EMA has recommended granting an extension of indication to Orfadin (nitisinone) to include the treatment of alkaptonuria in adult patients.

This rare disorder affects one in every 250,000 to 1 million people and is more common in certain areas of Slovakia. It is characterised by the inability of the body to metabolize homogentisic acid (HGA) due to the lack of an enzyme. People with alkaptonuria typically develop arthritis, particularly in the spine and large joints. 50 percent of patients require at least one joint replacement by the time they are 55. Affected individuals can also suffer from heart problems and kidney stones. There are currently no approved medicines for alkaptonuria and treatment options are limited to dealing with the outcomes of the disease as they arise. Therefore, there is an unmet medical need for patients with this rare disorder.

Orfadin is already approved in the European Union (EU) for the treatment of hereditary tyrosinaemia type 1 (HT-1). This is a rare disease in which the body is unable to completely break down the amino acid tyrosine, and harmful substances are formed, causing serious liver problems and liver cancer.

Nitisinone, the active substance in Orfadin, reduces urinary excretion and blood levels of HGA. The reduction in HGA levels before the onset of noticeable blue-black pigmentation in cartilage and connective tissue prevents the development of the debilitating signs and symptoms of the disease, which usually don’t manifest until early adulthood.

The development of Orfadin for the treatment of alkaptonuria was enabled by the work carried out within the Clinical Development of Nitisinone for Alkaptonuria (DevelopAKUre) program by an international research consortium. The European Commission contributed to the funding of DevelopAKUre with a grant of approximately 6 million euros in the context of the 7th Framework Program (FP7), the EU’s research and innovation funding programme for the years 2007-2013.

The opinion of EMA’s human medicines committee (CHMP) is based on data from a randomised clinical study that compared the efficacy and safety of treatment with nitisinone to no treatment over a period of four years. A total of 138 patients with alkaptonuria were included. The primary objective was to measure reduction of HGA levels in the urine. Patients who were assigned to nitisinone achieved a 99.7% reduction, compared to those who received no treatment. The study also recorded a favourable effect of nitisinone in reducing the severity of the disease according to an internationally agreed set of parameters – the All Alkaptonuria Severity Score Index (AKUSSI score).

The most common side effects noted in the context of clinical trials in patients with alkaptonuria were elevated levels of the amino acid tyrosine, disorders of the eye such as eye pain and inflammation of the cornea (i.e. keratopathy) and infections of the airways.

The opinion adopted by the CHMP at its September 2020 meeting is an intermediary step on Orfadin’s path to patient access in this new indication. The CHMP opinion will now be sent to the European Commission for the adoption of a decision on an EU-wide marketing authorisation. Once a marketing authorisation has been granted, decisions about price and reimbursement will take place at the level of each Member State, taking into account the potential role/use of this medicine in the context of the national health system of that country.

Posted on the EMA website on 18 September 2020