Antiparasitics in Animal Health: Quo Vadis?

Abstract

Antiparasitics for the treatment of companion animals and livestock is one of the largest global market segments in the animal health industry.Parasitic infections caused by endo- and ectoparasites – the latter also transmitting vector-borne diseases – are among the most significant diseases worldwide, in both animals and humans.Most of the antiparasitic active pharmaceutical ingredients were developed more than 20 years ago. Isoxazolines, which first entered the market in 2014, are one of the very rare exceptions and a true success story. Currently, the four leading animal health companies market four isoxazolines in diverse dog and cat products.Drug and multidrug resistance is increasingly common across all parasites. In livestock, it is a significant and widespread problem. In dogs and cats, drug resistance is as yet less serious.The discovery of novel antiparasitics is of utmost importance to overcome resistance and to fill the development pipeline. Antiparasitics acting on endo- or ectoparasites represent the second largest segment of the global animal health market, accounting for 23% of market share. However, relatively few novel antiparasitic agents have been introduced into the market during recent decades. One exception, and a groundbreaking 21st century success story, are the isoxazolines, whose full potential has not yet been entirely explored. Unfortunately, resistance issues are present across most parasitic diseases, which generates a clear market need for novel resistance-breaking antiparasitics with new modes/mechanisms of action. Recent advances in science and technologies strongly suggest that the time is right to invest in new modalities such as parasitic vaccines or in environmentally friendly interventions. Antiparasitics acting on endo- or ectoparasites represent the second largest segment of the global animal health market, accounting for 23% of market share. However, relatively few novel antiparasitic agents have been introduced into the market during recent decades. One exception, and a groundbreaking 21st century success story, are the isoxazolines, whose full potential has not yet been entirely explored. Unfortunately, resistance issues are present across most parasitic diseases, which generates a clear market need for novel resistance-breaking antiparasitics with new modes/mechanisms of action. Recent advances in science and technologies strongly suggest that the time is right to invest in new modalities such as parasitic vaccines or in environmentally friendly interventions. Animal health is focused on the management and control of diseases in order to ensure the health of both livestock (see Glossary) and companion animals. The global market for animal health products approaches €30 billion per year, with an annual growth rate outstripping that of human medicine. Products include biologicals (e.g., vaccines), antiparasitics/parasiticides, anti-infectives (e.g., antibiotics, antifungals), other pharmaceuticals (e.g., antihypertensives, antidiabetics), and medical feed additives (Figure 1, Key Figure). The current animal health market is understood to be driven primarily by three factors:(i)Pet owners, farmers, and veterinarians prefer more technically advanced and more convenient treatments.(ii)The growing world population increasingly demands affordable sources of protein from food animals and animal products, requiring improvements in livestock health care.(iii)The development of resistance requires new resistance-breaking preventatives and treatments. Due to the high economic impact and the immediate relevance for animal health, antiparasitics, also referred to as parasiticides, currently represent the second largest segment of the global animal health market – taking turns almost on a yearly basis with biologicals as the largest segment – accounting for €7 billion in sales (23% of the market share) (Figure 1, Figure 2). In addition, animal health plays an important role in furthering the ‘One Health’ initiative, which is dedicated to improving the lives of all species – human and animal – through the integration of human medicine, veterinary medicine, and environmental sciencei. Parasitic infections account for some of the most significant diseases worldwide, in both animals and humans, and are of enormous socioeconomic importance. Despite significant treatment advances in the preceding half century, they remain a major threat to livestock farming and cause large deficits for the agricultural economy. Effective parasite control is thus essential for profitability in intensive livestock production [1.Deplazes P. et al.Parasitology in Veterinary Medicine. Wageningen Academic Publishers, 2016Crossref Google Scholar,2.Mehlhorn H. Encyclopedia of Parasitology.4th edn. Springer Nature, 2016Google Scholar]. Parasites also affect the well-being of companion animals and, due to their often zoonotic nature, represent threats to human health. Infections of humans with parasitic helminths belong to the most frequent infectious diseases worldwide, estimated to affect up to 25% of the world population, especially in warmer climates. Prevention of parasite infections in animals