R&D MODEL & PORTFOLIO
PROJECT START: July 2010 OVERALL OBJECTIVE: Fully investigate the profile of VL-2098 as
PROJECT START: September 2015 OVERALL OBJECTIVE: Progress and evaluate a nitroimidazole as
an NCE for VL
2015 OBJECTIVE: Decision on whether or not to move the
a potential treatment for VL
2015 OBJECTIVE: Select a compound to progress from the
nitroimidazooxazine backup programme
VL-2098 was chosen for development from a selection of 70 nitroimidazoles belonging to four chemical sub-classes as a very potent and safe molecule. An in-depth evaluation of its efficacy, pharmacokinetic, and early safety profile showed the compound to be potent against L. donovani in vitro and efficacious in acute and chronic VL animal models after oral dosing. However, toxicology and pharmacokinetic studies performed in three animal species indicated a link between dose, length of treatment, and testicular toxicity. Further studies of longer duration were undertaken in order to determine the safety margin, but as it was not possible to establish any therapeutic window between plasma exposures in the most sensitive animal model and efficacious exposures in the two rodent species, the decision was taken to close the project in early 2015.
MAIN PARTNERS: TB Alliance, USA; Advinus Therapeutics, India;
Following the termination of the VL-2098 project in early 2015, the decision was taken to progress with lead compounds from two sub-series previously identified from the nitroimidazooxazine backup programme (DNDI-8219 and DNDI-0690) which had good efficacy in vivo, better solubility, and lower potential for cardiotoxic effects. A 14-day toxicity evaluation carried out in 2015 led to DNDI-0690 nomination as a pre-clinical candidate in September 2015. In addition, with other potential lead compounds for VL, DNDI-0690 was profiled in vitro against CL-causing strains of Leishmania at the London School of Hygiene & Tropical Medicine and the Walter Reed Army Institute of Research and showed good to excellent activity, consistent with their activity against L. donovani and L. infantum.
MAIN PARTNERS: London School of Hygiene and Tropical Medicine
Endolytics, USA; Accelera, Italy; Aptuit, Italy; London School of Hygiene & Tropical Medicine (LSHTM), UK; Laboratory for Microbiology, Parasitology and Hygiene (LMPH), Belgium
(LSHTM), UK; TB Alliance, USA; Auckland University, New Zealand; Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Belgium; WuXi AppTech, China; Aptuit, Italy; Accelera, Italy
Fexi sulfone (completed)
PROJECT START: January 2015 OVERALL OBJECTIVE: Investigate the potential of developing fexinidazole sulfone as a treatment for VL 2015 OBJECTIVE: Take decision on whether to develop
Oral fexinidazole is under development as a treatment for our kinetoplastid diseases, and is most advanced for HAT. When absorbed it functions as a pro-drug for the rapidly formed sulfoxide (M1) and sulfone (M2) metabolites which are 10x more active than fexinidazole itself in in vitro tests and also exhibit a higher drug exposure at all dose levels. Fexinidazole sulfone was considered for development as a drug to replace fexinidazole, and the dossier was reviewed in 2015. In October 2015 the decision was taken not to progress fexinidazole sulfone as there was no clear advantage over fexinidazole; the latter continues to undergo evaluation for VL in combination with miltefosine.
30 › DNDi Annual Report 2015