In December 2004, the Bill and Melinda Gates Foundation of Seattle, Washington, awarded a $42.6 million, 5-year grant to develop a semi-synthetic form of artemisinin, a highly effective anti-malarial drug. Currently, artemisinin is derived from the leaves of a traditional Chinese medicinal plant that Westerners often call sweet Annie (Artemisia annua L., Asteraceae).1 The Gates Foundation awarded the grant to the Institute for OneWorld Health to fund a partnership among Amyris Biotechnologies, OneWorld Health, and the University of California at Berkeley. The goal of the partnership is to create a more affordable and accessible semi-synthetic version of the anti-malarial drug artemisinin. The partners are collaborating to manufacture microbes: single-celled bacteria that produce a semi-synthetic version of artemisinin, which is a purified bioactive substance from sweet Annie.
Malaria is a deadly, yet preventable disease that infects between 300-500 million people annually, and it claims the lives of one million Africans each year. Most of the malaria-related deaths occur to children under the age of five. According to the most recent World Health Organization (WHO) figures, 3.2 billion people living in 107 countries or territories are at risk for contracting the illness.2 In Africa, the countries with the highest disease burden also experience a 1.3 % annual reduction in economic growth.3 "It is unacceptable that 3,000 African children die every day from a largely preventable disease," said Mr. Gates in his press release. "Malaria is robbing Africa of its people and its potential."4
Development of Semi-Synthetic Artemisinin
Artemisinin is part of the new class of anti-malarial drugs known as Artemisinin-based Combination Therapies (ACTs).2 ACTs are significant because they have been approved by various international health organizations such as the WHO and the United Nations Children's Fund (UNICEF) as the first-line treatment for malaria in Africa.
Kinkead Reiling, PhD, co-founder of Amyris Biotechnologies, said that researchers are genetically engineering microbes to produce a chemical precursor of artemisinin, which is then purified from the microbe and chemically manipulated to create artemisinin. "We're taking what nature does best and linking it to what chemistry does best. It's the best of both worlds," Reiling said (oral communication, July 2005).
Jack Newman, PhD, co-founder of Amyris Biotechnologies, said that the partnership hopes to have this bioequivalent, microbially-produced artemisinin available for distribution within 5 years (oral communication, February 2005). According to Joanne Hasegawa, associate director of communications for the Institute for OneWorld Health, "If we meet our milestones within that timeframe, we will have a regulatory package, which includes all the studies necessary to satisfy an FDA or European regulatory body with other requirements for safety," (oral communication, June 2005).
Shortage of Plant-Based Artemisinin
An artemisinin shortage became apparent shortly after international health organizations, such as the Global Fund, WHO, UNICEF, and the United States Agency for International Development, decided to phase out the older less-effective conventional drugs, such as chloroquine, amodiaquine, or sulfadoxine-pyrimethamine,5 and officially adopt ACT combinations, which use artemisinin and its derivates arthemether and artesunate.6
Over the years, the inappropriate use, poor management, and continued use of conventional anti-malarial drugs have all contributed to increased resistance to these drugs, which has increased mortality and morbidity.5
"When you don't take the full dosage of an antibiotic, it can contribute to resistance so that the drugs don't work. We want to make the semi-synthetic drug so inexpensive that it takes away the incentive to not take the pills, save them, or sell them," says Reiling, referring to the resistance problems associated with chloroquine-type anti-malarial drugs that pre-dated artemisinin.
In November 2004, the New York Times reported that until early 2004, the total annual consumption of raw artemisinin was about 30 tons. The price of artemisinin had remained constant for several years at $115 per pound. In April 2004, when the WHO forecasted that the total world requirements for 2005 would be between 130 to 220 tons, the price of artemisinin jumped to $180 dollars per pound, then to $365, and later to $455 per pound.6 To combat the shortage and steep price increases, each member of the partnership is taking specific steps to help ensure the affordability of artemisinin. For example, UC-Berkeley gave Amyris and OneWorld royalty-free licenses to develop its technology for the anti-malarial drug.7 "Our goal is to cut the total price of the drug by 10 times, down to about 25 cents per dosing," Reiling said (oral communication, February 2005).