is not only necessary for animal welfare, and the human–animal bond, but it also reduces the risk of transmission to humans [1.Deplazes P. et al.Parasitology in Veterinary Medicine. Wageningen Academic Publishers, 2016Crossref Google Scholar,2.Mehlhorn H. Encyclopedia of Parasitology.4th edn. Springer Nature, 2016Google Scholar]. Parasites are generally classified as endo- or ectoparasites, depending on whether they live in or on the host, respectively. Ectoparasites, such as fleas, ticks, lice, or flies are, with some exceptions (e.g., Cochlyomyia-induced myiasis in South America or tick paralysis in Australia), not life-threatening by themselves but can reduce food intake, produce toxins, and/or cause traumatic damage due to lesions, leading to a significant impairment of well-being and performance, such as weight gain or milk production. In addition, the major threat related to ectoparasites is that many of them (e.g., ticks) are effective vectors for the transmission of severe diseases [1.Deplazes P. et al.Parasitology in Veterinary Medicine. Wageningen Academic Publishers, 2016Crossref Google Scholar,2.Mehlhorn H. Encyclopedia of Parasitology.4th edn. Springer Nature, 2016Google Scholar]. Most active pharmaceutical ingredients (APIs) for ectoparasitics originated from research/discovery in crop protection, and many of the leading animal health companies in the ectoparasiticides sector have existing or historical links to crop protection businesses [3.Sparks T.C. Insecticide discovery: an evaluation and analysis.Pestic. Biochem. Physiol. 2013; 107: 8-17Crossref PubMed Scopus (143) Google Scholar,4.Sparks T.C. et al.The new age of insecticide discovery-the crop protection industry and the impact of natural products.Pestic. Biochem. Physiol. 2019; 161: 12-22Crossref PubMed Scopus (46) Google Scholar]. Endoparasites, such as parasitic worms and protozoa, cause both subclinical diseases as well as clinical manifestations with high morbidity and mortality. Despite their medical and socioeconomic importance, current treatments and prevention still rely primarily on old chemotherapeutic or chemo-metaphylactic control programs [1.Deplazes P. et al.Parasitology in Veterinary Medicine. Wageningen Academic Publishers, 2016Crossref Google Scholar,2.Mehlhorn H. Encyclopedia of Parasitology.4th edn. Springer Nature, 2016Google Scholar]. Only a very few with antiparasitic have been introduced to the market in recent include the et new of effective PubMed Scopus Google and a of and et al.The of a of of in the PubMed Scopus Google and the of isoxazolines as ectoparasiticides for dogs and a novel effective on PubMed Scopus Google Scholar]. Most of the antiparasitic were developed more than 20 years and the market is driven to a large by and et and for of veterinary antiparasitic programs to for new antiparasitic for human and Scopus Google Scholar]. Animal health companies have focused on that and existing the market is than of the market is by four major market in animal Animal Animal and Animal is driven by the four companies that have to the of antiparasitic (Figure 2). the antiparasitic market and for an animal health a market due to the high market and global into requires a evaluation of the development of an and an to of active ingredients have been developed into products for the treatment and control of animal parasites. The of endo- and ectoparasiticides has with the in the of (e.g., that both The to control both endo- and ectoparasites has to the of can be on and or on issues on the one – in and parasite – and the for on the other have increasingly to the development of products that or more active ingredients from the endo- and in recent years (Figure et of and and control Scopus Google Scholar]. companion current products for the treatment of ectoparasites and with a protection of the the major and the dog in are the of almost the only drug in companion for and products are The major has been prevention and control of and in some are more products protection for a to reduce of animals. such as the control all major and are currently by other and for and for The of antiparasitics are well in in (e.g., (e.g., and (e.g., which include the and natural or of products from can have both and and can be as The ectoparasiticides and isoxazolines, and growth such as the and the et of and and control Scopus Google Scholar]. The introduced into the animal health market in 2014, are the isoxazolines (Figure a novel effective on PubMed Scopus Google Scholar]. first in the the isoxazolines represent the largest and the most new of and introduced for animal health in the 21st century to ectoparasiticides of the Scopus Google Scholar]. and of and and them effective ectoparasiticides a novel effective on PubMed Scopus Google Scholar]. the four products include from et and of of a new for PubMed Scopus Google et al.The discovery of a new for Scopus Google et of as a new for Scopus Google from et al.The novel of and and Biochem. PubMed Scopus Google from et of a for PubMed Scopus Google and of a novel for Scopus Google and from (Figure et al.The novel a to PubMed Scopus Google and the for development of the isoxazolines the of an health discovery with a pharmaceutical