EU/3/03/168

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Orphan designation

On 20 October 2003, orphan designation (EU/3/03/168) was granted by the European Commission to MolMed SpA, Italy, for herpes simplex 1 virus-thymidine kinase and truncated low affinity nerve growth factor receptor transfected donor lymphocytes for the adjunctive treatment of haematopoietic cell transplantation.

Herpes simplex 1 virus-thymidine kinase and truncated low affinity nerve growth factor receptor transfected donor lymphocytes has been authorised in the EU as Zalmoxis since 18 August 2016.

What is haematopoietic cell transplantation?

Haematopoietic cells are cells that can produce mature blood cells. They can be found in the bone marrow, the spongy tissue inside the large bones in the body and in low concentrations in the peripheral blood. In certain haematological diseases, where the bone marrow is not able to produce mature blood cells, it is appropriate to use a treatment called transplantation, which consists in replacing the abnormal cells of the immune system and bone marrow with healthy cells generally either from the same person (autologous) or from a donor (allogenic). A severe complication of allogenic haematopoietic cell transplantation is the development of a disease called Graft versus Host Disease (GvHD). This complication involves a reaction between the donor cells (graft) and the recipient's native tissues (host) leading to injury of the recipient’s tissues. Severe graft versus host disease can be largely avoided by the removal of certain white blood cells, the so-called T lymphocytes, from the graft before it is administered to the recipient patient. However, a strong reduction of these T cell increases the incidence of disease relapse, rejection of the transplant and occurrence of viral infections. Therefore, in case of relapse, delayed administration of donor T cells may be used. However, severe graft versus host disease represents a relatively frequent and potentially life-threatening complication of delayed infusion of donor T cells.

What are the methods of treatment available?

There are several classes of authorised medicinal products such as anti-infectives (given in order to prevent infection with some viruses or fungi), growth factors, serum-prophylaxis agents, and vaccines, which are used as additional treatment. Gancyclovir is authorised in the Community as an additional treatment (or adjunctive treatment) of the condition, in order to prevent infections with some viruses. However, there are no products authorised to improve the treatment with donor lymphocytes, which may be the case for the product subject to this designation.

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

According to the information provided by the sponsor approximately 8,000 patients are treated with haematopoietic cell transplantation each year in the European Union.

*Disclaimer: The number of patients affected by the condition is estimated and assessed for the purpose of the designation, for a European Community population of 385,000,000 (Eurostat 2002) and may differ from the true number of patients affected by the condition. This estimate is based on available information and calculations presented by the sponsor at the time of the application.

How is this medicinal product expected to act?

Cells involved in the immune response called T-lymphocytes are isolated from the donor and inoculated (transfected) with a viral gene (herpes simplex 1 virus –thymidine kinase) which makes them particularly susceptible to an antiviral medicine called gancyclovir. Therefore, once these Tlymphocyte cells containing the viral gene are administered to the recipient patient they can be eliminated (destroyed) by treatment with gancyclovir in case that they start to react against the
recipient tissues, namely when the risk of the development of graft versus host disease is imminent. Associated to the viral gene, herpes simplex 1 virus-thymidine kinase, these cells receive also an additional gene which is used as a marker for selecting only the cells in which the transfection was successful before the administration to the recipient patient.

What is the stage of development of this medicinal product?

At the time of submission of the application for orphan designation, clinical trials in patients treated with haematopoietic cell transplantation were ongoing.

The proposed medicinal product was not marketed anywhere worldwide for the adjunctive treatment of haematopoietic cell transplantation or designated as orphan medicinal product elsewhere for this condition, at the time of submission.

According to Regulation (EC) No 141/2000 of 16 December 1999, the Committee for Orphan Medicinal Products (COMP) adopted on 10 September 2003 a positive opinion recommending the grant of the above-mentioned designation.

Opinions on orphan medicinal products designations are based on the following cumulative criteria:
  • the seriousness of the condition,
  • the existence or not of alternative methods of diagnosis, prevention or treatment and 
  • either the rarity of the condition (considered to affect not more than five in ten thousand persons in the Community) or the insufficient return of development investments.

Designated orphan medicinal products are still investigational products which were considered for designation on the basis of potential activity. An orphan designation is not a marketing authorisation. As a consequence, demonstration of the quality, safety and efficacy will be necessary before this
product can be granted a marketing authorisation.

Key facts

Product details for <p>Herpes simplex 1 virus-thymidine kinase and truncated low affinity nerve growth factor receptor transfected donor lymphocytes</p>
Active substanceHerpes simplex 1 virus-thymidine kinase and truncated low affinity nerve growth factor receptor transfected donor lymphocytes
Medicine NameZalmoxis
Disease/conditionAdjunctive treatment in haematopoietic cell transplantation
Date of decision20/10/2003
OutcomePositive
Orphan decision numberEU/3/03/168

Review of designation

On 28 June 2016, the Committee for Orphan Medicinal Products (COMP) completed its review of the designation EU/3/03/168 for Zalmoxis (allogeneic T cells genetically modified with a retroviral vector encoding for a truncated form of the human low affinity nerve growth factor receptor (ΔLNGFR) and the herpes simplex I virus thymidine kinase (HSV-TK Mut2))1 as an orphan medicinal product for the adjunctive treatment of haematopoietic stem cell transplantation. 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 undergoing haematopoietic stem cell transplantation. The COMP recommended that the orphan designation of the medicine be maintained2.


1 Previously known as ‘herpes simplex 1 virus-thymidine kinase and truncated low affinity nerve growth factor receptor transfected donor lymphocytes’.

2 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 Zalmoxis for: ‘adjunctive treatment in haploidentical haematopoietic stem cell transplantation of adult patients with high-risk haematological malignancies’.

This falls within the scope of the product’s designated orphan indication, which is ‘adjunctive treatment of haematopoietic stem cell transplantation’.

The COMP concluded that there had been no change in the seriousness of the condition since the orphan designation in 2003. Haematopoietic stem cell transplantation remains long-term debilitating and life threatening because it makes the patient more susceptible to severe infections and may lead to graft-versus-host disease (when transplanted cells attack the body).

Prevalence of the condition

The sponsor provided updated information on the prevalence of haematopoietic stem cell transplantation based on data from the annual activity survey of the European Society of Blood and Marrow Transplantation.

On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of haematopoietic stem cell transplantation remains below the ceiling for orphan designation. At the time of the review of the orphan designation, it was estimated that 0.32 people in 10,000 per year undergo haematopoietic stem cell transplantation. This is equivalent to a total of around 16,000 people per year 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 use in haematopoietic stem cell transplantation. These included medicines to reduce the risk of infections and to help restore the immune system, such as antiviral medicines, antifungal medicines, immunoglobulins (blood proteins that have been extracted from donor plasma), growth factors and vaccines. Medicines that suppress the immune system, such as ciclosporin, were used for the treatment of graft-versus-host disease.

Significant benefit of Zalmoxis

The COMP concluded that the claim of a significant benefit of Zalmoxis in haematopoietic stem cell transplantation is justified because Zalmoxis was shown to improve survival and reduce the number of patients who developed graft-versus-host disease after haematopoietic stem cell transplantation, compared with data from databases of previous patients who received the best standard care after transplantation.

Therefore, although other methods for the treatment of this condition have been authorised in the EU, the COMP concluded that Zalmoxis is of significant benefit to patients undergoing haematopoietic stem cell transplantation.

Conclusions

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

Related information

Sponsor’s contact details:

MolMed SpA
Via Olgettina 58
Milan
Italy
Tel. +39 02 212 771
Fax: +39 02 21 27 72 20
E-mail: info@molmed.com

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.