Filarial DiseasesResearch

 

  • Target disease: Filarial diseases
  • Main partners (since project start): AbbVie, USA; Boehringer Ingelheim, Animal Health Business Unit (formerly Sanofi Merial), USA; Celgene Corporation, USA; GlaxoSmithKline, UK; Johnson & Johnson, USA; Medicines for Malaria Venture, Switzerland; Merck, USA; National Institute of Health, USA; National Museum of Natural History Paris (MNHN), France; Northwick Park Institute for Medical Research, UK; Novartis Centre de la Recherche Santé Animale, Switzerland; Salvensis, UK; University Hospital of Bonn, Germany; University of North Carolina, Office of Technology Development, USA.
  • Funding (since project start): Bill & Melinda Gates Foundation, USA; Federal Ministry of Education and Research (BMBF through KfW), Germany; Brian Mercer Charitable Trust, UK.

 

Overall Objective:

  • Identify new drug candidates, by accessing and evaluating registered drugs, pre-clinical and clinical candidates, focused sets and libraries with known anthelminthic activity from animal and human health companies

 

 

With the limited throughput of phenotypic screening against filarial nematodes, screening large chemical libraries is not possible and DNDi has negotiated access to smaller focused chemical series that are more likely to give rise to drug candidates. These include indications sets (compounds that have progressed to pre-clinical or clinical research but failed to reach the market), well-annotated sets of compounds (e.g. bioavailable sets or compounds which have been through lead optimization), chemical series from veterinary anti-infective research programs, or orthologous sets (compounds directed against human targets with similar gene sequences to the parasites). Over 7,000 compounds were screened in vitro (Onchocerca) and in vivo (Litmosoides model) in 2014, including from bioavailability sets (such as AbbVie, GlaxoSmithKline, Sanofi), and other libraries with specific properties or indications (for example NIH, MMV): approximately 100 compounds have shown activity. Those with appropriate pharmacokinetic profiles are being screened in rodent models of onchocerciasis and lymphatic filariasis. Drug repurposing is high risk, but with the potential to be highly rewarding if successful; and although most compounds will probably not be suitable as macrofilaricidal drugs, they will be a rich resource for developing new clinical candidates.

In addition to compounds that kill the adult worm, DNDi is also investigating compounds that target the endosymbiotic Wolbachia bacterium. A number of promising drug candidates for both targets are under review.

 

In 2017, well-characterized libraries of compounds that had been extensively optimized for other indications were provided to DNDi by several pharmaceutical companies for screening. Early screening of 530 compounds has been completed with Salvensis, Merck Sharp & and Dohme, University of Carolina, AbbVie, and others. From this initial screen, a full lead optimization programme has been undertaken in collaboration with Celgene with further exploration of identified hits (505 compounds). This effort will continue through 2018, with the aim of delivering a pre-clinical candidate for filarial diseases.

 

Last update: August 2018