Antiparasitics in Animal Health: Quo Vadis?

Antiparasitics for the treatment of companion animals and livestock is one largest global market segments in animal health industry.Parasitic infections caused by endo- ectoparasites – latter also transmitting vector-borne diseases are among most significant worldwide, both humans.Most antiparasitic active pharmaceutical ingredients were developed more than 20 years ago. Isoxazolines, which first entered 2014, very rare exceptions a true success story. Currently, four leading companies isoxazolines diverse dog cat products.Drug multidrug resistance increasingly common across all parasites. In livestock, it widespread problem. dogs cats, drug as yet less serious.The discovery novel antiparasitics utmost importance to overcome fill development pipeline. acting on or represent second segment market, accounting 23% share. However, relatively few agents have been introduced into during recent decades. One exception, groundbreaking 21st century story, isoxazolines, whose full potential has not entirely explored. Unfortunately, issues present parasitic diseases, generates clear need resistance-breaking with new modes/mechanisms action. Recent advances science technologies strongly suggest that time right invest modalities such vaccines environmentally friendly interventions. Animal focused management control order ensure (see Glossary) animals. The products approaches €30 billion per year, an annual growth rate outstripping human medicine. Products include biologicals (e.g., vaccines), antiparasitics/parasiticides, anti-infectives antibiotics, antifungals), other pharmaceuticals antihypertensives, antidiabetics), medical feed additives (Figure 1, Key Figure). current understood be driven primarily three factors:(i)Pet owners, farmers, veterinarians prefer technically advanced convenient treatments.(ii)The growing world population demands affordable sources protein from food products, requiring improvements care.(iii)The requires preventatives treatments. Due high economic impact immediate relevance health, antiparasitics, referred parasiticides, currently taking turns almost yearly basis €7 sales (23% share) Figure 2). addition, plays important role furthering ‘One Health’ initiative, dedicated improving lives species through integration medicine, veterinary environmental sciencei. Parasitic account some humans, enormous socioeconomic importance. Despite preceding half century, they remain major threat farming cause large deficits agricultural economy. Effective parasite thus essential profitability intensive production [1.Deplazes P. et al.Parasitology Veterinary Medicine. Wageningen Academic Publishers, 2016Crossref Google Scholar,2.Mehlhorn H. Encyclopedia Parasitology.4th edn. Springer Nature, 2016Google Scholar]. Parasites affect well-being and, due their often zoonotic nature, threats health. Infections humans helminths belong frequent infectious estimated up 25% population, especially warmer climates. Prevention only necessary welfare, human–animal bond, but reduces risk transmission generally classified ectoparasites, depending whether live host, respectively. Ectoparasites, fleas, ticks, lice, flies are, Cochlyomyia-induced myiasis South America tick paralysis Australia), life-threatening themselves can reduce intake, produce toxins, and/or traumatic damage lesions, impairment performance, weight gain milk production. related many them ticks) effective vectors severe Most (APIs) ectoparasitics originated research/discovery crop protection, ectoparasiticides sector existing historical links protection businesses [3.Sparks T.C. Insecticide discovery: evaluation analysis.Pestic. Biochem. Physiol. 2013; 107: 8-17Crossref PubMed Scopus (143) Scholar,4.Sparks al.The age insecticide discovery-the industry natural products.Pestic. 2019; 161: 12-22Crossref (46) Endoparasites, worms protozoa, subclinical well clinical manifestations morbidity mortality. importance, treatments prevention still rely old chemotherapeutic chemo-metaphylactic programs Only drugs activity years; these sheep anthelmintic APIs monepantel (Zolvix®) [5.Kaminsky R. al.A class anthelmintics against drug-resistant nematodes.Nature. 