EU/3/13/1127

On 7 June 2013, orphan designation (EU/3/13/1127) was granted by the European Commission to Pfizer Limited, United Kingdom, for inotuzumab ozogamicin for the treatment of B-cell acute lymphoblastic leukaemia.

Inotuzumab ozogamicin has been authorised in the EU as Besponsa since 29 June 2017.

What is B-cell acute lymphoblastic leukaemia?

Acute lymphoblastic leukaemia (ALL) is a cancer of the white blood cells called lymphocytes. Lymphocytes include T cells and B cells, and in B-cell ALL the lymphocytes affected are B cells, which multiply too quickly and live for too long so there are too many of them circulating in the blood. These abnormal B-cells are not fully developed and do not work properly. Over a period of time, they replace the normal white blood cells, red blood cells and platelets in the bone marrow (the spongy tissue inside the large bones in the body, where blood cells are produced).

B-cell ALL is a long-term debilitating and life-threatening disease because the abnormal immature cells take the place of the normal white blood cells, reducing the patient’s ability to fight infections and causing organ damage.

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

At the time of designation, B-cell ALL affected approximately 0.4 in 10,000 people in the European Union (EU). This was equivalent to a total of around 20,000 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 27), Norway, Iceland and Liechtenstein. This represents a population of 509,000,000 (Eurostat 2013).

What treatments are available?

Treatment for B-cell ALL is complex and depends on a number of factors including the extent of the disease, whether it has been treated before and the patient’s age, symptoms and general state of health. At the time of designation, the main treatment for B-cell ALL was chemotherapy (medicines to treat cancer) followed by or combined with radiotherapy (treatment with radiation). Haematopoietic (blood) stem-cell transplantation was also used. This is a complex procedure where the patient receives stem cells from a matched donor to help restore the bone marrow.

The sponsor has provided sufficient information to show that inotuzumab ozogamicin might be of significant benefit for the treatment of B-cell ALL because it selectively targets the abnormal B-cell causing the leukaemia and early studies show beneficial effects in patients not responding to previous treatment. These assumptions 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?

Inotuzumab ozogamicin is made up of two components:

• calicheamicin, a substance toxic for cells;
• a monoclonal antibody (a type of protein) that has been designed to recognise and attach to CD22, a protein that is found on the surface of B cells where it regulates their activation and interaction with other cells of the immune system.

Once attached to the cancerous B cell, the medicine is expected to be taken up by the cell where calicheamicin becomes active, causing breaks in its DNA and thereby killing the cancer cell.

What is the stage of development of this medicine?

The effects of inotuzumab ozogamicin 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 B-cell ALL were ongoing.

At the time of submission, inotuzumab ozogamicin was not authorised anywhere in the EU for B-cell ALL. It has been designated as an orphan medicinal product in the United States for this condition.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 17 April 2013 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 10 to 12 May 2017, the Committee for Orphan Medicinal Products (COMP) reviewed the designation EU/3/13/1127 for Besponsa (inotuzumab ozogamicin), as an orphan medicinal product for the treatment of B-cell acute lymphoblastic leukaemia (ALL). 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 B-cell ALL. The COMP recommended that the orphan designation of the medicine be maintained¹.

¹ 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 the same 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 Besponsa ‘ as monotherapy the treatment of adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukaemia (ALL)’.

This falls within the scope of the product’s designated orphan indication, which is B-cell ALL.

The COMP concluded that there had been no change in the seriousness of the condition since the orphan designation in 2013. B-cell ALL remains a condition that is debilitating in the long term and life threatening, particularly due to its effects on normal white blood cells, reducing the patient’s ability to fight infections and causing organ damage.

Prevalence of the condition

The sponsor provided updated information on the prevalence of B-cell ALL based on data from the Globocan 2012 database and the scientific literature.

On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of B-cell ALL 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 estimated to be less than 1 in 10,000 people. This is equivalent to a total of fewer than 51,000 people in the EU.

Existence of other methods of treatment

At the time of the review of the orphan designation, several chemotherapy medicines were authorised in the EU for the treatment of ALL. In addition, Blincyto (blinatumomab) had been approved in the EU in November 2015 for the treatment of adults with B-cell precursor ALL.

Significant benefit of Besponsa

The COMP concluded that the claim of a significant benefit of Besponsa in B-cell ALL is justified based on data from a main study with Besponsa in patients whose disease had come back after previous treatment or had not responded to previous treatment. Results showed that Besponsa was more effective than chemotherapy alone.

Compared with Blincyto, the COMP considered that Besponsa is easier to give (one-hour infusion as opposed to a continuous infusion which requires the patient to stay in hospital for several days).

Therefore, although other methods for the treatment of this condition have been authorised in the EU, the COMP concluded that Besponsa is of significant benefit to patients affected by B-cell ALL.

Conclusions

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

Further information on Besponsa (inotuzumab ozogamicin) can be found in the European public assessment report (EPAR) on the Agency’s website.