Oxfendazole mediates macrofilaricidal efficacy against the filarial nematode Litomosoides sigmodontis in vivo and inhibits Onchocerca spec. motility in vitro

Abstract

A major impediment to eliminate lymphatic filariasis and onchocerciasis is the lack of effective short-course macrofilaricidal drugs or regimens that are proven to be safe for both infections. In this study we tested oxfendazole, an anthelmintic shown to be well tolerated in phase 1 clinical trials. In vitro , oxfendazole exhibited modest to marginal motility inhibition of adult worms of Onchocerca gutturosa , pre-adult worms of Onchocerca volvulus and Onchocerca lienalis microfilariae. In vivo , five days of oral treatments provided sterile cure with up to 100% macrofilaricidal efficacy in the murine Litomosoides sigmodontis model of filariasis. In addition, 10 days of oral treatments with oxfendazole inhibited filarial embryogenesis in patent L . sigmodontis -infected jirds and subsequently led to a protracted but complete clearance of microfilaremia. The macrofilaricidal effect observed in vivo was selective, as treatment with oxfendazole of microfilariae-injected naïve mice was ineffective. Based on pharmacokinetic analysis, the driver of efficacy is the maintenance of a minimal efficacious concentration of approximately 100 ng/ml (based on subcutaneous treatment at 25 mg/kg in mice). From animal models, the human efficacious dose is predicted to range from 1.5 to 4.1 mg/kg. Such a dose has already been proven to be safe in phase 1 clinical trials. Oxfendazole therefore has potential to be efficacious for treatment of human filariasis without causing adverse reactions due to drug-induced microfilariae killing.

An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical Disease

“…However, two drugs that are on the DNDi (The Drugs for Neglected Diseases initiative) portfolio as macrofilaricidal candidates, oxfendazole and emodepside, [ 82 , 83 ] have similar IC 50 values against filarial species. The anthelmintic drug oxfendazole, which is currently used in veterinary medicine, was reported to have IC 50 of 7.6 µM (day 14 in culture) and 28.6 µM (day 19 in culture) at inhibiting motility of O. volvulus L5 larvae [ 84 ] and emodepside, another veterinary anthelmintic, has been reported to have a submicromolar motility inhibition IC 50 (0.8 µM) in adult female B. malayi [ 85 ].…”

“…Overall, our integrated computational and experimental in vitro screening approach has proven to be highly successful for identifying new early leads and their putative parasite targets, while also confirming their essentiality for filarial adult worm fitness in phenotypic in vitro assays. Phenotypic in vitro drug screening based on motility of adult filarial worms has been extensively used to assess the potency of various chemical classes on filarial worm viability [ 84 , 85 , 112 , 113 , 114 , 115 ]. This study, however, not only undertook multiple screening assays in different species, sex and developmental stages of filarial worms adding rigor to the identification of potential drugs, but also using the computational analyses has subsequently allowed us to prioritize and expand the set of promising target and drug paired compounds (azoles and APIs) to show broad pan-filarial anti-macrofilarial activity.…”

Effects of an injectable long-acting formulation of ivermectin on Onchocerca ochengi in zebu cattle

“…Three candidates have recently been tested as part of phase 1 trials. The first is oxfendazole [1], which belongs to the benzimidazole family and could have the advantage of killing the adult worms without affecting the mf, and thus would not induce adverse effects, particularly in case of coinfection with Loa loa [27,48]. Ongoing trials (phase 1 and phase 2 against Trichuris trichiura) will enable us to evaluate its possible toxicity [25].…”

Dual RNAseq analyses at soma and germline levels reveal evolutionary innovations in the elephantiasis-agent Brugia malayi, and adaptation of its Wolbachia endosymbionts

“…This loss of Wolbachia is also macrofilaricidal, unlike any classical anthelminthic drug currently in use, since the adult nematode lifespan is dramatically reduced from >10 years to months [12]. In the context of emerging anthelminthic drug resistance, biomedical research is focusing on the search for both new anti-filarials and potent anti-Wolbachia compounds [9,[13][14][15][16][17][18][19].…”