EU/3/14/1284

On 4 July 2014 orphan designation (EU/3/14/1284) was granted by the European Commission to Basilea Medical Ltd, United Kingdom, for isavuconazonium sulfate for the treatment of invasive aspergillosis.

Update: isavuconazonium sulfate (Cresemba) has been authorised in the EU since 15 October 2015. Cresemba is indicated in adults for the treatment of invasive aspergillosis.

Consideration should be given to official guidance on the appropriate use of antifungal agents.

What is invasive aspergillosis?

Invasive aspergillosis is an infection caused by species of fungi known as Aspergillus. These fungi are very widely present in the air, but normally do not cause disease. In some people, usually when the immune system (the body’s natural defences) is weakened, the fungus can attack and invade through the lungs and spread throughout the body via the bloodstream, damaging other organs and tissues including the heart, kidney, liver, brain, and bones.

Invasive aspergillosis is a life-threatening disease that can be fatal due to damage to the lungs and other organs.

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

At the time of designation, invasive aspergillosis affected less than 2 in 10,000 people in the European Union (EU). This was equivalent to a total of fewer than 102,000 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).

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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 511,100,000 (Eurostat 2014).

What treatments are available?

At the time of designation, several medicines were authorised in the EU for the treatment of invasive aspergillosis, including voriconazole, posaconazole and amphotericin B.

The sponsor has provided sufficient information to show that isavuconazonium sulfate might be of significant benefit for patients with invasive aspergillosis because clinical studies have shown that it is as effective as authorised treatments but may have an improved safety profile, particularly with respect to effects on the liver. 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?

Isavuconazonium sulfate is a product that belongs to the ‘triazole’ class of antifungal medicines. Once in the body, it is converted into its active form, isavuconazole, which is thought to work by blocking the actions of enzymes that are involved in making ergosterol, an important component of fungal cell membranes. Without a functional cell membrane, the Aspergillus fungus is expected to die or prevented from spreading.

What is the stage of development of this medicine?

The effects of the medicine have been evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials with isavuconazonium sulfate in patients with invasive aspergillosis were ongoing.

At the time of submission, the medicine was not authorised anywhere in the EU for invasive aspergillosis. Orphan designation of isavuconazonium sulfate had been granted in the United States for treatment of this condition.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 14 May 2014 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.

During its meeting of 1 to 3 September 2015, the Committee for Orphan Medicinal Products (COMP) reviewed the designation EU/3/14/1284 for Cresemba (isavuconazole) as an orphan medicinal product for the treatment of invasive aspergillosis. 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 are authorised in the European Union (EU), the COMP also considered whether the medicine is of significant benefit to patients with invasive aspergillosis. 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.

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

The Committee for Medicinal Products for Human Use (CHMP) recommended the authorisation of Cresemba for the treatment of ‘invasive aspergillosis’.

This falls within the scope of one of the product’s designated orphan indications, which is: ‘invasive aspergillosis’.

The COMP concluded that there had been no change in the seriousness of the condition since the orphan designation in 2014. Invasive aspergillosis, a fungal infection, remains a condition that is life-threatening due to damage to the lungs and other organs.

Prevalence of the condition

The sponsor provided updated information on the prevalence of invasive aspergillosis based on data from the published literature.

On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of invasive aspergillosis 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 less than 2 people in 10,000. This is equivalent to a total of fewer than 102,000 people in the EU.

Existence of other methods of treatment

At the time of the review of the orphan designation, other treatments were authorised in the EU for the treatment of invasive aspergillosis, with voriconazole being the primary treatment. Other medicines included posaconazole and amphotericin B.

Significant benefit of name of product

The COMP concluded that the claim of a significant benefit of Cresemba in invasive aspergillosis is justified on the basis of data showing improved safety of the medicine compared with other treatments, including reduced effects on the liver.

Therefore, although other methods for the treatment of this condition have been authorised in the EU, the COMP concluded that Cresemba is of significant benefit to patients affected by invasive aspergillosis.

Conclusions

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