R&D MODEL & PORTFOLIO
PROJECT START: April 2012 OVERALL OBJECTIVE: Generate new drug candidates for the
PROJECT START: 2010 OVERALL OBJECTIVE: Identify and evaluate new biological
treatment of Chagas to be assessed in clinical trials
markers of therapeutic efficacy in chronic Chagas disease and to promote research
An opportunistic approach was undertaken to assess compounds issuing from the VL-2098 back-up programme (nitroimidazooxazine series) showing activity against T. cruzi in vitro, evaluating the most promising candidates in in vivo models of Chagas disease. Given the ongoing clinical development of fexinidazole for Chagas disease, further progression was put on hold and will only recommence if a need arises.
PARTNERS: TB Alliance, USA; Auckland University, New Zealand; Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Belgium; WuXi AppTech, China; LSTMH, UK
• Follow-up validation and characterization studies on selected markers identified through proteomic-based platforms and other studies • Progress Non-Human Primate Study through 12 month assessment and immunosuppression phase
Chagas H2L (Chagas Hit to Lead)
PROJECT START: On-going OVERALL OBJECTIVE: Identify new leads series from current ongoing Hit-to-Lead activities to move them into lead optimization 2015 OBJECTIVE: Identify new chemical series to progress into
Hit-to-Lead and lead optimization stages
Multiple hits from screening with several pharmaceutical partners or from other sources have been progressed into hit confirmation and expansion studies. Several promising series, issued from the published hit list from “GSK kinetoplastid Boxes” and Celgene, have been identified and are currently moving into the hit-to-lead stage; one series showed Proof of Principle in vivo and is in Lead Optimization. In order to identify hit series with a different mechanism of action, the screening cascade has been modified to filter out potential CYP51 inhibitors (same mechanism of action as posaconazole or ravuconazole), and prioritizing trypanocidal compounds early on. The insights gained from additional in vitro assays, coupled with a new in vivo model based on BioLuminescent Imaging, was developed at the LSHTM. The model predicts the outcome of benznidazole and posaconazole in clinical trials, enabling compounds to be moved forward with more confidence. Opportunities for new candidates to include in the pipeline are continually under review. Preliminary mapping and set-up of discovery activities are continuing in Latin America in accordance with the global DNDi strategy of empowerment of and funding from the regional offices.
MAIN PARTNERS: Centre for Drug Candidate Optimization, Monash