Discovery of ABBV-4083, a novel analog of Tylosin A that has potent anti-Wolbachia and anti-filarial activity

Geldern, Thomas W von; Morton, Howard E.; Clark, Rick F.; Brown, Barbara A.; Johnston, Kelly L.; Ford, Louise; Specht, Sabine; Carr, Robert; Stolarik, DeAnne; Ma, Jun; Rieser, Matthew J.; Struever, Dominique; Frohberger, Stefan J.; Koschel, Marianne; Ehrens, Alexandra; Turner, Joseph D.; Hübner, Marc P.; Hoerauf, Achim; Taylor, Mark J.; Ward, Stephen A.; Marsh, Kennan C.; Kempf, Dale J.

doi:10.1371/journal.pntd.0007159

Cited by 30 publications

(45 citation statements)

References 14 publications

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“…The present studies addressed several important aspects of the in vivo efficacy of the novel anti- Wolbachia agent ABBV-4083 [17, 18]. Using highly suppressive doses, the kinetics of Wolbachia depletion in female adult worms were investigated and the potential of using Wolbachia depletion in microfilariae as surrogate marker was ascertained.…”

Section: Discussionmentioning

confidence: 99%

“…The observed clearance of peripheral microfilaremia by ABBV-4083 was comparable to previous studies in L . sigmodontis -infected jirds using the anti- Wolbachia candidates ABBV-4083 and AWZ1066S starting at 8wpt and reaching complete absence of peripheral microfilariae by 12-15wpt [17, 18, 23]. Kinetic analysis of the embryogenesis indicated that as early as 4wpt the number of stretched microfilariae within the uteri were reduced by >90%, consistent with a half-life of the microfilariae within the peripheral blood of around 3–4 weeks [34] and a drop of peripheral microfilariae loads beginning around 8wpt.…”

Section: Discussionmentioning

confidence: 99%

“…ABBV-4083 is a tylosin analogue which has improved potency and oral bioavailability compared to tylosin and has been shown to be efficacious in rodent models using the filarial nematodes Litomosoides sigmodontis , B . malayi and Onchocerca ochengi [17, 18]. Thus, ABBV-4083 represents a promising anti- Wolbachia candidate, and its safety in humans has recently been assessed in a phase 1 clinical trial (https://www.dndi.org/diseases-projects/portfolio/abbv-4083/).…”

Section: Introductionmentioning

confidence: 99%

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In vivo kinetics of Wolbachia depletion by ABBV-4083 in L. sigmodontis adult worms and microfilariae

et al. 2019

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Depletion of Wolbachia endosymbionts of human pathogenic filariae using 4–6 weeks of doxycycline treatment can lead to permanent sterilization and adult filarial death. We investigated the anti- Wolbachia drug candidate ABBV-4083 in the Litomosoides sigmodontis rodent model to determine Wolbachia depletion kinetics with different regimens. Wolbachia reduction occurred in mice as early as 3 days after the initiation of ABBV-4083 treatment and continued throughout a 10-day treatment period. Importantly, Wolbachia levels continued to decline after a 5-day-treatment from 91.5% to 99.9% during a 3-week washout period. In jirds, two weeks of ABBV-4083 treatment (100mg/kg once-per-day) caused a >99.9% Wolbachia depletion in female adult worms, and the kinetics of Wolbachia depletion were recapitulated in peripheral blood microfilariae. Similar to Wolbachia depletion, inhibition of embryogenesis was time-dependent in ABBV-4083-treated jirds, leading to a complete lack of late embryonic stages (stretched microfilariae) and lack of peripheral microfilariae in 5/6 ABBV-4083-treated jirds by 14 weeks after treatment. Twice daily treatment in comparison to once daily treatment with ABBV-4083 did not significantly improve Wolbachia depletion. Moreover, up to 4 nonconsecutive daily treatments within a 14-dose regimen did not significantly erode Wolbachia depletion. Within the limitations of an animal model that does not fully recapitulate human filarial disease, our studies suggest that Wolbachia depletion should be assessed clinically no earlier than 3–4 weeks after the end of treatment, and that Wolbachia depletion in microfilariae may be a viable surrogate marker for the depletion within adult worms. Furthermore, strict daily adherence to the dosing regimen with anti-Wolbachia candidates may not be required, provided that the full regimen is subsequently completed.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In vivo kinetics of Wolbachia depletion by ABBV-4083 in L. sigmodontis adult worms and microfilariae

et al. 2019

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“…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/).…”

