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Orphan designation

This medicine is now known as venetoclax.

On 6 December 2012, orphan designation (EU/3/12/1080) was granted by the European Commission to AbbVie Ltd, United Kingdom, for 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide for the treatment of chronic lymphocytic leukaemia.

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide has been authorised in the EU as Venclyxto since 5 December 2016.

The sponsorship was transferred to AbbVie Deutschland GmbH & Co. KG, Germany, in March 2018.

What is chronic lymphocytic leukaemia?

Chronic lymphocytic leukaemia (CLL) is cancer of a type of white blood cell called B-lymphocytes. In this disease, the lymphocytes multiply too quickly and live for too long, so that there are too many of them circulating in the blood. The cancerous lymphocytes look normal, but they are not fully developed and do not work properly. Over a period of time, the abnormal cells replace the normal white cells, red cells and platelets (components that help the blood to clot) in the bone marrow (the spongy tissue inside the large bones in the body).

CLL is the most common type of leukaemia and mainly affects older people. It is rare in people under the age of 40 years. CLL is a long-term debilitating and life-threatening disease because some patients develop severe infections.

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

At the time of designation, CLL affected approximately 3 in 10,000 people in the European Union (EU)*. This is equivalent to a total of around 152,000 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).

*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 506,300,000 (Eurostat 2011).

What treatments are available?

Treatment for CLL 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. Patients whose CLL is not causing any symptoms or is only getting worse very slowly may not need treatment. Treatment for CLL is only started if symptoms become troublesome. At the time of designation, the main treatment for CLL was chemotherapy (medicines to treat cancer).

The sponsor has provided sufficient information to show that this medicine might be of significant benefit for patients with CLL because it works in a different way to existing treatments and early studies show that it might improve the outcome of patients whose disease does not respond or has come back after previous 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?

This medicine is expected to work by blocking proteins called Bcl-2. These proteins allow cells to stay alive by preventing the natural process that leads to cell death (apoptosis). Bcl-2 proteins can be found in high concentration in cancer cells. By blocking the action of these proteins, the medicine is expected to make cancer cells more responsive to this natural process, causing their death and slowing the growth of the cancer. As Bcl-2 proteins have been shown to be associated with resistance to conventional chemotherapy, it is expected that this medicine will reduce resistance and allow other medicines to be more effective in their treatment.

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 CLL were ongoing.

At the time of submission, this medicine was not authorised anywhere in the EU for CLL. Orphan designation of the medicine has been granted in the United States for CLL. 

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 7 November 2012 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.

Key facts

Product details for <p>4-(4-{[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide&#160;(venetoclax)</p>
Active substance4-(4-{[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (venetoclax)
Medicine NameVenclyxto
Disease/conditionTreatment of chronic lymphocytic leukaemia
Date of decision06/12/2012
Orphan decision numberEU/3/12/1080

Review of designation

On 14 October 2016, the Committee for Orphan Medicinal Products (COMP) completed the review of the designation EU/3/12/1080 for Venclyxto (venetoclax1) as an orphan medicinal product for the treatment of chronic lymphocytic leukaemia. 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 chronic lymphocytic leukaemia. The COMP recommended that the orphan designation of the medicine be maintained2.

1Previously known as 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide.

2The 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 Venclyxto with the following indication:

‘Venclyxto monotherapy is indicated for the treatment of chronic lymphocytic leukaemia (CLL) in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B cell receptor pathway inhibitor.

Venclyxto monotherapy is indicated for the treatment of CLL in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B cell receptor pathway inhibitor.’

This falls within the scope of the product’s designated orphan indication, which is: ‘treatment of chronic lymphocytic leukaemia’.

The COMP concluded that there had been no change in the seriousness of the condition since the orphan designation in 2012. Chronic lymphocytic leukaemia remains a condition that is debilitating in the long-term and life threatening, particularly due to the risk of reduced blood cells, enlarged livers and spleens and severe infection.

Prevalence of the condition

The sponsor provided updated information on the prevalence of chronic lymphocytic leukaemia based on data from registries.

On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of CLL 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 approximately 4.8 people in 10,000. This is equivalent to a total of around 250,000 people in the EU.

Existence of other methods of treatment

At the time of the review of the orphan designation, several chemotherapy or immunotherapy medicines (treatments that stimulate the immune system to kill cancer cells) were authorised in the EU for the treatment of chronic lymphocytic leukaemia, including bendamustine, chlorambucil, cyclophosphamide, fludarabine, obinutuzumab, ofatumumab and rituximab.

Medicines known as B cell receptor pathway inhibitors such as ibrutinib and idelalisib were also used, including in patients with 17p deletion or TP53 mutation. These genetic changes make patients unsuitable for treatment with a combination of chemotherapy and immunotherapy medicines.

Significant benefit of Venclyxto

The COMP concluded that the claim of a significant benefit of Venclyxto is justified because the medicine has been shown to improve symptoms in patients with few treatment options, such as patients with 17p deletion or TP53 mutation who had not responded well to B cell receptor pathway inhibitors, and patients without these mutations who had not responded either to such treatments or to chemotherapy and immunotherapy medicines.

In one main study, Venclyxto led to a treatment response in the majority of patients with 17p deletion or a TP53 mutation. In another study, Venclyxto produced a response in more than half of patients with or without 17p deletion or a TP53 mutation but whose CLL had failed to respond to treatments with B‑cell receptor pathway inhibitors.

Therefore, although other methods for the treatment of this condition have been authorised in the EU, the COMP concluded that Venclyxto is of significant benefit to patients affected by chronic lymphocytic leukaemia.


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

Further information on the current regulatory status of Venclyxto can be found in the European public assessment report (EPAR) on the Agency’s website.

Sponsor’s contact details

AbbVie Deutschland GmbH & Co. KG
67061 Ludwigshafen
Tel. +49 621 589 3382

Patients' organisations

For contact details of patients’ organisations whose activities are targeted at rare diseases, see:

  • Orphanet, a database containing information on rare diseases which includes a directory of patients’ organisations registered in Europe;
  • European Organisation for Rare Diseases (EURORDIS), a non-governmental alliance of patient organisations and individuals active in the field of rare diseases.