EU/3/09/683

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Orphan designation

On 28 October 2009, orphan designation (EU/3/09/683) was granted by the European Commission to Special Products Ltd, United Kingdom, for cholic acid for the treatment of inborn errors in primary bile acid synthesis responsive to treatment with cholic acid.

The sponsorship was transferred to FGK Representative Service GmbH, Germany, in December 2011.

For a list of the administrative updates to this public summary of opinion please refer to the PDF document below.

What are inborn errors in primary bile acid synthesis?

Inborn errors in primary bile acid synthesis are a group of diseases in which the liver does not produce (‘synthesise’) enough ‘primary bile acids’. These acids are the main components of the bile, a fluid that helps digestion, and include cholic acid and chenodeoxycholic acid. The lack of bile acids is caused by inborn genetic abnormalities.

Patients lacking primary bile acids produce abnormal bile acids instead. These acids can damage the liver. In some cases, this can lead to liver failure. Not all errors in primary bile acid synthesis can be treated with cholic acid. Therefore, patients with these conditions can be divided into two groups, depending on whether they are responsive to treatment with cholic acid or not.

Inborn errors in primary bile acid synthesis responsive to treatment with cholic acid are a group of long-term debilitating and life-threatening diseases because they can severely damage the liver.

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

At the time of designation, inborn errors in primary bile acid synthesis responsive to treatment with cholic acid affected approximately 0.07 in 10,000 people in the European Union (EU). This was equivalent to a total of around 3,500 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 27), Norway, Iceland and Liechtenstein. At the time of designation, this represented a population of 504,800,000 (Eurostat 2009).

What treatments are available?

At the time of designation, no satisfactory methods were authorised in the EU for the treatment of inborn errors in primary bile acid synthesis responsive to treatment with cholic acid. Patients with severe liver disease may need a liver transplant. Chenodeoxycholic acid and another bile acid called ursodeoxycholic acid, although authorised for other conditions, were used to treat inborn errors in primary bile acid synthesis.

How is this medicine expected to work?

Cholic acid is expected to work by replacing some of the missing bile acids in patients with inborn errors in primary bile acid synthesis. This is expected to decrease the production of abnormal bile acids and contribute to the normal activity of bile acids, therefore relieving the symptoms of these diseases.

What is the stage of development of this medicine?

The sponsor of this application has not conducted any studies with cholic acid. However, it provided the results of studies on the effects of cholic acid in experimental models and of clinical trials from the published literature to support its application for orphan designation.

At the time of submission, cholic acid was not authorised anywhere in the EU for inborn errors in primary bile acid synthesis responsive to treatment with cholic acid. Orphan designation of cholic acid had been granted in the EU and the United States of America for inborn errors in primary bile acid synthesis.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 2 September 2009 recommending the granting of this designation.

Update: 
Cholic acid (Cholic Acid FGK) has been authorised in the EU since 4 April 2014 for the treatment of inborn errors in primary bile acid synthesis due to Sterol 27-hydroxylase (presenting as cerebrotendinous xanthomatosis, CTX) deficiency, 2- (or a-) methylacyl-CoA racemase (AMACR) deficiency or Cholesterol 7a-hydroxylase (CYP7A1) deficiency in infants, children and adolescents aged 1 month to 18 years and adults.

More information on Cholic Acid FGK can be found in the European public assessment report (EPAR).

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 Community) 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>Cholic acid</p>
Active substanceCholic acid
Medicine NameCholic Acid FGK
Disease/conditionTreatment of inborn errors in primary bile acid synthesis responsive to treatment with cholic acid
Date of decision28/10/2009
OutcomePositive
Orphan decision numberEU/3/09/683

Review of designation

During its meeting of 7 to 9 January 2014, the Committee for Orphan Medicinal Products (COMP) reviewed the designation EU/3/09/683 for Kolbam, previously Cholic acid FGK (cholic acid)as an orphan medicinal product for the treatment of inborn errors in primary bile acid synthesis responsive to treatment with cholic acid. The COMP assessed whether, at the time of marketing authorisation, the medicinal product still met the criteria for orphan designation. The Committee looked at the seriousness and prevalence of the condition, and the existence of other methods of treatment. As other methods of treatment for patients with this condition are authorised in the European Union (EU), the COMP also looked at the significant benefit of the product over existing treatments. The COMP recommended that the orphan designation of the medicine be maintained*.


*The maintenance of the orphan designation at time of marketing authorisation would, except in specific situations, give an orphan medicinal product 10 years of market exclusivity in the EU. This means that in the 10 years after its authorisation similar products with a comparable therapeutic indication cannot be placed on the market.

For a list of the administrative updates to this public summary of opinion please refer to the PDF document below.

Life-threatening or long-term debilitating nature of the conditions

The Committee for Medicinal Products for Human Use (CHMP) recommended the authorisation of Kolbam for:

‘treatment of inborn errors of primary bile acid synthesis, in infants from one month of age for continuous lifelong treatment through adulthood, encompassing the following single enzyme defects:

  • Sterol 27-hydroxylase (presenting as cerebrotendinous xanthomatosis, CTX) deficiency;
  • 2- (or α-) methylacyl-CoA racemase (AMACR) deficiency;
  • Cholesterol 7 α-hydroxylase (CYP7A1) deficiency.’

This falls within the scope of the product’s designated orphan indication, which is: ‘treatment of inborn errors in primary bile acid synthesis responsive to treatment with cholic acid’.

The COMP concluded that there had been no change in the seriousness of the condition since the orphan designation in 2009. Inborn errors in primary bile acid synthesis responsive to treatment with cholic acid remain a group of long-term debilitating and life-threatening diseases because they can severely damage the liver.

Prevalence of the conditions

The sponsor informed the COMP that there is no evidence to suggest an increase in the prevalence of inborn errors in primary bile acid synthesis.

On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of these conditions remains below the ceiling for orphan designation, which is 5 people in 10,000. At the time of the review of the orphan designation, the prevalence was still estimated to be approximately 0.07 people in 10,000. This is equivalent to a total of around 4,000 people in the EU.

Existence of other satisfactory methods of treatment

At the time of the review of the orphan designation, Orphacol (cholic acid) was authorised in the EU for the treatment of inborn errors in primary bile acid synthesis due to a deficiency in two specific liver enzymes: 3β-hydroxy-Δ5-C27-steroid oxidoreductase or Δ4-3-oxosteroid-5β-reductase.

Significant benefit over existing treatments

The COMP noted that another medicine containing cholic acid (Orphacol) is authorised for the treatment of inborn errors of primary bile acid synthesis; however Orphacol is authorised in patients lacking different liver enzymes than those in whom Kolbam is to be used. The Committee therefore concluded that the claim of a significant benefit of Kolbam in the treatment of inborn errors of primary bile acid synthesis is justified by the fact that this medicine is used in a specific group of patients for whom no treatment option exists.

Conclusions

Based on the data submitted and the scientific discussion within the COMP, the COMP considered that Kolbam still meets the criteria for designation as an orphan medicinal product and that Kolbam should remain in the Community Register of Orphan Medicinal Products.

Sponsor’s contact details

FGK Representative Service GmbH
Heimeranstrasse 35
80339 München
Germany
Tel. +49 89 89311933
Fax +49 89 89311920
E-mail: edgar.fenzl@fgk-rs.com

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.