Statistics from Altmetric.com
IN all the media coverage following the announcement of the winners of this year's Nobel prize for physiology or medicine, an interesting aspect has tended to be overlooked. The prize was awarded in two parts this year, for discoveries which have revolutionised the treatment of parasitic diseases affecting people in some of the world's poorest populations: to Youyou Tu, of China, for her discovery of the antimalarial drug artemisinin, and jointly to William C. Campbell and Satoshi Ō mura, for their discovery of the endectocide avermectin. As the Nobel Assembly explained, artemisinin has significantly reduced mortality rates for patients suffering from malaria, while derivatives of avermectin, most notably ivermectin, have radically lowered the incidence of river blindness and lymphatic filariasis, as well as showing efficacy against other parasitic diseases. ‘These two discoveries,’ the assembly pointed out, ‘have provided humankind with powerful new means to combat these debilitating diseases that affect hundreds of millions of people annually. The consequences in terms of improved human health and reduced suffering are immeasurable.’
These and other aspects of the discoveries have been widely reported. However, what seems to have been missing from many of the media reports is mention of the fact that one of these drugs was initially developed, and successfully marketed, for veterinary use. At a time when interest is being expressed in ‘One Health’, and when there is concern about the prospect of new classes of drug being developed for use in human patients, let alone in animals, the story of how ivermectin found application in human medicine is every bit as inspiring as that behind the discovery of the drug itself.
The discovery arose out of a research partnership established in 1973 between the Kitasato Institute in Japan and Merck, Sharpe and Dohme (MSD) research laboratories in the USA, which involved screening naturally produced compounds for potential therapeutic activity. Satoshi Ō mura, a microbiologist at the Kitasato Institute with expertise in detecting biologically active compounds produced by environmental microorganisms, isolated a new species of Streptomyces from soil, and sent it, along with about 50 other microbial samples which looked promising, to the MSD laboratories in the USA for further testing. (Famously, the soil samples were taken near a golf course overlooking the sea at Kawana.) In the USA, William Campbell, a parasitologist who originally graduated from Trinity College, Dublin, showed that a component from one of the cultures was remarkably efficient against parasites in domestic and farm animals; this component was purified and named avermectin, and subsequently modified to an even more effective compound, ivermectin.
Ivermectin was introduced to the market as a veterinary antiparasitic drug in 1981. It proved to be highly effective, and also highly successful, soon becoming the market leader. Five years after its introduction it was registered for use in 46 countries and was being used worldwide to treat approximately 320 million cattle, 151 million sheep, 21 million horses and 5.7 million pigs; in 2004, annual sales were about US $1 billion (Ō mura and Crump 2004).
As well as being effective against intestinal nematodes, ivermectin was also found to have durable long-term activity against microfilariae (first stage larvae) of filarial nematodes. In 1977, encouraged by positive results from animal studies, especially in terms of reducing canine heartworm, Campbell proposed that the avermectin class should be tested for use in humans with parasitic infections causing river blindness (onchocerciasis), which had long been a problem in many parts of the world. The first human trials involving ivermectin (under the brand name Mectizan) began in Senegal in 1981, followed by large-scale field trials in Ghana, Guatemala, Ivory Coast, Liberia, Mali, Senegal and Togo. Following an international partnership involving the public and private sectors, as well as governments and affected communities in disease endemic countries, the human formulation of ivermectin was registered for use by French regulators in 1987, with mass administration starting in 1988.
Use of ivermectin transformed the treatment of river blindness, control of which had previously relied on the use of insecticides to reduce populations of the blackfly vector in affected regions. However, in view of the fact that the communities affected by river blindness were unlikely to be in a position to afford the drug, a key element in the success of the programme was a decision by MSD to make it available free of charge. In 1987, having received the consent of the Kitasato Institute, which agreed to forgo royalties, P. Roy Vagelos, then chief executive of MSD, announced that ivermectin would be provided free of charge for the treatment of river blindness, for ‘as long as it is needed’. In 1998, donation of the drug was extended to include programmes aimed at eliminating lymphatic filariasis (elephantiasis) in regions where lymphatic filariasis and onchocerciasis coexist. As the Nobel Assembly pointed out when announcing the Nobel prizes last week, both river blindness and lymphatic filariasis are on the World Health Organization's list of Neglected Tropical Diseases, and the targets for the elimination of these diseases (2020 for lymphatic filariasis and 2025 for onchocerciasis) are now within reach.
Reflecting on the development of ivermectin in an article published more than a decade ago in Nature Reviews Microbiology, Ō mura and Crump (2004) remarked that serendipity played a role and that ‘The drug arose from a unique international collaboration between the public and private sectors. The development process also incorporated the world's first and largest drug donation programme and involved a unique association between governments, non-governmental organisations and industry.’ Serendipity is hard to engineer and the combination of circumstances that led to the success of ivermectin is perhaps unlikely to be repeated. Nevertheless, with attention now focusing on where new generations of drugs might come from, particularly with regard to antimicrobials, it is worth reflecting on the history of its development and what might be learned for the future.