EU/03/14/1276

On 4 June 2014, orphan designation (EU/03/14/1276) was granted by the European Commission to Basilea Medical Ltd, the United Kingdom, for isavuconazonium sulfate for the treatment of mucormycosis.

Update: isavuconazonium sulfate (Cresemba) has been authorised in the EU since 15 October 2015. Cresemba is indicated in adults for the treatment of mucormycosis in patients for whom amphotericin B is inappropriate.

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

What is mucormycosis?

Mucormycosis is a severe infection with fungi of the order Mucorales. These fungi are commonly found in the environment, such as in soil and decaying matter, and usually only cause disease in people who have a weakened immune system, including patients receiving dialysis for kidney failure and those who have uncontrolled diabetes or acute myeloid leukaemia (a cancer of the blood). It is a serious infection that can affect the sinuses, brain, lungs, and sometimes the skin. Depending on the organ involved symptoms may include facial pain, chest pain, fever and ulcerations.

Mucormycosis is a life-threatening disease because the fungi can invade the surrounding blood vessels causing blood clots and cause death of the infected tissue in affected organs.

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

At the time of designation, mucormycosis affected approximately 0.06 in 10,000 people in the European Union (EU). This was 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).

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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 for the treatment of mucormycosis in the EU.

The sponsor has provided sufficient information to show that this medicine might be of significant benefit for patients with mucormycosis because preliminary clinical data showed a favourable response to the medicine in patients who did not respond to treatment with currently authorised medicines. 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 anti-fungal 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 fungus is expected to die or is 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 the medicine in patients with mucormycosis were ongoing.

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

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 9 April 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/3/14/1276 for Cresemba (isavuconazole) as an orphan medicinal product for the treatment of mucormycosis. 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 mucormycosis. 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: ‘mucormycosis in patients for whom amphotericin B is inappropriate.’

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

The COMP concluded that there had been no change in the seriousness of the condition since the orphan designation in 2014. Mucormycosis, a fungal infection, remains a condition that is debilitating in the long term or life threatening, because the fungi can invade the surrounding blood vessels causing blood clots and cause death of the infected tissue in affected organs.

Prevalence of the condition

The sponsor provided updated information on the prevalence of mucormycosis 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 mucormycosis 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 0.06 people in 10,000. This is equivalent to a total of around 3,000 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 mucormycosis, including amphotericin B.

Significant benefit of name of product

The COMP concluded that the claim of a significant benefit of Cresemba in mucormycosis is justified on the basis of data supporting the use of the medicine in patients who are not eligible for treatment with amphotericin B.

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 mucormycosis.

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.