Onchocerciasis
The origins of ivermectin as a human drug are inextricably linked with Onchocerciasis (or River Blindness), a chronic human filarial disease caused by infection with Onchocerca volvulus worms. The parasites are transmitted via the bite of infected blackflies of the genus Simulium, which breed in highly-oxygenated, fast-flowing rivers and watercourses. In the human body, immature larval forms of the parasite create nodules in subcutaneous tissue, where they mature into adult worms. After mating, female worms can release up to 1000 microfilariae a day for some 10–14 years. These move through the body, and when they die they cause a variety of conditions, including skin rashes, lesions, intense itching, oedema and skin depigmentation (Fig. (Fig.2 ).2 ). Microfilariae also invade the eye, causing visual impairment and loss of vision, onchocerciasis being the second leading cause of blindness caused by an infectious disease.17) The disease causes visual damage for some 1–2 million people, around half of who will become blind.18)
Figure 2.
Mali: an old man, blinded by onchocerciasis, with leopard skin on his legs and nodules on his abdomen. Credit line: WHO/TDR/Crump.
In the early-1970s, the disease was endemic in 34 countries: 27 in Africa; 6 in the Americas; and 1 in the Arabian Peninsula. The World Health Organization (WHO) later estimated that 17.7 million people were infected worldwide, of whom some 270,000 were blind, and another 500,000 severely visually disabled. The burden of onchocerciasis was particularly extreme in the hyper-endemic belt across sub-Saharan Africa. Communities in these areas exhibited high rates of visual disability caused by Onchocerciasis, up to 40% in some areas, which caused immeasurable negative impact on individual and community health, reducing economic capacity and productivity, and leading to the abandonment of fertile agricultural lands.19)
By 1973, Onchocerciasis had been recognised by the then head of the World Bank, Robert McNamara, as a major disease of massive health and socioeconomic importance and one in dire need of combating in West Africa, and he became the key agent for change. In 1974, following international recognition of the dramatic consequences of disabling and disfiguring Onchocerciasis in Africa, four United Nations agencies, including the World Bank, launched the Onchocerciasis Control Programme in West Africa (OCP). The programme covered 1.2 million km2, protecting 30 million people in 11 countries from River Blindness.
Go to:
Drug donation
For over a decade, OCP operations were exclusively based on the spraying of insecticides by helicopters and aircraft over the breeding sites of vector blackflies in order to kill their larvae. Following the registration of ivermectin (produced under the brand name Mectizan®) for human use in 1987, in a hitherto unprecedented move and with unheralded commitment, Mectizan® was donated by the manufacturing company, Merck & Co. Inc., to treat onchocerciasis in all endemic countries for as long as it was needed. The resultant drug donation programme was the first, largest, longest running and most successful of all—and proved a model for all others that have followed. Ivermectin began to be distributed in 1988, with operations being organized through the independent Mectizan Donation Program (MDP) established and funded by Merck. Thereafter, OCP control operations changed from exclusive vector control to larviciding combined with ivermectin treatment or, in some areas, to ivermectin treatment alone. Ivermectin swiftly became the drug of choice for the treatment of Onchocerciasis due to its unique and potent microfilaricidal effects, the absence of severe side effects and its excellent safety. It is now the sole tool being used in disease elimination campaigns in the 16 other African countries where the disease exists, orchestrated by the African Programme for Onchocerciasis Control (APOC), which commenced operations in 1996. A single annual dose of 150 µg/kg of ivermectin, given orally, can reduce the level of skin microfilariae to zero and, by interfering with worm embryogenesis, can delay the build-up of new microfilariae for a period of up to two years. OCP was closed in December 2002 after virtually stopping disease transmission in all target nations except Sierra Leone where operations were hampered by civil war.
The process, from the discovery of ivermectin’s activity against onchocercal microfilariae to the successful distribution programme from 1988 onward, was neither an easy or direct path. Success was achieved through groundbreaking and innovative partnerships. The journey was a complex undertaking, incorporating scientific uncertainty, conflicting views, ambiguity, frustration, individual innovation and unexpected twists and turns. The actual discovery of ivermectin was an international team effort involving a unique, pioneering Public Sector/Private Sector partnership and the commitment and vision of several key individuals. Ivermectin’s development into a drug for human use also involved a number of organizational, individual and pharmacological variables—together with a large slice of luck, educated insight and personal commitment.