2008; 452: 176-180Crossref (367) Scholar] derquantel (Startect®, combination abamectin) [6.Geurden T. efficacy combined oral formulation derquantel-abamectin resistant gastro-intestinal nematodes UK.Vet. Parasitol. 2012; 189: 308-316Crossref (13) Scholar], chemical cats [7.Weber Selzer P.M. Isoxazolines: chemotype highly ectoparasites.ChemMedChem. 2016; 11: 270-276Crossref (58) widely used today ago, extent generics offering similar profiles [8.Geary T.G. al.Target identification mechanism-based screening anthelmintics: application research search indications.in: Antiparasitic Antibacterial Drug Discovery. Wiley-VCH, 2009: 3-15Crossref (25) largely incremental innovations meet, modestly surpass, customers’ expectations. Accordingly, environment competitive. More 70% share held players health: Zoetis, Boehringer Ingelheim Health, MSD Elanco/Bayer Health. innovation notably same access vast majority Nevertheless, remains extremely attractive is, business, key volume relevance. An entry this field thorough possible options, integrated strategic concept, organizational commitment work towards goalii. A substantial number traditional differentiation become blurred advent, 1980s, compounds avermectins/milbemycins) provide categories. capacity led definition endectocides. Endectocides based specific molecules dosages, combinations. Resistance hand distinct geographic regions classes broad-spectrum combine two ectoparasiticide groupings 1) [9.Woods D.J. al.Comparison anti-ectoparasite anti-endoparasite therapies strategies.in: Meng C.Q. Sluder A.E. Ectoparasites. 2018: 1-23Crossref (1) For animals, ticks fleas period at least 1 month. Endoparasiticides, like macrocyclic lactones, target gastrointestinal heartworm, Dirofilaria immitis, endemic areas, while tapeworms treated via addition praziquantel, cestodicidal animalsiii. Requirements cattle small-ruminant complex. ectoparasitic traditionally also, flies; however, lice becoming important. should long handling nematodes. Flukes cestodes controlled actives: triclabendazole, closantel, clorsulon flukes, praziquantel niclosamide cestodesiii. main described numerous publicationsiii. Endoparasiticides use comprise benzimidazoles fenbendazol), imidazothiazoles (i.e., levamisole), tetrahydropyrimidines pyrantel), lactones ivermevctin), avermectins milbemycins, synthetic derivatives fermentation soil microorganisms (Streptomyces spp). Macrocyclic lactone formulations arthropods, therefore endectoparasiticides. pyrethrins pyrethroids, organophosphates, carbamates, formamidines, pyrazoles, neonicotinoids, spinosyns, semicarbazones, insect regulators juvenile hormone analogue S-methoprene benzoylphenyl urea lufenuroniii latest class, 3) Although identified agrochemical sector, probably exciting insecticidal acaricidal date (Box [10.Long A. preeminent early twenty-first century.in: 319-351Crossref (4) Isoxazolines inhibit γ-aminobutyric acid chloride channels glutamate-gated insects acarids mites), making To date, marketed isoxazoline Nexgard® (afoxolaner, AH) [11.Shoop W.L. al.Discovery mode action afoxolaner, parasiticide dogs.Vet. 2014; 201: 179-189Crossref (122) Scholar, 12.Xu M. afoxolaner: dogs.in: Ectoparasites: Discovery Against Moving Targets. 259-271Crossref (3) 13.Letendre L. al.Development afoxolaner 273-294Crossref Bravecto® (fluralaner, [14.Gassel fluralaner: selective inhibition arthropod gamma-aminobutyric acid- L-glutamate-gated insecticidal/acaricidal activity.Insect Mol. Biol. 45: 111-124Crossref (160) Simparica® (sarolaner, Zoetis) [15.McTier T.L. sarolaner: novel, orally administered, broad-spectrum, 222: 3-11Crossref (85) Scholar,16.Woods McTier Discovery, development, commercialization sarolaner (Simparica®), 295-318Crossref Credelio® (lotilaner, Elanco) [17.Rufener lotilaner (CredelioTM): non-competitive antagonist invertebrates acid-gated (GABACls).Parasit. Vectors. 