Section: Introductionmentioning

confidence: 99%

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

Boussinesq

Enyong²,

Chounna-Ndongmo³

et al. 2020

Parasite

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The availability of a safe macrofilaricidal drug would help to accelerate onchocerciasis elimination. A trial was conducted in Cameroon to evaluate the effects of a subcutaneous injectable long-acting formulation of ivermectin (LAFI) on the microfilariae (mf) and adult stages of Onchocerca ochengi. Ten zebu cattle naturally infected with the parasite were injected subcutaneously with either 500 mg (group A, N = 4), or 1000 mg long-acting ivermectin (group B, N = 4) or the vehicle (group C, N = 2). Skin samples were collected from each animal before, and 6, 12, and 24 months after treatment to measure microfilarial densities (MFDs). Nodules excised before, and 6 and 12 months after treatment were examined histologically to assess the adult worms’ viability and reproductive status. Blood samples were collected at pre-determined time-points to obtain pharmacokinetic data. Before treatment, the average O. ochengi MFDs were similar in the three groups. Six months after treatment, all animals in groups A and B were free of skin mf, whereas those in group C still showed high MFDs (mean = 324.5 mf/g). Only one ivermectin-treated animal (belonging to group A) had skin mf 12 months after treatment (0.9 mf/g). At 24 months, another animal in group A showed skin mf (10.0 mf/g). The histologic examination of nodules at 6 and 12 months showed that LAFI was not macrofilaricidal but had a strong effect on embryogenesis. The new LAFI regimen might be an additional tool to accelerate the elimination of human onchocerciasis in specific settings.

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“…In contrast, Wolbachia -infected filarial nematodes require their Wolbachia endosymbionts for survival, with Wolbachia depletions causing defects in proper nematode development and reproduction, eventually leading to host death ( Slatko et al 2010 ; Landmann et al 2011 ; Taylor et al 2010 ). As such, antibiotics can be used to treat nematode diseases such as lymphatic filariasis and onchocerciasis ( Taylor et al 2014 ; Taylor et al 2005 ; Clare et al 2019 ; Hong et al 2019 ; von Geldern et al 2019 ; Jacobs et al 2019 ; Taylor et al 2019 ).…”

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confidence: 99%

A Meta-Analysis of Wolbachia Transcriptomics Reveals a Stage-Specific Wolbachia Transcriptional Response Shared Across Different Hosts

Chung

Basting

Patkus

et al. 2020

G3 Genes|Genomes|Genetics

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Wolbachia is a genus containing obligate, intracellular endosymbionts with arthropod and nematode hosts. Numerous studies have identified differentially expressed transcripts in Wolbachia endosymbionts that potentially inform the biological interplay between these endosymbionts and their hosts, albeit with discordant results. Here, we re-analyze all previously published major Wolbachia RNA-Seq transcriptomics data sets using a single workflow consisting of the most up-to-date algorithms and techniques, with the aim of identifying trends or patterns in the pan-Wolbachia transcriptional response. We find that data from one of the early studies in filarial nematodes did not allow for robust conclusions about Wolbachia differential expression with these methods, suggesting the original interpretations should be reconsidered. Across datasets analyzed with this unified workflow, there is a general lack of global gene regulation with the exception of a weak transcriptional response resulting in the upregulation of ribosomal proteins in early larval stages. This weak response is observed across diverse Wolbachia strains from both nematode and insect hosts suggesting a potential pan-Wolbachia transcriptional response during host development that diverged more than 700 million years ago.

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Discovery of ABBV-4083, a novel analog of Tylosin A that has potent anti-Wolbachia and anti-filarial activity

Cited by 30 publications

References 14 publications

In vivo kinetics of Wolbachia depletion by ABBV-4083 in L. sigmodontis adult worms and microfilariae

In vivo kinetics of Wolbachia depletion by ABBV-4083 in L. sigmodontis adult worms and microfilariae

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

A Meta-Analysis of Wolbachia Transcriptomics Reveals a Stage-Specific Wolbachia Transcriptional Response Shared Across Different Hosts

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