EU/3/15/1602

On 11 January 2016, orphan designation (EU/3/15/1602) was granted by the European Commission to Dr Ulrich Granzer, Germany, for live attenuated Listeria monocytogenes transfected with plasmids encoding the HPV-16E7 protein fused to a truncated fragment of the Lm protein listeriolysin O (also known as axalimogene filolisbac) for the treatment of anal cancer.

What is anal cancer?

Anal cancer is a cancer of the tissues of the anus. Bleeding from the anus is often the first sign of the disease. Other symptoms include pain, discomfort and itching and small lumps around the anus, difficulty controlling bowels (faecal incontinence) and ulcers. Sometimes the cancer causes no symptoms.

A number of risk factors are linked to anal cancer, one of them being infection with the human papilloma virus (HPV), the same virus that causes cervical cancer.

Anal cancer is a long-term debilitating disease due to its symptoms such as incontinence, bleeding, itching and non-healing ulcers. This disease is also life threatening and associated with shortened life expectancy.

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

At the time of designation, anal cancer affected approximately 0.4 in 10,000 people in the European Union (EU). This was equivalent to a total of around 21,000 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 512,900,000 (Eurostat 2015).

What treatments are available?

At the time of designation, several medicines were authorised for the treatment of anal cancer in the EU. Treatments for anal cancer included radiotherapy (treatment with radiation) and chemotherapy (medicines to treat cancer).

The sponsor has provided sufficient information to show that the medicine might be of significant benefit for patients with anal cancer because early studies show that it might improve survival in patients whose disease came back after previous standard treatment. 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?

The medicine works by stimulating the patient’s immune system, the body’s natural defences, so that it targets and destroys the cancer cells. It is made of live Listeria monocytogenes bacteria, which have been attenuated (weakened) so that they do not cause disease in humans. The bacteria have also been modified to produce large amounts of the ‘human papilloma virus 16 E7’ (HPV-16E7 protein). HPV-16E7 is found at high levels on cells in anal cancer caused by HPV type 16. The HPV-16E7 protein on the bacteria has been attached to a protein called listeriolysin O, which helps it to stimulate the body’s immune system.

When the medicine is given, the patient’s immune system is expected to learn to treat HPV-16E7 as ‘foreign’. This is expected to stimulate an immune response against the cancer cells carrying HPV-16E7 on their surface, resulting in the immune system attacking and destroying the cancer cells.

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 anal cancer were ongoing.

At the time of submission, the medicine was not authorised anywhere in the EU for anal cancer. Orphan designation of the medicine had been granted in the United States for treatment of HPV-positive associated anal cancer.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 10 December 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.

The Committee for Orphan Medicinal Products reviews the orphan designation of a product if it is approved for marketing authorisation.