the first in et and control Scholar]. that and with to the potential and of of is as et and their as Scholar]. with on in which developed by et and control Scholar]. by and of their in and et as antiparasitic Scholar]. Animal of to the with the by for the of on the developed first by and as a of the of Animal in et and their as Scholar]. with an – – in which originated from et as the of in as a of the of by (see Figure in The development of the isoxazolines the of an health discovery with a pharmaceutical the first in et and control Scholar]. that and with to the potential and of of is as et and their as Scholar]. with on in which developed by et and control Scholar]. by and of their in and et as antiparasitic Scholar]. Animal of to the with the by for the of on the developed first by and as a of the of Animal in et and their as Scholar]. with an – – in which originated from et as Scholar]. the of in as a of the of by (see Figure in has been that the of the isoxazolines is the active the is et al.The antiparasitic is a of PubMed Scopus Google Scholar]. et and of of a new for PubMed Scopus Google et al.The discovery of a new for Scopus Google and et al.The novel of and and Biochem. PubMed Scopus Google were the first products in the and as active a novel effective on PubMed Scopus Google Scholar]. products not only related to the new but also with the in a market by the active have the of such into the in et of a for PubMed Scopus Google and in et al.The novel a to PubMed Scopus Google into the market years the in the is that the of in dogs new but also the potential for to the The isoxazolines have been to by a new in the the for an new to which has thus to the of four veterinary products ectoparasites on In addition, products, such as et of the of of in the prevention of in PubMed Scopus Google and et of a novel and natural and tick on dogs as veterinary in have been In of and are in the to the products for have been for in are products which are to to as with isoxazolines (e.g., for cats, or in (e.g., for cats, et of of a new of for with PubMed Scopus Google et of for in PubMed Scopus Google Scholar]. also have potential for the development of more than the current or of and tick isoxazolines have in such as et of in a clinical in dogs with PubMed Scopus Google and in dogs et of for the treatment of PubMed Scopus Google in et of for in PubMed Scopus Google et and of a of for the treatment and prevention of and the treatment of in as veterinary in the 2019; PubMed Scopus Google and in et al.The of of on and impact on PubMed Scopus Google Scholar]. has also been on such as et of the of in dogs with PubMed Scopus Google and et of the of in 2019; PubMed Scopus Google new to control with other with a veterinary – for and et and for of veterinary antiparasitic programs to for new antiparasitic for human and Scopus Google – isoxazolines to have potential for development in other In they also be active lice, and a novel effective on PubMed Scopus Google et veterinary for control of vector-borne human PubMed Scopus Google Scholar]. has been in as a of human et and evaluation of a of in the for human PubMed Scopus Google Scholar]. isoxazolines also be to diseases, such as as in dogs et of an of to dogs from by PubMed Scopus Google or diseases of humans, such as human and for which have been in the et and control et and their as et and control et as antiparasitic et and their as et as Scholar]. However, for the time the as to isoxazolines on the vectors et transmission of vector-borne PubMed Scopus Google of dogs and from and of transmission to PubMed Scopus Google Scholar]. be essential that the is the is a novel effective on PubMed Scopus Google Scholar]. resistance is increasingly common across all et al.The of resistance in PubMed Scopus Google Scholar]. The is significant – with to resistance to in and – by et resistance as a to the discovery of new and Scopus Google Scholar]. resistance is also in of (e.g., resistance to et of the livestock 2019; PubMed Scopus Google Scholar]. In all of novel are as resistance with new of and/or to of drug with the development of resistance in resistance to in has been relatively to – and years for et that resistance PubMed Scopus (46) Google Scholar]. However, resistance is widespread relatively few of have been introduced recent decades. Most of the belong to one of four – and – which all in a et of infections by PubMed Scopus Google Scholar]. resistance to one be by resistance to other of – referred to as on the of for the control of parasitic in the of 2019; PubMed Scopus Google Scholar]. The full of resistance in is multidrug resistance in has been on in the and and more In most of resistance to were as the but resistance is also in and control of of in PubMed Scopus Google and management of resistance in of PubMed Scopus Google and control of of in PubMed Scopus Google Scholar]. In of and in resistance to all of has in many of the resistance in and PubMed Scopus Google Scholar]. has also been in and in and The development of resistance in PubMed Scopus Google et resistance in in a PubMed Scopus Google et of parasitic of and the role of advanced for and drug resistance – an 2013; PubMed Scopus Google et of