Go to:
Development of ivermectin for human use
In the mid-1970s, the global community mobilized itself to address the major problems of neglected tropical diseases. Following the setting up of the OCP in 1974, the UN-based Special Programme for Research & Training in Tropical Diseases (TDR) was established in 1975.20) Onchocerciasis, one of two filarial infections among TDR’s eight target diseases, was at that time a major public health problem affecting 20–40 million people in endemic areas. At exactly this time, a specialized novel anthelmintic mouse screening model in Merck’s research laboratories was identifying the avermectins in the microbial sample sent by the Kitasato Institute, of which ivermectin would become the most successful derivative.
At the time, there were no safe and acceptable drugs available to treat Onchocerciasis, which had plagued Africa for centuries, effectively leading to the creation of the OCP and its vector control focus. TDR quickly found that, despite many pharmaceutical companies, such as Bayer, Hoffman-LaRoche, CIBA-Geigy and Rhône-Poulenc, carrying out routing screening for filaricidal compounds, no companies were interested in developing suitable anti-Onchocerca drugs, as there was no apparent commercial market. Worse still, Onchocerca species would not develop to maturity in any rodents, making it impossible to screen compounds in an animal model against the target organism.21) It had been shown that O. volvulus could infect chimpanzees (Pan troglodites) but it was deemed unethical to use these animals for the necessary large-scale research, even though some testing of compounds was undertaken.22,23) Consequently, the OCP opted to devote operations to aerial larviciding via helicopters and small fixed-wing planes. It was a very ‘vertical’ programme, mainly coordinated through the World Bank and other UN agencies, with multimillion dollar contracts given to a US-based helicopter company and to an American chemical company for the insecticides.
Meanwhile, with respect to research needs, TDR had identified six specific areas that required special attention, with the discovery of effective and safe chemotherapeutic agents considered to be the highest priority. In 1975, only two drugs were available for the treatment of onchocerciasis: diethylcarbamazine (DEC) and suramin. The use of both was highly unsatisfactory. DEC, which was known to kill microfilariae, caused violent and even dangerous hypersensitivity reactions in the human host. Suramin, developed 50 years previously for treatment of Sleeping Sickness, was the only drug considered for killing adult worms but was highly toxic, often causing severe and occasionally fatal reactions. Moreover, parasitological cure of patients using DEC and suramin required lengthy and expensive treatment given under medical supervision. Therefore, the TDR Scientific Working Group (SWG), composed of leading independent scientists in the field from around the globe, including industry, decided that the priority was a new and non-toxic macrofilaricide (to kill adult worms), a macrofilaricide being determined to be substantially preferable to a microfilaricide (which would target immature worms).24)
At the first meeting of TDR’s Filariasis Scientific Steering Committee in 1976, it was reported that Programme staff had visited 16 major pharmaceutical companies but had found none actively working on onchocerciasis. Nor was there any validated model for screening. The Committee agreed that the high cost of maintaining screening facilities for drugs against tropical diseases was a significant deterrent to industrial involvement.25) TDR acted to rectify this situation and thereby engage industry in the search for a new drug. Unfortunately, O. volvulus parasites can only develop fully in humans and a few primates. Fortunately, the closest relative to the human parasite is O. ochengi, found in cattle, which is restricted to Africa and which is also transmitted by the same vector. The O. ochengi cattle model thus facilitated experimental studies, in the field and laboratory-based, that were not possible in humans, leading to detailed knowledge of the parasite’s life cycle (Fig. (Fig.3 ).3 ). From 1977 on, TDR provided technical and financial support to establish a comprehensive screening system for Onchocercal filaricides. The Programme identified five academic and private research institutions with technical capacities and facilities for primary and secondary screens: the University of Georgia (USA), University of Giessen (Germany), the Wellcome Foundation (UK), the London School of Hygiene and Tropical Medicine (UK) and the University of Tokyo (Japan). TDR provided some US$2.25 million to these Public Sector institutions for primary and secondary screening of compounds, while pressing pharmaceutical companies to donate compounds for testing with the promise of full confidentiality. Additionally, TDR established a unique tertiary screen, using cattle, for compounds showing positive results in any secondary screen. Based at the James Cook University of North Queensland, Australia, the screen, costing almost US$435,000, was the best predictor of what a compound would do in humans. Some 10,000 compounds, many supplied by leading pharmaceutical companies as coded samples, passed through the screening network, including several from Merck.26)
Figure 3.
Life cycle of Onchocerca volvulus.
