Project aim: Registration of two artesunate-based combination therapies for use in endemic countries in Africa, Asia and Latin America. Drugs to reach patients by 2006. About malaria: Every year, malaria kills 1-2 million people. 90% of deaths occur in sub-Saharan Africa. The disease is present in over 100 countries and threatens 40% of the world's population. Treatments exist but, in recent decades, drugs such as chloroquine or sulphadoxine-pyrimethamine have become increasingly ineffective because of drug resistance. Resistance has spread so far that it now represents a serious threat to global public health (see map below).
Scientists now agree that the most effective treatment against malaria is a combination of drugs using artemisinin derivatives, highly potent extracts of the Chinese plant Artemesia annua. Artemisinin-based combination therapy (ACT) is the quickest and most reliable way of clearing malaria infection, and it is very well tolerated. Using a combination of drugs shortens the treatment course, and has also been shown to protect each individual drug from resistance. The World Health Organization (WHO) is now actively encouraging malaria-endemic countries to switch to ACT, and many of them are starting to do so. Overall, 40 countries in the world have included ACT in their malaria treatment protocols and a further 14 are considering doing so. Why the need for fixed-dose combinations? Compliance to treatment is crucial to ensure treatment effectiveness and prevent future resistance to ACT. But when combinations are provided as two separate drugs, patients might take only of one the two drugs or fail to complete the whole course. The protection against resistance is also lost if one drug can be taken without the other. To optimise patient compliance, it is therefore important to provide patients with fixed-dose combinations (two drugs combined into one tablet) rather than separate tablets. So far, only one fixed-dose ACT exists, CoartemÃ?® (an association of artemether and lumefantrine). Although extremely effective, it needs to be taken with a fatty meal, can cause gastric side-effects, and is expensive. New fixed-dose combinations are therefore necessary to offer endemic countries a wider range of treatment options adapted to their needs. This is what the Drugs for Neglected Diseases Initiative (DNDi) has set out to do. Basic facts about DNDi's Fixed-dose Artesunate Combination Therapy (FACT) project One of the first priorities of DNDi is the fast-track development and testing of two fixed-dose ACTs: artesunate with amodiaquine (AS/AQ) for use in Africa, and artesunate with mefloquine (AS/MQ) for use in Asia and Latin America. The use of a fixed-dose combination, in strengths adapted to the patients' ages, will allow a simple treatment of just three days, with a single daily administration of one or two tablets. The advantages are manifold:
- Rapid effect
- High cure rate (over 90%)
- Reduction of potential for transmission (less infective parasite in the blood)
- Ease of use (which increases compliance and therefore treatment effectiveness)
- Coverage of the whole population at risk (treatment can be used in both children and adults)
- Prevention of resistance and therefore further reduction of transmission
- Cheaper than buying combination of separate tablets or blister pack FACT: phases of development The FACT project has already undertaken:
- Formulation of the two fixed-dose combinations in both adult and child dosages: combining the two drugs, maintaining correct dosage of both components, and testing for stability under stress (e.g. heat and humidity). Ã?¿ Stable formulations have been developed.
- Batch production of fixed-dose combinations: pilot-scale productions for use in clinical trials and stability studies for registration.
- Production of AS/MQ with Far Manguinhos in Brazil and AS/AQ contracted out to a company in Germany. Randomised controlled trials of the two combinations are now ready to start in Burkina Faso (for AS/AQ) and Thailand (AS/MQ). Each trial will involve more than 500 patients (adults and children), and will compare the use of the fixed-dose combination to the free association of separate tablets. Results are expected in 2005. Complete registration dossiers are being prepared simultaneously and will be filed at the end of 2005. The combinations are expected to become available to patients in 2006. Future use of fixed-dose combinations in malaria-endemic countries Twelve countries have already adopted artesunate amodiaquine as their national first-line treatment and five have adopted first-line artesunate mefloquine . These countries will undoubtedly choose to switch to fixed-dose combinations once they become available, and many other countries may choose to adopt them. Assessing future need for ACT, the World Health Organization has forecast that in 2005, 90 to 150 million treatments will be needed (based on total morbidity estimates). Africa, the worst-hit continent, makes up 60-70% of this global requirement. To meet this huge need several industrial partners will have to be involved in the manufacture of both combinations at low cost. All malaria-endemic countries will benefit from the availability of a wider range of safe, effective and easy to use fixed-dose combinations.