a total of around 103,000 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 517,400,000 (Eurostat 2018).

At the time of designation, no satisfactory methods of treatment were authorised in the EU for patients affected by the condition. Patients were given medicines that act on the renin-angiotensin system (RAS), which may if started early enough help slow the progression of kidney disease. As the disease worsens, kidney dialysis and kidney transplant may be needed.

Bardoxolone methyl is expected to work by activating a protein called NrF2, which triggers the production of other proteins that reduce inflammation and help protect cells. It is also expected to block the production of a protein called NF-ĸB, which is involved in causing inflammation. These two actions are expected to help reduce the scarring and kidney damage in patients Alport syndrome.

The effects of bardoxolone methyl have been evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials with bardoxolone methyl in patients with Alport syndrome were ongoing.

At the time of submission, bardoxolone methyl was not authorised anywhere in the EU for Alport syndrome. Orphan designation of bardoxolone methyl had been granted in the United States for this condition.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 19 April 2018 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.