The origins of ivermectin as a human drug are inextricably linked with Onchocerciasis (or River Blindness), a chronic human filarial disease caused by infection with Onchocerca volvulus worms. The parasites are transmitted via the bite of infected blackflies of the genus Simulium, which breed in highly-oxygenated, fast-flowing rivers and watercourses. In the human body, immature larval forms of the parasite create nodules in subcutaneous tissue, where they mature into adult worms. After mating, female worms can release up to 1000 microfilariae a day for some 10–14 years. These move through the body, and when they die they cause a variety of conditions, including skin rashes, lesions, intense itching, oedema and skin depigmentation (Fig. (Fig.2 ).2 ). Microfilariae also invade the eye, causing visual impairment and loss of vision, onchocerciasis being the second leading cause of blindness caused by an infectious disease.17) The disease causes visual damage for some 1–2 million people, around half of who will become blind.18)
Figure 2.
Mali: an old man, blinded by onchocerciasis, with leopard skin on his legs and nodules on his abdomen. Credit line: WHO/TDR/Crump.
In the early-1970s, the disease was endemic in 34 countries: 27 in Africa; 6 in the Americas; and 1 in the Arabian Peninsula. The World Health Organization (WHO) later estimated that 17.7 million people were infected worldwide, of whom some 270,000 were blind, and another 500,000 severely visually disabled. The burden of onchocerciasis was particularly extreme in the hyper-endemic belt across sub-Saharan Africa. Communities in these areas exhibited high rates of visual disability caused by Onchocerciasis, up to 40% in some areas, which caused immeasurable negative impact on individual and community health, reducing economic capacity and productivity, and leading to the abandonment of fertile agricultural lands.19)
By 1973, Onchocerciasis had been recognised by the then head of the World Bank, Robert McNamara, as a major disease of massive health and socioeconomic importance and one in dire need of combating in West Africa, and he became the key agent for change. In 1974, following international recognition of the dramatic consequences of disabling and disfiguring Onchocerciasis in Africa, four United Nations agencies, including the World Bank, launched the Onchocerciasis Control Programme in West Africa (OCP). The programme covered 1.2 million km2, protecting 30 million people in 11 countries from River Blindness.
Go to:
Drug donation
For over a decade, OCP operations were exclusively based on the spraying of insecticides by helicopters and aircraft over the breeding sites of vector blackflies in order to kill their larvae. Following the registration of ivermectin (produced under the brand name Mectizan®) for human use in 1987, in a hitherto unprecedented move and with unheralded commitment, Mectizan® was donated by the manufacturing company, Merck & Co. Inc., to treat onchocerciasis in all endemic countries for as long as it was needed. The resultant drug donation programme was the first, largest, longest running and most successful of all—and proved a model for all others that have followed. Ivermectin began to be distributed in 1988, with operations being organized through the independent Mectizan Donation Program (MDP) established and funded by Merck. Thereafter, OCP control operations changed from exclusive vector control to larviciding combined with ivermectin treatment or, in some areas, to ivermectin treatment alone. Ivermectin swiftly became the drug of choice for the treatment of Onchocerciasis due to its unique and potent microfilaricidal effects, the absence of severe side effects and its excellent safety. It is now the sole tool being used in disease elimination campaigns in the 16 other African countries where the disease exists, orchestrated by the African Programme for Onchocerciasis Control (APOC), which commenced operations in 1996. A single annual dose of 150 µg/kg of ivermectin, given orally, can reduce the level of skin microfilariae to zero and, by interfering with worm embryogenesis, can delay the build-up of new microfilariae for a period of up to two years. OCP was closed in December 2002 after virtually stopping disease transmission in all target nations except Sierra Leone where operations were hampered by civil war.
The process, from the discovery of ivermectin’s activity against onchocercal microfilariae to the successful distribution programme from 1988 onward, was neither an easy or direct path. Success was achieved through groundbreaking and innovative partnerships. The journey was a complex undertaking, incorporating scientific uncertainty, conflicting views, ambiguity, frustration, individual innovation and unexpected twists and turns. The actual discovery of ivermectin was an international team effort involving a unique, pioneering Public Sector/Private Sector partnership and the commitment and vision of several key individuals. Ivermectin’s development into a drug for human use also involved a number of organizational, individual and pharmacological variables—together with a large slice of luck, educated insight and personal commitment.
