LISBON — More antimalarial drugs are in the developmental pipeline today than at any other time in history, Dr. Elizabeth A. Ashley reported at the 12th International Congress on Infectious Diseases.
Two main factors can explain this welcome state of affairs. One is the impressive productivity of Chinese scientists in the People's Republic in exploiting the potential of Artemisia annua, the plant also known as sweet wormwood or qing hao, from which artemisinin and related drugs are derived.
The other major factor has been the recent creation of public-private partnerships to aggressively support the drug development process, from compound identification through regulatory approval. In 2006 alone, the Medicines for Malaria Venture will take on 5–10 new drug discovery projects. Other major players include the Drugs for Neglected Diseases Initiative and World Health Organization-sponsored programs.
Universities, foundations, pharmaceutical companies, and other institutions have pitched in. For example, the Walter Reed Army Institute of Research is expediting development of intravenous artesunate for severe malaria. Food and Drug Administration approval could come next year, said Dr. Ashley of the University of Oxford Tropical Medicine Program and the Shoklo Malaria Research Unit, Mae Sot, Thailand.
But the first new drugs for uncomplicated falciparum malaria to reach the market will be novel combinations of old drugs. WHO malaria treatment guidelines issued earlier this year declare artemisinin-combination therapies (ACTs) the new standard of care because strains resistant to chloroquine and sulfadoxine/pyrimethamine have become so common. The emphasis now is on developing affordable fixed-dose ACTs in a single pill having at least two unrelated mechanisms of action to prevent artemisinin resistance and boost adherence.
Only one fixed-dose ACT is available internationally. Artemether-lumefantrine (Coartem) is registered in 75 nations. Novartis markets it at a subsidized cost of $2.50 per course for adults. That's still a lot of money in the poorest parts of the world, but “it's easy to imagine that once other fixed combinations come into the market, prices will fall,” Dr. Ashley said.
Among the new combinations of old drugs that are likely to earn broad international approval within the next year or so are artesunate-pyronaridine, dihydroartemisinin-piperaquine, chlorproguanil-dapsone-artesunate, artesunate-mefloquine, and artesunate-amodiaquine, she said at the congress, which was sponsored by the International Society for Infectious Diseases.
Some of these agents are undergoing redevelopment to meet international standards. Dihydroartemisinin-piperaquine, for example, has been used extensively in China and Vietnam since 1989 but isn't used elsewhere because China's Good Manufacturing Practice standards aren't internationally recognized.
That's also the case for parenteral artesunate. The older Chinese/Vietnamese version has to be mixed with a small vial of sodium bicarbonate shortly before administration. In contrast, the Walter Reed product designed for international approval comes premixed in an ampule.
“It's going to be a 10-cc volume, the only drawback of which will be for intramuscular injection in children in endemic countries. But this is certainly good news for returning travelers to the U.S. who otherwise would be faced with quinine,” Dr. Ashley observed.
The physician noted that the landmark South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) recently showed in 1,461 randomized patients with severe falciparum malaria a compelling 35% reduction in the relative risk of death with artesunate (Lancet 2005;366:717–25).
Ten or more antimalarial drugs are poised for approval in 3–5 years. Many are novel agents, some acting on new targets. They include cysteine protease inhibitors to curb hemoglobin degradation, third-generation antifolates, synthetic peroxides, and farnesyltransferase inhibitors. Also in development are new synthetic artemisinin derivatives devoid of neurotoxicity in animals, unlike earlier derivatives.
In addition, tafenoquine is a long-acting 8-aminoquinoline now in clinical trials to replace 2 weeks of primaquine for nonfalciparum malaria. As with primaquine, it is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency.
The emphasis now is on developing affordable fixed-dose artemisinin-combination therapies in a single pill. DR. ASHLEY