resistance and of parasite control in PubMed Scopus Google Scholar]. of resistance to most major of are et that resistance PubMed Scopus (46) Google et of infections by PubMed Scopus Google Scholar]. of major is years in the market, resistance to et new of effective PubMed Scopus Google has in the in and treatments et of of and 2013; PubMed Scopus Google Scholar]. to products to control in dogs and also but is not to be as as in livestock parasites. are of a of with a of the of but often the cause be to a that resistance or of have growing resistance for ectoparasites by in the with more Insecticide resistance in Scopus Google et of and resistance in dogs in PubMed Scopus Google et of resistance in PubMed Scopus Google Scholar]. to of dogs and is not yet an with exceptions such as for in the the of the have from the and for the of are still effective and et resistance in of and of for PubMed Scopus Google Scholar]. In resistance in in the has been related to the of and from and from to the dog population et drug resistance in the an 2019; PubMed Scopus Google Scholar]. In resistance to is widespread in on resistance and Scopus Google et resistance in from in and PubMed Scopus Google Scholar]. resistance to and has been in many resistance in is for only but is on resistance and Scopus Google et resistance in from in and PubMed Scopus Google Scholar]. resistance be as a major of in antiparasitics, the development of products with is also such as a of for a livestock which the of necessary during the active or a in a that is for to with parasite control One is the of a which is with a tick and (e.g., most of the a the as well as the a convenient for a of endo- and control in one the cat population is in many in the more is necessary in the development of parasite control in cats, which be by both and due to their and have to their and to environmental their in some it also the of into new In addition, the impact of almost of and animals the world not be in the of of and on vectors and vector-borne are PubMed Scopus Google and impact on human PubMed Scopus Google and affect PubMed Scopus Google Scholar]. include the of the which originated from of and the and the across all of P. et of and PubMed Scopus Google and the of the across from in the et of and in in PubMed Scopus Google Scholar]. The of the in dogs and all – from in and first in in in – is et of with a of and in in and 2019; PubMed Scopus Google Scholar]. and – both vector-borne diseases by a of flies – and a of other vector-borne diseases also to have and are in new on the of companion vector-borne diseases in animals in 2019; PubMed Scopus Google et of and on the of in PubMed Scopus Google Scholar]. is that recent with global be for such as the need for and of and and to for an parasite control of and on vectors and vector-borne are PubMed Scopus Google and impact on human PubMed Scopus Google and affect PubMed Scopus Google Scholar]. and development of new is a major in antiparasitic a of new in recent in is to an pharmaceutical – from discovery to the and management of a discovery the basis of such a a drug the discovery into a development which through all for the development and of a new a (Figure The antiparasitic drug discovery is of three major or and the basis for all drug discovery an intensive is to active effective in the is by a and dedicated to a active with the drug One of the most important in a new antiparasitic drug is the and of and and/or et discovery approaches Scopus Google Scholar]. The of is the of for yet in drug discovery include and most antiparasitic products were by of and natural in or in animal or in and for many protozoa, and from advances in drug and with in and In a is generally for with a parasite that is or to a for chemotherapeutic The is that the of an essential parasite can to that the The of the drug discovery is to in improving in the are to have the of the and are for as drug et and for of veterinary antiparasitic programs to for new antiparasitic for human and Scopus Google et and development of veterinary antiparasitic present and PubMed Scopus Google et and of in veterinary Parasitic and Scopus Google Scholar]. The and in the discovery of veterinary antiparasitic well with in the human pharmaceutical However, the in the veterinary of to parasitic and also the to during the drug discovery In human health, a drug has been in animal health can a and a clinical in animals et discovery approaches Scopus Google Scholar]. and vaccines parasitic diseases have the potential to impact the antiparasitic few vaccines parasite have been but only in to and the development of vaccines for parasitic diseases is more has been very success in antiparasitic vaccines in human or veterinary et of infections by PubMed Scopus Google – still a to PubMed Scopus Google in drug or PubMed Scopus Google et current PubMed Scopus Google et parasite present and PubMed Scopus Google Scholar]. from is one of the it only protection in and is et of for control of tick on PubMed Scopus Google Scholar]. and vaccines (e.g., to in are but have protection In to the live are with the only for in a production et of the livestock 2019; PubMed Scopus Google of drug resistance in PubMed Scopus