Chemotherapy of protozoal infections

Obiettivo

A.BACKGROUND

The health of the vast majority of the world's population is at risk of infection by protozoan parasites. Malaria, leishmaniasis and trypanosomiasis are causes of the suffering of hundreds of millions of people in both tropical and subtropical zones of the world. However, the available therapeutic tools for the treatment of these diseases are extremely limited. Many of the available drugs were developed in the first part of this century and are not without risk. Some of the drugs such as the arsenicals in the treatment of late stage sleeping sickness or the antimonials for the treatment of leishmaniasis, can only be applied with permanent medical surveillance or hospitalization. Many of the parasites have developed some degree of resistance, which in the case of malaria now has extended to almost all available drugs and the prevalence of multiple drug resistance has become a major public health problem. A further development of resistance is expected by the fact that most of the available compounds belong to a restricted group of chemical structures that are widely applied often by self-medication.

Previous funding by International and National organizations, such as the Commission of the European Union (CEU), the United Nations Development Programme (UNDP)/World Bank/World Health Organization (WHO) Programme for Research and Training in Tropical Diseases (TDR) and the Wellcome Trust (at present one of the most important funding organizations for biomedical research in the UK), into the basic studies of metabolic differences between parasite and host, or via more traditional routes, has led to the identification of a great number of novel and potential chemotherapeutic targets and many new lead compounds have been identified.

However, the costs and risks of the development of new drugs for the Third World by the pharmaceutical industry are out of balance with the perceived limited profits and the long pay-back period. Repeatedly the production of existing drugs that have already been produced for many years is threatened with discontinuation, because of limited markets or the potential risks incurred by the companies because of suspicion of toxicity, teratogenicity or carcinogenicity of those compounds. For environmental reasons, there is in Germany now the threat of a ban of the production of arsenical drugs, desperately needed for the treatment of African sleeping sickness. Already this year thousands of people have died in Zaire, Angola and other endemic countries for lack of drugs due to a break in the production of melarsoprol. Thus within the present setting it is almost impossible for the pharmaceutical industry to embark upon the development of new anti-parasitic drugs. Therefore, specific measures have to be taken by National and International Agencies to activate actual product development. In this respect an initiative recently taken by the UNDP/World Bank/WHO Programme for Research and Training in Tropical Diseases to set up an Alliance for Product Development, that involves close contacts with Pharmaceutical Industry, is exemplary (see Annex 1).

Despite the above problems, the private sector may not yet have been lost for anti-parasitic drug development for various reasons: there may be real market opportunities for antimalarial drugs; on a quantitative basis, there is more demand for antimalarials, both as prophylactics as well as for treatment, than for any other medication in the world. Basic research in the area of trypanosomatids, responsible for South American Chagas' disease, African sleeping sickness and the three manifestations of leishmaniasis (the visceral, the cutaneous and the mucocutaneous form of the disease) has revealed that these organisms are all closely related, harbouring highly similar metabolic pathways and cellular structures, offering possibilities for one drug to act on more than one type of parasite.

B.OBJECTIVES AND BENEFITS

Research and Development is becoming more and more complex and costly. It is estimated that the development of a new drug costs as much as ECU 150 million (US $200 million) and may take ten years or more. Successful drug development requires large and dedicated teams of professionals to encompass discovery and the various steps of development, registration, and distribution. This expertise and these resources are only available within the pharmaceutical industry. Today, only very few companies can afford to embark on the development of a new drug and they usually target high volume, high profit diseases.

For tropical diseases, the pharmaceutical industry has indicated the need for collaboration with Academia, National Governments and specialized National and International organizations (WHO, the CEU and Wellcome), before they consider embarking upon the development of any anti-parasitic compounds. International bodies could help in expediting drug research and in curtailing the costs of drug development. The international and national research programmes have created a wealth of possibilities for early drug evaluation. In the case of parasitic diseases, this requires a large number of different model systems for each given compound. As an example for African trypanosomiasis, to maintain in vitro cultures of both human and bovine bloodstream-form trypanosomes, rodent in vivo models of both the acute early phase and the late (meningoencephalitic) phase as well of primates, for the sake of drug development, is obviously too costly for any individual company, against the background of the market value of potential products. Collaboration between the private and the public sector research institutes could facilitate the wide evaluation of new drugs.

