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Orphan designation

On 11 January 2012, orphan designation (EU/3/11/945) was granted by the European Commission to Dr Ulrich Granzer, Germany, for ornithine phenylacetate for the treatment of acute liver failure.

The sponsorship was transferred to Voisin Consulting S.A.R.L., France, in September 2014, to Amiculum Consulting Limited, United Kingdom, in February 2017, and to Mallinckrodt Pharmaceuticals Ireland Limited, Ireland, in April 2018.

What is acute liver failure?

Acute liver failure is the sudden loss of normal liver functions in a patient with a previously normal liver and without evidence of chronic (long-term) liver disease. The most common first sign of liver failure is yellowing of the skin (jaundice). Acute liver failure brings serious complications such as bruising and bleeding due to impaired blood clotting, cerebral oedema (swelling around the brain), convulsions (fits) and coma. The most common causes of acute liver failure in the European Union (EU) are toxic damage (for example due to consumption of large amounts of alcohol or overdose of medicines such as paracetamol) or viral hepatitis (an infectious disease that affects the liver).

Acute liver failure is a long-term debilitating and life-threatening disease because of its damaging effects on the brain and other organs.

What is the estimated number of patients?

At the time of designation, acute liver failure affected approximately 0.06 in 10,000 people in the EU. This is equivalent to a total of around 3,000 people*, and is below the ceiling for orphan designation, which is 5 people in 10,000. This isbased 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 27), Norway, Iceland and Liechtenstein. At the time of designation, this represented a population of 509,000,000 (Eurostat 2012).

What treatments are available?

At the time of designation, the main treatment option for acute liver failure was liver transplantation. Patients with acute liver failure caused by paracetamol overdose were treated with N-acetylcysteine.

The sponsor has provided sufficient information to show that ornithine phenylacetate might be of significant benefit for patients with acute liver failure because early studies in experimental models show that it may improve the treatment of patients with this condition. This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.

How is this medicine expected to work?

Ornithine phenylacetate is expected to reduce the high levels of ammonia seen in the blood of patients with acute liver failure. Ammonia is a substance naturally produced by the body which may cause harm if it is not processed normally. One function of the liver is to transform this substance into urea which is then harmlessly eliminated in the urine. When the liver fails, it cannot transform ammonia into urea. The ammonia then accumulates in the blood and the brain causing many of the symptoms of acute liver failure.

Ornithine phenylacetate is made of two substances, ornithine and phenylacetate. Ornithine is used by muscle cells to produce glutamine, an amino acid. Production of glutamine from ornithine requires ammonia, which is taken up from excess ammonia circulating in the blood. Phenylacetate is then expected to attach to glutamine forming a substance that is eliminated in the urine.

What is the stage of development of this medicine?

At the time of submission of the application for orphan designation, the evaluation of the effects of ornithine phenylacetate in experimental models was ongoing.

At the time of submission, no clinical trials with ornithine phenylacetate in patients with acute liver failure had been started.

At the time of submission, ornithine phenylacetate was not authorised anywhere in the EU for acute liver failure or designated as an orphan medicinal product elsewhere for this condition.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 9 November 2011 recommending the granting of this designation.

Opinions on orphan medicinal product designations are based on the following three criteria:
  • 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.

Key facts

Product details for <p>Ornithine phenylacetate</p>
Active substanceOrnithine phenylacetate
Medicine Name
Disease/conditionTreatment of acute liver failure
Date of decision11/01/2012
Orphan decision numberEU/3/11/945

Review of designation

The Committee for Orphan Medicinal Products reviews the orphan designation of a product if it is approved for marketing authorisation.

Sponsor’s contact details

Mallinckrodt Pharmaceuticals Ireland Limited
College Business & Technology Park
Dublin 15
Tel. +353 1 6960000

Patients' organisations

For contact details of patients’ organisations whose activities are targeted at rare diseases, see:

  • Orphanet, a database containing information on rare diseases which includes a directory of patients’ organisations registered in Europe.
  • European Organisation for Rare Diseases (EURORDIS), a non-governmental alliance of patient organisations and individuals active in the field of rare diseases.