Google Scholar]. In of some antiparasitic vaccines have been developed a in the et of a on of the and of PubMed Scopus Google with annual sales of as well as et an of PubMed Scopus Google PubMed Scopus Google in some a with annual sales of vaccines are they only protection and are often not well in drug or PubMed Scopus Google et current PubMed Scopus Google Scholar]. In they a market of in for by of has been on the market for more than years et of a parasitic Scholar]. The has a market on the global but is in of and the for a the the protection through of high of by of a et of parasite in PubMed Scopus Google for in in by the in it has been to and the production still on large of worms from et al.The of for in in and PubMed Scopus Google Scholar]. are in to et of infections by PubMed Scopus Google et parasite present and PubMed Scopus Google et al.The potential for vaccines worms of PubMed Scopus Google Scholar]. The of the with the of in and other advanced in the development on a of the et an for PubMed Scopus Google et of the major parasitic 2019; PubMed Scopus Google P. in PubMed Scopus Google Scholar]. such as that of – as one of the parasite to with and the – new et from and cause PubMed Scopus Google of of and PubMed Scopus Google et PubMed Scopus Google Scholar]. resistance development as a and for new and to the antiparasitics In to the such as improving of a in of the world is increasingly production in and animal production. the of or products that reduce or parasite – on and – new for the animal health on (e.g., and for as an and control the is to the animal as the and the right time which to a of on et of in PubMed Scopus Google et with to PubMed Scopus Google Scholar]. a of it with high in it and for the approaches were also for and ticks, especially on and with the with control et as agents for the Scopus Google et of and of and PubMed Scopus Google et of PubMed Scopus Google Scholar]. in approaches a with a potential and into the antiparasitics is currently to such new which have potential to cause a significant to the the and demands T.C. et al.The new age of insecticide discovery-the crop protection industry and the impact of natural products.Pestic. Biochem. Physiol. 2019; 161: 12-22Crossref PubMed Scopus (46) Google Scholar]. The animal health industry for approaches to to new animal health pharmaceutical with in the development of novel products, are increasingly in with are for the of potential is and the science and are increasingly and order to for new antiparasitics, companies of products developed in other to veterinary and to new new and new and in new is not by and the of science are and new technologies are and in Animal health in and and them to new to the market in order to current and market animal health pharmaceutical with in the development of novel products, are increasingly in with are for the of potential is and the science and are increasingly and In order to for new antiparasitics, companies of products developed in other to veterinary and to new new and new and in new is not by and the of science are and new technologies are and in Animal health in and and them to new to the market in order to current and market the animal health antiparasitics represent a large market an in which significant is to such as and (see the need for is few new of have been introduced in recent with the of the However, drug discovery in to and advances have to an on approaches in drug is to as the both the of and the of by a gain in and related approaches have from the of of However, has also with to in that a – – not the current of new it is the of approaches that most be the to more the and of is to to a more for effective drug discovery approaches be by the and in (e.g., but also in the be and to new resistance-breaking antiparasitic to control and parasitic diseases in the of the and the groundbreaking parasite the pharmaceutical industry the for the development of global and the growing world population impact parasitic diseases for animals and humans in the the be and to new resistance-breaking antiparasitic to control and parasitic diseases in the of the and the groundbreaking parasite the pharmaceutical industry the for the development of global and the growing world population impact parasitic diseases for animals and humans in the and for and their and are very to and for their in and the of a drug that the such as have to or in a (e.g., primarily for a or that live on the of for and of one of of a that to have which are a of the The to and only one of a is for the the other is less or that live in the and of their such as and of an of a pharmaceutical drug the protection of the drug animals (e.g., in an agricultural to produce and such as and of or antiparasitics to animals to the or as animals with clinical infections are their clinical the of an the and is by which is the of the as well as by environmental the of of a in a population a by the of in that the of a parasite to the of of an antiparasitic were is present is a of a population with a to of an than in a population of the an infectious caused by a infectious such as a or that has from an animal to a the first human the infectious to one other in

Topics & Concepts