A framework has to be created, which should allow a free flow of scientific results related to drug action and drug efficacy in which the pharmaceutical industry should feel confident to take part in joint ventures, to share investments, risks and eventually benefits.

The network that is to be put in place should create the environment for facilitating exchange of information and ensuring that opportunities are created, evaluated and developed. Regular meetings would be held to facilitate such interactions.

The idea stems from the concept of the "virtual company", that is: a temporary and open alliance of Academia, independent companies and public institutes sharing expertise, resources, costs, risks and eventually access to the market. The involvement of research programmes would facilitate the networking and provide moral support to the concept. The virtual company approach differs from the more classical cooperation in that it has no tangible high capital and management entity; rather it capitalizes on what each partner can best contribute, and lasts for the time of a specific project (like a task force). Thus partners can be coopted according to their expertise in relation to the current projects. The major added value of such an approach is that it allows rapid progress and cost sharing, capitalizes on strengths, and requires the mobilization of only limited (dedicated) staff. It does not require external costs nor building up new in-house capacities.

Coordination of the networking will still be relatively management-intensive and contractual arrangements might slow down the process significantly. Therefore, it is felt that the platform to be created by the new COST Action should be mainly involved in reviewing the problems involved in drug development and in promoting the interaction between scientists, the private sector and political bodies and to provide them with the knowledge and know-how for the identification of new drugs. However, the actual development of a compound could also be supported by other activities. In this connection is should be emphasized that this initiative will reinforce and consolidate the European role in this field and complement efforts that have been initiated by WHO.

C.SCIENTIFIC PROGRAMME

The major activity in this concerted action will be the phased planning and setting up of a number of expert meetings addressing the different stages of drug development. The topics that will be addressed are:

1)the identification of new drug targets with special emphasis on targets that are common to more than one parasite; the identification of new lead compounds and of compounds with known activity that deserve further development;

2)in vitro and in vivo models for drug testing and their respective merits and disadvantages;

3)the improvement of existing drug regimes through a better knowledge of their pharmacology and through the application of combination therapies;

4)interaction with the pharmaceutical industry and identification of additional funds for drug development for parasitic diseases.

An additional purpose of these workshops will be the preparation of expert documents that may assist National and International Agencies in seeking financial and moral support from and participation by pharmaceutical industry. These meetings will bring together a number of former EEC/STD3 and former COST Action 815 members, as well as present and future EU INCO-DC contract holders that have already identified new drug targets and lead compounds, or that

have relevant expertise in the various model systems available for drug screening. The proposed initial participants are indicated under Part II (Additional Information, List of experts). Specific consultants will be invited to participate in the workshops, according to the subject of the agenda, as well as representatives from European drug firms, public sector institutes and the European Union. In the first year of the COST Action programme the first two of a series of meetings are being planned. At the first workshop, that will place not later than six months after having signed the MoU with the Council, the strategy for future meetings will be developed by the participating members. Future participants that will include representatives of drug companies and National and International Agencies, also will be identified at an early stage.

In parallel to this new COST Action, which is entirely set up as a concerted action, an application for financial support of the regular shared cost aspects of this "Chemotherapy of protozoal Infections" network will be submitted to the CEU's INCO-DC programme, pharmaceutical industry, as well as the Member States in which the major activities addressed in this proposal take place, will be approached for additional funding, not only for extended collaboration but also to complement the laboratory activities in the area of drug-activity testing. In addition specific support will be sought to sustain the major activities in the Third World related to this proposal. It is, therefore, our intention to involve equally the International Organization for Chemistry in Development (IOCD) in these activities in order to promote the dialogue with Third-World chemists. The Member States most involved in the present proposal are: Belgium, France, United Kingdom, Sweden, Germany, Switzerland and Spain. Drug firms with an interest in antiprotozoal drugs that will be approached to participate in the initial workshops are: Glaxo-Wellcome, Rhone-Poulenc, Janssen Pharmaceutica, Novartis, Hoffman La Roche, Mrieux, Bayer, Zeneca, Hoechst, Marion Roussel, and Pharmacia-Upjohn.

