EU/3/15/1504

On 19 June 2015, orphan designation (EU/3/15/1504) was granted by the European Commission to Roche Registration Limited, United Kingdom, for obinutuzumab for the treatment of follicular lymphoma.

Obinutuzumab for the treatment of follicular lymphoma has been authorised in the EU as Gazyvaro since 13 June 2016.

What is follicular lymphoma?

Follicular lymphoma is a cancer of a type of white blood cell called B lymphocytes or B cells. In follicular lymphoma, the B cells multiply too quickly and live for too long, so there are too many of them in the lymph nodes. The first sign of the disease is usually a lump in the neck, under the arm or in the groin area, caused by an enlarged lymph node. Patients may also have fever, weight loss, tiredness and night sweats.

Follicular lymphoma is usually diagnosed in people aged over 50 years. It is a life-threatening and long-term debilitating disease due to organ damage and the cancer coming back.

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

At the time of designation, follicular lymphoma affected approximately 2.4 in 10,000 people in the European Union (EU). This was equivalent to a total of around 123,000 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 512,900,000 (Eurostat 2015).

What treatments are available?

At the time of designation, the main treatments for follicular lymphoma available in the EU included chemotherapy (medicines to treat cancer) combined with immunotherapy (medicines that stimulate the body’s own immune system to kill the cancer cells). The medicines bendamustine, ibritumomab tiuxetan, interferon alfa 2b and rituximab were specifically authorised for the treatment of follicular lymphoma.

The sponsor has provided sufficient information to show that this medicine might be of significant benefit for patients with follicular lymphoma because early studies show that patients whose disease has come back after treatment might respond to treatment with obinutuzumab. 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?

Obinutuzumab is a monoclonal antibody, a type of protein that has been designed to recognise and attach to a specific structure (called an antigen) that is found on certain cells in the body. Obinutuzumab has been designed to attach to a protein called CD20, which is present on the surface of all B cells, including the large number of cancerous B cells that are present in the lymph nodes of patients with follicular lymphoma. When obinutuzumab attaches to CD20, it is expected to cause the death of the cancerous B cells, slowing down the growth of the cancer.

Obinutuzumab is currently authorised in the EU as Gazyvaro for use in combination with chlorambucil (another cancer medicine) to treat patients with previously untreated chronic lymphocytic leukaemia.

What is the stage of development of this medicine?

The effects of obinutuzumab have been evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials with obinutuzumab in patients with follicular lymphoma were ongoing.

At the time of submission, obinutuzumab was not authorised anywhere in the EU for follicular lymphoma. Orphan designation of obinutuzumab has been granted in the United States for follicular lymphoma.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 13 May 2015 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 17 to 19 May 2016, the Committee for Orphan Medicinal Products (COMP) reviewed the designation EU/3/15/1504 for Gazyvaro (obinutuzumab) as an orphan medicinal product for the treatment of follicular lymphoma. The COMP assessed whether, at the time of addition of a new indication to the 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 follicular lymphoma. 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 extending the approved use of Gazyvaro to include the following indication:

‘Gazyvaro in combination with bendamustine followed by Gazyvaro maintenance is indicated for the treatment of patients with follicular lymphoma who did not respond or who progressed during or up to 6 months after treatment with rituximab or rituximab-containing regimen’.

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

The COMP concluded that there had been no change in the seriousness of the condition since the orphan designation in 2015. Follicular lymphoma remains a condition that is debilitating in the long term and life-threatening, particularly due to organ damage and the cancer coming back.

Prevalence of the condition

The sponsor provided updated information on the prevalence of follicular lymphoma based on data from the GLOBOCAN 2012 database, as well as data from US National Cancer Institute’s SEER cancer registry.

On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of follicular lymphoma 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 4 people in 10,000. This is equivalent to a total of fewer than 205,000 people in the EU.

Existence of other methods of treatment

At the time of designation, the main treatments for follicular lymphoma available in the EU included chemotherapy (medicines to treat cancer) combined with immunotherapy (medicines that stimulate the body’s immune system to kill the cancer cells). The chemotherapy medicines bendamustine and idelalisib and the immunotherapy rituximab and ibritumomab tiuxetan were specifically authorised for the treatment of follicular lymphoma.

Significant benefit of Gazyvaro

The COMP concluded that the claim of a significant benefit of Gazyvaro over bendamustine and rituximab is justified on the basis of study data on patients with follicular lymphoma in whom treatment with rituximab had either not worked or had stopped working. Patients treated with Gazyvaro and bendamustine lived significantly longer on average without their disease getting worse than patients treated with bendamustine alone (29.2 months versus 13.7 months).

Idelalisib is approved for use on its own in follicular lymphoma patients whose disease has not responded to two previous treatments. The significant benefit of Gazyvaro over idelalisib is justified because whereas idelalisib is only used after two previous treatments have failed, Gazyvaro in combination with bendamustine can be used earlier after one previous treatment with rituximab (either alone or in combination with other cancer medicines) has failed.

Unlike Gazyvaro, ibritumomab tiuxetan must be radiolabelled (tagged with a radioactive compound) before use. The significant benefit of Gazyvaro over ibritumomab tiuxetan is justified because it spares patients the side effects linked to radioactive treatment.

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

Conclusions

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