Bulletin of the World Health Organization

New type of R&D cooperation spawns malaria drugs

Artemisinin-based combination therapy drugs (ACTs) are the most effective malaria medicines to date, but many of the world’s poorest countries can not afford them. Two ACTs that are due to go on the market this year may help to fill the gap.

Members of the Brazilian team at Farmanguinhos.
Members of the Brazilian team at Farmanguinhos.

Artemisinin-based combination therapy drugs (ACTs) drugs are seen as a new way forward to treat malaria. But combining these medicines into a single tablet is often a challenge, and like most innovations is rarely tackled by scientists in developing countries.

Recently, however, a team from Brazil’s Farmanguinhos, an institute of the Oswaldo Cruz Foundation (FIOCRUZ), solved the scientific puzzle of how to combine two antimalarials, artesunate and mefloquine, into one tablet.

“Artesunate is a very tricky substance to work with,” said Solange Wardell, coordinator of the Brazilian team, adding: “a slight increase in humidity could make artesunate decompose, thereby ceasing to be active.”

Wardell said it was essential that the combined drug be stable in tropical, humid climates where malaria is prevalent. It took a year of experiments to achieve that stability.

Brazil is one of several countries involved in a project run by a non-profit group Drugs for Neglected Diseases Initiative (DNDi) to develop fixed-dose artesunate-based combination medicines. Brazil’s state-owned laboratory Farmanguinhos is perhaps best known for manufacturing generic versions of antiretroviral drugs that have helped to cut treatment costs for AIDS in developing countries.

As striking as Brazil’s role was the participation of other unusual players in the project. Traditionally, research and development (R&D) in the pharmaceutical sector is done in developed countries; little innovation comes out of developing countries due to lack of funds, know-how and research-based pharmaceutical industries. This project based mainly on cooperation between developing countries marks a change. In addition to Brazil, Burkina Faso, Malaysia and Thailand were key players.

Malaria kills more children aged under 5 years old in sub-Saharan African than any other infection.
WHO/Stephenie Hollyman
Malaria kills more children aged under five years old in sub-Saharan Africa than any other infection.

When Jean-René Kiechel, who held senior R&D management positions in the pharmaceutical industry, left the industry after three decades, he certainly broke the mould. “I heard about DNDi and was interested in the fact that it was trying to develop new drugs for neglected diseases. I felt I could contribute,” said Kiechel, who subsequently became the project manager for the malaria medicines initiative.

Drug resistance is a major problem for treating malaria. In many parts of Africa single treatments for malaria, such as chloroquine, have lost their effectiveness because malaria parasites in humans’ blood have become resistant to drugs designed to kill them. As a result, there is a huge demand for ACTs, drugs based on derivatives of artemisinin, a potent extract of the Artemesia annua plant.

No resistance to ACTs has been reported to date, but there is currently only one fixed-dose ACT combination on the market, Coartem, produced by Novartis. This product is on the WHO prequalification list of products recommended for purchase by UN and other agencies. WHO and UNICEF are making it available at US$ 2.4 per adult course of treatment, but for some countries even this is too expensive.

Every year Africa accounts for more than 60% of an estimated 350–500 million clinical cases of malaria globally, while children in Africa account for 80% of nearly one million malaria-related deaths worldwide according to WHO’s Rollback Malaria department.

Many African countries have changed their national malaria treatment policy, switching from single to combination treatment. But the problem is that countries can not afford the new combination drugs, which are much more expensive than the old medicines.

Another problem is the laborious way medicines must be taken to treat malaria. Failure to stick to the exact dosages, taking one drug without the other or, as, often happens, not completing the course can reduce the effectiveness of the treatment.

Seeing the urgent need to develop a more effective and more affordable form of malaria treatment, Geneva-based DNDi sought to develop two fixed-dose combinations each containing two d rugs in one tablet. “The idea was that instead of having to take a different number of drugs each day you would take one or two fixed-dose combination tablets once a day for three days,” Kiechel said.

While the Brazilian team combined artesunate and mefloquine into a medicine known as AS/MQ, a team at the University of Bordeaux 2, France, combined artesunate and amodiaquine to produce a second antimalarial, AS/AQ.

The UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) provided scientific advice for the project, and helped coordinate clinical trials. Funding came from different sources. DNDi provided US$ 4.4 million for both the clinical research and registration application scheduled for this year; INCODEV, a European Union programme that promotes cooperation between developing countries provided US$ 1.39 million; Farmanguinhos contributed US$ 614 000. In addition, TDR provided US$ 538 000 and Médecins Sans Frontières (MSF) provided US$ 180 000.

Children in Africa account for 80% of nearly one million malaria-related deaths worldwide.
WHO/Stephenie Hollyman
Children in Africa account for 80% of nearly one million malaria-related deaths worldwide.

In parallel with the Brazilians, the French team was coordinated by Pascal Millet of the Bordeaux University 2 School of Medicine. He set up a public–private partnership with the university’s laboratories and French start-up, Ellipse Pharmaceuticals, to develop AS/AQ. Like the Brazilians, this team also succeeded in developing a stable combination.

The next step was the clinical trials. The Sains University in Malaysia did some of the studies, including Phase 1 trials of AS/AQ in healthy human volunteers, prepared technical reports for the drug registration files for both projects, and provided analytical support for other studies required for registration. Dr Visweswaran Navaratnam, Professor of Tropical Clinical Pharmacology at Sains, was the Scientific Programme Leader supervising this part of the project.

The team from Burkina Faso’s Centre National de Recherche et de Formation sur le Paludisme did the safety and efficacy field trial of AS/AQ. Their contribution was also crucial, explained Kiechel, because they conducted trials among small children there. Children aged under one year are one of the most vulnerable groups to malaria.

The third phase of clinical trials of AS/MQ were done by a team from Mahidol University in Thailand, further testimony to the project’s cooperation between developing countries. Sornchai Looareesuwan, Director of Emerging and Re-emerging Diseases Research Programme and his team did studies to compare the efficacy and tolerability of the combined AS/MQ drug with that of the two component drugs taken separately.

DNDi has a contract with French pharmaceutical group, Sanofi-Aventis, to manufacture AS/AQ. The first marketing authorization applications were expected to have been submitted at the end of 2005. The French group has indicated that it will make AS/AQ available at cost price to the national health services of countries that have registered it, as well as to NGOs and international organizations, according to Clive Ondari, Coordinator at WHO’s department of Medicines Policy and Standards. Farmanguinhos is in discussions with possible partners in Asia to manufacture AS/MQ.

Once AS/AQ and AS/AM are approved by regulators and prequalified by WHO, developing countries will be eligible for grants from the Global Fund to fight HIV/AIDS, Tuberculosis and Malaria to purchase the new products.

“The biggest challenge for us will be to obtain all the requirements needed for exporting the drug,” said Wardell, explaining that registering AS/MQ in Brazil and other countries was a new activity for Farmanguinhos. To help them, DNDi has provided a consultant.

Like the Brazilians, other teams from developing countries involved in the project took on unfamiliar tasks. Navaratnam said the need to supplement and integrate varying levels of knowledge and skills between partners in developed and developing countries had been a challenge. “Additional time was needed to ensure new methodologies transferred were properly adapted and realized,” he said.

The challenge, from Millet’s point of view, was uniting scientists and private entities towards the same goal of providing a stable pharmaceutical product that was transferable to an industrial partner. Nevertheless Millet, like other players, echoed how pleased he was to “work on an international project with so many different and complementary people at the international level”.

Clare Davidson, Sao Paulo.