D.ORGANIZATION AND TIMETABLE

The basic idea to introduce this new COST Action during the end of COST Action 815 is to avoid loss of impetus and expertise gained during the implementation of COST Action 815.

The first workshop

The first workshop, that is being planned to take place in autumn of 1997 or early 1998, will be prepared by the management committee of the new COST Action that will meet on 15 and 16 May 1997 in Leuven, Belgium on the occasion of the final COST 815 Acrival meeting. Topics that will be prepared for inclusion in this first workshop will be: the mode of action of the recommended, as well as experimental, drugs available for the treatment of trypanosomiasis, leishmaniasis and malaria and the identification of novel drug targets and drug targets common to more than one parasite. Working documents will be prepared by the participants with the aim of creating a comprehensive inventory of the existing and experimental drugs that are presently available for the treatment of protozoal diseases, a description of their mode of action, their limitations due to restricted availability, price, toxicity and resistance and recommendations for the need for new and better drugs. Special emphasis will be given to compounds with known activity in animal models, that have so far not been developed by Pharmaceutical Industry.

The second meeting

A second workshop, to be held in the second half of 1998, the date and place of which will still have to be decided, will address all the available in vitro and in vivo models for drug testing, their respective merits and disadvantages, the results obtained with these systems for the identification of active compounds and the selection of new lead compounds for further drug development. Working documents prepared before the start of the meeting may be used in the preparation of guidelines to improve and refine drug-screening procedures and that may assist chemists and drug developers in the synthesis of more active and less toxic compounds. The second workshop will also be devoted to the selection of additional parasitic diseases where specific problems with drug treatment have been identified and the selection of new partners for participation in future workshops.

Further workshops

Further workshops will be organized at a pace of at least one per year on a rolling schedule by the different participants of the new COST Action.

Documents

The documents ensuing from the workshops will be prepared in such a way that they can be used as reference documents for both workers in the area of parasitology and tropical medicine as well as for policy makers. They are meant as a catalyst to bring together the scientists from Academia, the field worker,

the government representative as well as the representatives from the pharmaceutical industry to work out new avenues for the development of novel and better drugs. They will give, on a disease by disease basis, a detailed account of the following items: overview of the present situation; discussion of the general problems encountered; the state of the art in drug treatment, including resistance; new drugs under development; experimental drugs in the process of being tested; areas of research that may lead to new drugs; old drugs that may need new attention; needs and requirements from National and International Organizations and Pharmaceutical Industry; prospects for the future. The documents will be distributed widely amongst chemists, parasitologists, government representatives and representatives of international organizations and drug companies.

E.ECONOMIC DIMENSION

The following COST countries have actively participated in the preparation of the Action or otherwise indicated their interest: Belgium, Denmark, France, Germany, Hungary, Italy, The Netherlands, Spain, Sweden, Switzerland, United Kingdom.

On the basis of national estimates provided by the representatives of these countries and taking into account the coordination costs to be covered over the COST budget of the European Commission, the overall cost of the activities to be carried out under the Action has been estimated, at 1997 prices, at roughly ECU 10 million.

This estimate is valid under the assumption that all the countries mentioned above but no other countries will participate in the Action. Any departure from this will change the total cost accordingly.

Programma(i)

IC-COST - European cooperation in the field of scientific and technical research (COST), 1971-

Argomento(i)

7 - Medical Research

Invito a presentare proposte

Data not available

Meccanismo di finanziamento

Data not available

Coordinatore

N/A

Contributo UE

Nessun dato

Indirizzo

Belgio

Costo totale