Go to:
Development of ivermectin for human use
In the mid-1970s, the global community mobilized itself to address the major problems of neglected tropical diseases. Following the setting up of the OCP in 1974, the UN-based Special Programme for Research & Training in Tropical Diseases (TDR) was established in 1975.20) Onchocerciasis, one of two filarial infections among TDR’s eight target diseases, was at that time a major public health problem affecting 20–40 million people in endemic areas. At exactly this time, a specialized novel anthelmintic mouse screening model in Merck’s research laboratories was identifying the avermectins in the microbial sample sent by the Kitasato Institute, of which ivermectin would become the most successful derivative.
At the time, there were no safe and acceptable drugs available to treat Onchocerciasis, which had plagued Africa for centuries, effectively leading to the creation of the OCP and its vector control focus. TDR quickly found that, despite many pharmaceutical companies, such as Bayer, Hoffman-LaRoche, CIBA-Geigy and Rhône-Poulenc, carrying out routing screening for filaricidal compounds, no companies were interested in developing suitable anti-Onchocerca drugs, as there was no apparent commercial market. Worse still, Onchocerca species would not develop to maturity in any rodents, making it impossible to screen compounds in an animal model against the target organism.21) It had been shown that O. volvulus could infect chimpanzees (Pan troglodites) but it was deemed unethical to use these animals for the necessary large-scale research, even though some testing of compounds was undertaken.22,23) Consequently, the OCP opted to devote operations to aerial larviciding via helicopters and small fixed-wing planes. It was a very ‘vertical’ programme, mainly coordinated through the World Bank and other UN agencies, with multimillion dollar contracts given to a US-based helicopter company and to an American chemical company for the insecticides.
Meanwhile, with respect to research needs, TDR had identified six specific areas that required special attention, with the discovery of effective and safe chemotherapeutic agents considered to be the highest priority. In 1975, only two drugs were available for the treatment of onchocerciasis: diethylcarbamazine (DEC) and suramin. The use of both was highly unsatisfactory. DEC, which was known to kill microfilariae, caused violent and even dangerous hypersensitivity reactions in the human host. Suramin, developed 50 years previously for treatment of Sleeping Sickness, was the only drug considered for killing adult worms but was highly toxic, often causing severe and occasionally fatal reactions. Moreover, parasitological cure of patients using DEC and suramin required lengthy and expensive treatment given under medical supervision. Therefore, the TDR Scientific Working Group (SWG), composed of leading independent scientists in the field from around the globe, including industry, decided that the priority was a new and non-toxic macrofilaricide (to kill adult worms), a macrofilaricide being determined to be substantially preferable to a microfilaricide (which would target immature worms).24)
At the first meeting of TDR’s Filariasis Scientific Steering Committee in 1976, it was reported that Programme staff had visited 16 major pharmaceutical companies but had found none actively working on onchocerciasis. Nor was there any validated model for screening. The Committee agreed that the high cost of maintaining screening facilities for drugs against tropical diseases was a significant deterrent to industrial involvement.25) TDR acted to rectify this situation and thereby engage industry in the search for a new drug. Unfortunately, O. volvulus parasites can only develop fully in humans and a few primates. Fortunately, the closest relative to the human parasite is O. ochengi, found in cattle, which is restricted to Africa and which is also transmitted by the same vector. The O. ochengi cattle model thus facilitated experimental studies, in the field and laboratory-based, that were not possible in humans, leading to detailed knowledge of the parasite’s life cycle (Fig. (Fig.3 ).3 ). From 1977 on, TDR provided technical and financial support to establish a comprehensive screening system for Onchocercal filaricides. The Programme identified five academic and private research institutions with technical capacities and facilities for primary and secondary screens: the University of Georgia (USA), University of Giessen (Germany), the Wellcome Foundation (UK), the London School of Hygiene and Tropical Medicine (UK) and the University of Tokyo (Japan). TDR provided some US$2.25 million to these Public Sector institutions for primary and secondary screening of compounds, while pressing pharmaceutical companies to donate compounds for testing with the promise of full confidentiality. Additionally, TDR established a unique tertiary screen, using cattle, for compounds showing positive results in any secondary screen. Based at the James Cook University of North Queensland, Australia, the screen, costing almost US$435,000, was the best predictor of what a compound would do in humans. Some 10,000 compounds, many supplied by leading pharmaceutical companies as coded samples, passed through the screening network, including several from Merck.26)
Figure 3.
Life cycle of Onchocerca volvulus.
