EU/3/16/1623 - orphan designation for treatment of ornithine transcarbamylase deficiency

adeno-associated viral vector serotype 8 encoding human ornithine transcarbamylase (avalotcagene ontaparvovec)

Overview

This medicine is now known as avalotcagene ontaparvovec.

On 21 March 2016, orphan designation (EU/3/16/1623) was granted by the European Commission to Pharma Gateway AB, Sweden, for adeno-associated viral vector serotype 8 encoding human ornithine transcarbamylase (also called DTX301) for the treatment of ornithine transcarbamylase deficiency.

The sponsorship was transferred to Ultragenyx Germany GmbH, Germany, in September 2020.

The sponsor’s address was updated in November 2020.

What is ornithine transcarbamylase deficiency?

Ornithine transcarbamylase deficiency is one of the inherited disorders known as 'urea-cycle disorders', which cause ammonia to accumulate in the blood. Patients with ornithine transcarbamylase deficiency lack 'ornithine transcarbamylase', one of the liver enzymes needed to get rid of excess nitrogen. In the absence of this enzyme, excess nitrogen accumulates in the body in the form of ammonia, which can be harmful at high levels, especially to the brain. Symptoms of the disease usually appear in the first few days of life and include lethargy (lack of energy), vomiting, loss of appetite, seizures (fits) and coma.

Ornithine transcarbamylase deficiency is a long-term debilitating and life-threatening disease that leads to altered brain function and is associated with poor overall survival.

What is the estimated number of patients affected by the condition?

At the time of designation, ornithine transcarbamylase deficiency affected approximately 0.1 in 10,000 people in the European Union (EU). This was equivalent to a total of around 5,000 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).

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*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 513,700,000 (Eurostat 2016).

What treatments are available?

At the time of designation, sodium phenylbutyrate (Ammonaps) and glycerol phenylbutyrate (Ravicti) were authorised in the EU for the treatment of some urea-cycle disorders, including ornithine transcarbamylase deficiency. In addition, patients were advised to control their dietary intake of proteins, which are rich in nitrogen, to reduce the amount of ammonia formed in the body. Liver transplantation was used to manage the condition in some people.

The sponsor has provided sufficient information to show that a single dose of this medicine might be of significant benefit for patients with ornithine transcarbamylase deficiency because early laboratory studies showed a reduction in the production of ammonia. 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?

This medicine is made of a virus that has been modified to contain the gene for the enzyme ornithine transcarbamylase, which is lacking in patients with ornithine transcarbamylase deficiency. When given by infusion (drip) to the patient, the virus is expected to carry the gene for ornithine transcarbamylase into the liver cells, enabling them to produce the missing enzyme for a long period. This is expected to reduce production of ammonia and prevent development of symptoms.

The type of virus used in this medicine ('adeno-associated virus') does not cause disease in humans.

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 this medicine in experimental models was ongoing.

At the time of submission, no clinical trials with the medicine in patients with ornithine transcarbamylase deficiency had been started.

At the time of submission, the medicine was not authorised anywhere in the EU for ornithine transcarbamylase deficiency 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 18 February 2016 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.

EU/3/16/1623: Public summary of opinion on orphan designation: Adeno-associated viral vector serotype 8 encoding human ornithine transcarbamylase for the treatment of ornithine transcarbamylase deficiency

Adopted Reference Number: EMA/COMP/164905/2016

Key facts

• Active substance:
  adeno-associated viral vector serotype 8 encoding human ornithine transcarbamylase (avalotcagene ontaparvovec)
• Intended use:
  Treatment of ornithine transcarbamylase deficiency
• Orphan designation status:
  Positive
• EU designation number:
  EU/3/16/1623
• Date of designation:
  21/03/2016
• Sponsor:

  Ultragenyx Germany GmbH;

Review of designation

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