2017; 10: 530Crossref (24) Scholar].Box 1Industry Consolidation Race InnovationThe showcases remarkable results agrochemical/animal race constantly evolving industry.Nissan patented 2005 [32.Mita, al. Nissan Chemical Industries, Ltd., Japan, (2005). Isoxazoline‐substituted benzamide compound noxious organism agent. WO2005085216.Google At time, Intervet (➔ SP-Intervet joined forces discover molecular what known fluralaner [33.Heckeroth, A.R. Int. BV, (2009). Isoxazoline compositions antiparasitics. WO2009024541.Google DuPont followed patents 2009, was subsequently Merial (now [34.Lahm, G.P. E. I. du Pont de Nemours Company, Naphthalene invertebrate pest agents. WO2009002809.Google Inspired activities, Pfizer (today independent Pfizer) initiated internal program synthesizing developing [35.Billen, D. al., Zoetis LLC, (2012). Spirocyclic WO2012120399.Google Ely Lilly’s Health Elanco Lilly), last enter scene, collaborated medicinal company Anacor (later acquired synthesis respective isoxazolines. successfully delivered goal, lotilaner, Novartis AH result takeover 2015 [36.Nanchen, S. AG, (2010). pesticide. WO2010070068.Google Bayer as-yet unmarketed (international nonproprietary name INN tigolaner, received 2017ix, Crop Science [37.Maue, Cropscience Aktiengesellschaft, (2014). Halogen-substituted pyrazole pest-control WO2014122083Google Scholar].Elanco finalized acquisition August 2020 consequence Monsanto Sciencevii,viii 2 text). industry. It demonstrated (S)-enantiomer component, whereas (R)-enantiomer inactive [18.Ozoe Y. A1443 potent blocker ligand-gated channels.Biochem. Biophys. Res. Commun. 2010; 391: 744-749Crossref (166) Scholar,12.Xu 2014 using racemate first-generation These provided much-needed breakthrough innovation, administration dominated topical spot-ons. Isolating would required additional years, significantly delaying introduction market. (market 2016) 2018) several later, containing isolated product. noticeable route brought benefits, particularly increased customer convenience reduced owner exposure compound(s). shown circumvent cross-resistance targeting binding pocket channels, setting stage innovative approach tackling infestations, far approval administered dogs. NexGard Spectra® (afoxolaner + milbemycin) [19.Beugnet F. al.Evaluation monthly plus milbemycin oxime (NexGard Spectra(®), Merial) adult Spirocerca lupi establishment experimentally infected 226: 150-161Crossref (6) Simparica Trio® (sarolaner moxidectin pyrantel) [20.Becskei C. al.Efficacy chewable tablet sarolaner, pyrantel (Simparica Trio™) flea infestations presented patients Europe.Parasit. 2020; 13Google launched. view developments, further combinations certainly pipelines fully explore scaffold’s potential. Following successful dogs, launched recently cats. easier administer compared products. They may contain alone spot-on fluralaner), Bravecto Plus® moxidectin; Stronghold Plus®, selamectin) [21.Becskei al.Speed kill selamectin induced Ixodes ricinus.Vet. 238: S8-S11Crossref (9) Scholar,22.Taenzler J. (Bravecto® Plus solution cats) Otodectes cynotis cats.Parasit. 2018; 595Crossref (8) long-acting formulations, providing 3 months control. Finally, real treating mite sarcoptic mange [23.Beugnet study naturally infested Sarcoptes scabiei.Parasite. 23: 26Crossref (35) demodicosis [24.Beugnet canine generalised demodicosis.Parasite. 14Crossref (51) ear [22.Taenzler Scholar,25.Vatta A.F. safety mites United States.Vet. 270: S3-S11Crossref (10) Dermanyssus poultry [26.Brauneis M.D. speed red (Dermanyssus gallinae) laying hens its reproduction.Parasit. 1-8Crossref (18) Their blood-feeding dipterans, mosquitoes [27.Liebenberg al.Assessment Aedes aegypti NexGard®.Parasite. 24: 39Crossref sandflies [28.Perier N. Phlebotomus perniciosus dogs.Parasite. 26: 63Crossref (5) allowing usage vectors. As initially example, benzimidazoles, ivermectin appear species, including humans. human-host parasitology applications, insects, mites, Scholar,29.Miglianico al.Repurposing diseases.Proc. Natl. Acad. Sci. U. 115: E6920-E6926Crossref Afoxolaner swine model [30.Bernigaud pharmacokinetic single dose scabiei porcine scabies infestation.Antimicrob. Agents Chemother. 62e02334-17Crossref (14) If so, might able impede arthropod-borne Lyme disease, [31.Baker C.F. al.Ability protect Borrelia burgdorferi infection transmitted wild scapularis ticks.Comp. Immunol. Microbiol. Infect. Dis. 49: 65-69Crossref even neglected tropical African trypanosomiosis (sleeping sickness), leishmaniosis, malaria, claims already made patent literature 33.Heckeroth, 34.Lahm, 35.Billen,