Preclinical development of an oral anti- Wolbachia macrolide drug for the treatment of lymphatic filariasis and onchocerciasis

Abstract

There is an urgent global need for a safe macrofilaricide drug to accelerate elimination of the neglected tropical diseases onchocerciasis and lymphatic filariasis. From an anti-infective compound library, the macrolide veterinary antibiotic, tylosin A, was identified as a hit against Wolbachia. This bacterial endosymbiont is required for filarial worm viability and fertility and is a validated target for macrofilaricidal drugs. Medicinal chemistry was undertaken to develop tylosin A analogs with improved oral bioavailability. Two analogs, A-1535469 and A-1574083, were selected. Their efficacy was tested against the gold-standard second-generation tetracycline antibiotics, doxycycline and minocycline, in mouse and gerbil infection models of lymphatic filariasis (Brugia malayi and Litomosoides sigmodontis) and onchocerciasis (Onchocerca ochengi). A 1- or 2-week course of oral A-1535469 or A-1574083 provided >90% Wolbachia depletion from nematodes in infected animals, resulting in a block in embryogenesis and depletion of microfilarial worm loads. The two analogs delivered comparative or superior efficacy compared to a 3- to 4-week course of doxycycline or minocycline. A-1574083 (now called ABBV-4083) was selected for further preclinical testing. Cardiovascular studies in dogs and toxicology studies in rats and dogs revealed no adverse effects at doses (50 mg/kg) that achieved plasma concentrations >10-fold above the efficacious concentration. A-1574083 (ABBV-4083) shows potential as an anti-Wolbachia macrolide with an efficacy, pharmacology, and safety profile that is compatible with a short-term oral drug course for treating lymphatic filariasis and onchocerciasis.

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

“…The second macrofilaricidal candidate is emodepside, whose efficacy was demonstrated in pre-clinical trials [29], and which was evaluated in two phase 1 trials, one using single ascending doses [24], and the other using multiple ascending doses (https://clinicaltrials.gov/ct2/show/NCT03383614). The last candidate is a drug called TylAMac (Tylosin Analogue Macrofilaricide, ABBV-4083), which is a macrolide antibiotic effective against Wolbachia [41,43], and which was also evaluated in a phase 1 trial terminated in 2018 (https://www. dndi.org/diseases-projects/portfolio/abbv-4083/).…”

The endosymbiont Wolbachia rebounds following antibiotic treatment

“…Wolbachia titers were reduced by >95% in female worms from rifampicin treated animals at the 1-week timepoint compared to those of worms from vehicle animals. The extensive reduction of Wolbachia titers in adult worms has been previously described in other rodent studies with filarial worms, but the studies were terminated 16-18 weeks post-treatment [26,27,29,40,50], and the long-term effects of antibiotic treatment on filarial worms and their Wolbachia were not evaluated in these models.…”

Moxidectin: an oral treatment for human onchocerciasis

“…Other compounds screened by A•WOL that have shown great promise in pre-clinical development, are high-dose rifampicin [110], rifampicin plus albendazole [111], and an optimized azaquinazoline (AWZ1066S) [112]. Other compounds (in the Drugs for Neglected Diseases initiative (DNDi) filariasis portfolio) [113] include oxfendazole (for which a phase I trial is being planned through the Helminth Elimination Platform (HELP)), emodepside (nearing phase II trial in Ghana for safety, tolerability, and dose/regimen selection), and TylAMac TM (ABBV-4083, developed by A•WOL in partnership with AbbVie [114]), for which a phase II proof-ofconcept trial is being prepared in the DRC [113]. Table 3 compares the characteristics, pharmacokinetics, pharmacodynamics, modalities of distribution in onchocerciasis-endemic communities, and regulatory status of ivermectin, moxidectin, and doxycycline for the treatment and control of O. volvulus infection.…”

“…In areas hypoendemic for onchocerciasis and co-endemic with loiasis at ≥20% prevalence, MDA is not advisable [13], but after establishing safe dosage and thresholds of L. loa microfilaremia levels [118], moxidectin could be used in TNT modalities of delivery that may potentially be more effective than using ivermectin (due to the enhanced curtailing of transmission that would result from more prolonged suppression of microfilaridermia). Doxycycline (already available) and other anti-Wolbachia macrofilaricides (in pre-clinical and clinical development [110][111][112][113][114]) offer an exciting prospect, as TTd for the former, and ideally with much shorter treatment courses for the latter, albeit requiring high rates of O. volvulus screening, therapeutic coverage, and adherence [107]. Large-scale and long-term (at least 14 years) larviciding of vector breeding sites was effective for vector control in the OCP [1] but unlikely to be implemented elsewhere.…”