Discovery of Ivermectin - American Chemical Society

1 National Historic Chemical Landmarks Chemists and Chemistry that Transformed Our Lives Discovery of Ivermectin Merck & Co., Inc. American Chemical Society The goal was to find an anthelmintic, that is, a drug that is effective against worm parasites (helminths). The goal, furthermore, was to find an anthelmintic that was not just a bit more potent than existing drugs, or a bit safer, or a bit broader in therapeutic spectrum, but to find one that was radically different.. William Campbell, Inventive Minds: Creativity in Technology, 1992. The story is so improbable it defies In 1971, mura took a sabbatical combination of eight closely related belief: a soil sample from Japan stops in the laboratory of Max Tishler compounds.

2 The researchers began suffering in Africa. It starts when a (1906 1989), an eminent professor chemically modifying the compounds, scientist discovers a lowly bacterium of chemistry at Wesleyan University tweaking their molecular structures near a golf course outside Tokyo. A in the A year earlier, Tishler had slightly to see if they could make aver- team of scientists in the United States retired from an illustrious research ca- mectin even more potent against par- finds that the bacterium produces reer at the pharmaceutical company asites and safer for the animals being compounds that impede the activity Merck. Before returning to Japan in treated.

3 By synthesizing thousands of of nematode worms. It is developed 1973, mura arranged a pioneering similar compounds, Merck scientists into a drug that wards off parasites agreement between the company found that, with slight Chemical in countless pets and farm animals, and the research institute. Kitasato modification, some of the avermectin averting billions of dollars in losses would continue to collect samples compounds displayed enhanced activ- worldwide. Extraordinarily, the drug and screen them, and then send the ity as well as safety. They dubbed the The new drug also prevents or treats human para- most promising ones to Merck Re- resulting pair of avermectin deriva- sitic diseases that would otherwise search Laboratories in Rahway, New tives Ivermectin .

4 The mixture was would go on cause blindness and other severe Jersey, for testing and development. 25 times more potent than existing to become the symptoms in hundreds of millions of The institute would receive royalties treatments for parasitic worms. predominant people in many of the poorest coun- from any products that were com- Further testing at Merck showed tries on Earth. mercialized through the partnership. agent in that Ivermectin could also fight The tale depends on an international At Merck Research Labs, a team led infestations by mites, ticks and botfly controlling the cast of thousands of scientists, medi- by parasitology specialist William parasites that cause huge economic parasitic diseases cal practitioners and other dedicated Campbell (*1930) began testing the losses in the livestock industry.

5 It was participants. It also involves a com- samples as potential treatments for effective against parasites in horses, that plague pany and research institute willing parasitic worms. A veterinary scientist cattle, pigs, sheep and dogs, and was the animals on to give a drug away for free to rid and zoologist by training, Campbell largely nontoxic to these animals. which humans the developing world of debilitating identified compounds that could be diseases. These gratifying results led Merck effectively developed as drugs for depend for food to commercialize Ivermectin as a Yet none of this would have happened livestock and other animals.

6 And fiber and veterinary treatment beginning in without that soil dug up in Japan To test potential treatments, the Merck 1981. Starting in 1987, the drug was companionship. and a healthy dose of serendipity. researchers first infected mice with also marketed to the public under the INTERNATIONAL DRUG Discovery nematodes and then fed each mouse brand name Heartgard (now sold William a different culture sample supplied by In the late 1960s and early 1970s, by the animal-health company Me- Campbell, mura's team. They found that one rial) to prevent heartworms in dogs. Satoshi mura (*1935), a microbiolo- culture was extraordinarily effective These products quickly became the Nobel Lecture, gist and bioorganic chemist at Tokyo's at ridding mice of worm infestations.

7 Top-selling veterinary medicines in Kitasato Institute, hunted for new 7 December 2015 This culture was derived from soil col- the world, with sales topping $1 billion sources of pharmaceuticals. He knew lected near a golf course in Kawana, annually. that some existing drugs, includ- about 80 miles southwest of Tokyo. ing antibiotics, had been derived TREATMENT FOR RIVER BLINDNESS. mura identified the bacterium in from compounds found in nature. that culture as a new strain, which The cycle of parasitic disease often So he developed screening methods was ultimately christened Streptomy- begins with a bug bite. to identify medicinally promising ces avermectinius.

8 Blackflies that breed in fast-flowing compounds from soil. His team col- lected thousands of soil samples from The Merck team isolated the active rivers carry the larvae of the worm around Japan, cultured bacteria from component produced by the bacte- that causes onchocerciasis (also them, and screened each culture for rium and named it avermectin. They known as river blindness) in humans. medicinal potential. found that avermectin is actually a When an infected fly bites a person, A N AT I O N A L H I S TO R I C C H E M I C A L L A N D M A R K. William Campbell (right) talks to Mohammed Aziz (center) and Kenneth Brown (left) at the 1987 press conference in Washington, , during which Merck CEO.

9 P. Roy Vagelos announced that the company would donate Ivermectin for the prevention of river blindness. technical and operational activities between Merck, WHO and a range of public and private stakeholders. Mectizan is also administered with albenda- zole a drug donated by GlaxoSmithKline . as part of a campaign to eliminate lymphatic filariasis (also known as elephantiasis), anoth- er tropical disease that disrupts the immune system and is common among people living in under-resourced settings in approximately 80 countries. Today, the MDP program reaches more than 250 million people, with more than 2 billion treatments donated since it was established.

10 With this support, health authorities hope to eliminate these diseases within the next decade. FURTHER DEVELOPMENTS. Additional uses for Ivermectin and other aver- mectin derivatives continue to be found, in- cluding the treatment of infestations by other the fly deposits worm larvae on the person's In its drug development efforts, Merck worms and by head lice, as well as scabies and skin. The parasites enter the body through worked with the World Health Organization strongyloidiasis. the bite wound, where they mature into adult (WHO) to design and implement human Even after Ivermectin went on the market, worms that live and breed.