OneWorld, a non-profit pharmaceutical, is performing the necessary regulatory and non-clinical work required by health agencies in the United States and Europe, so interested pharmaceutical manufacturers will be able to substitute the semi-synthetic version of artemisinin for the plant-derived product. Amyris, working on its first project since incorporation in 2003, will produce and sell the anti-malarial drug at its cost.7 "If we create a bigger volume, we can lower the price. It's an economy of scale," Reiling continued (oral communication, February 2005).
Benefits of Semi-Synthetic Artemisinin
The Gates grant to develop a semi-synthetic form of artemisinin is significant for several compelling reasons. First, an affordable, effective bioequivalent of artemisinin is important because the artemisinin derived from sweet Annie is extremely expensive. The plant-derived ACTs, which are available for $.75 and $2.75 per treatment,2 cost more than 10 times as much as the older more conventional anti-malarial drugs, such as chloroquine and sulfadoxine-pyrimethamine.6,8 If the grant work is successful, this new bioequivalent drug will be less expensive than the artemisinin derived from the plant. "If we are able to reach our production goals, our artemisinin will be less expensive than the current price for the plant-derived product, which is currently $2.40 per treatment. While this number is small by Western standards, it is prohibitive for those living in much of Africa," Reiling said (e-mail, June 16, 2005).
Second, there is a growing shortage of the plant-derived artemisinin as the drug transitions to the first-line treatment in most affected countries. Amyris scientists believe that the semi-synthetic drug will help with shortage problems because, "our process will be very scalable, and thus will be able to meet world demand," Reiling said (e-mail, June 16, 2005).
Third, the shortage of sweet Annie plants and the rising costs of production create considerable concern for the WHO and other international public health officials. According to a New York Times article, the rising demand for the drug, brought on by endorsement of international health organizations, coupled with the supply shortages, have caused the price of sweet Annie to quadruple.6
Finally, Reiling explains that another ancillary benefit of developing a consistent, affordable supply of bioequivalent artemisinin is that this new technology would have less of an environmental impact than traditional planting and cultivation (oral communication, February 2005).
References
1. Hasegawa J. Collaboration of biotech, academia, and nonprofit pharma could significantly reduce cost, boost supplies of antimalarial drug [press release]. San Francisco, CA: Institute for OneWorld Health; December 13, 2004.
2. WHO and UNICEF. Malaria World Report 2005. Available at: http://rbm.who.int/wmr2005/index.html. Accessed May 25, 2005.
3. WHO and UNICEF. Malaria Burden. World Malaria Report 2005. Available at: http://rbm.who.int/wmr2005/html/1-2.htm. Accessed May 27, 2005.
4. Fuller J. Funding Commitment to accelerate malaria research [press release]. Seattle, WA: Bill and Melinda Gates Foundation; September 21, 2004.
5. The World Health Organization. Roll Back Malaria Infosheet. Facts on ACTs (Artemisinin-based Combination Therapies), An Update on Recent Progress in Policy and Access to Treatment. Available at: http://www.rbm.who.int/cmc_upload/0/000/015/364/RBMInfosheet_9.htm. Accessed June 6, 2005.
6. McNeil DG Jr. Plant shortage leaves campaigns against malaria at risk. New York Times. November 14, 2004. Available at: http://www.nytimes.com/2004/11/14/international/asia/14malaria.html?ex=1134450000&en=7ce7c3af52873986&ei=5070.
7. Hasegawa J, Sanders R, Melis C. $42.6 million five-year grant from Gates Foundation for antimalarial drug brings together unique collaboration of biotech, academia and nonprofit pharma [press release]. San Francisco, California: Institute for OneWorld Health, UC Berkeley, Amyris Biotechnologies; December 13, 2004.
8. WHO and UNICEF. Global Financing, Commodities and Service Delivery. World Malaria Report 2005. Available: http://rbm.who.int/wmr2005/html/3-1.htm. Accessed: May 27, 2005.