Awarded Amount$2,257,442DiseaseNTD (Leishmaniasis)InterventionDrugDevelopment StageLead OptimizationCollaboration PartnersTakeda Pharmaceutical Company Limited , Drugs for Neglected Diseases initiative
Introduction and Background of the Project
This project originates from a successful collaboration between Takeda Pharmaceutical Company Ltd. (Takeda) and the Drugs for Neglected Diseases initiative (DNDi) via the GHIT Funded NTD Drug Discovery Booster program. The unique approach to identification and progression of novel compounds as inhibitors of protozoan parasites supported by the NTD Drug Discovery Booster program has ultimately led to the development of compounds with candidate-level efficacy in animal models of visceral leishmaniasis (VL). Lead compounds in the series S07 with good efficacy and safety profiling have been identified and progressed in partnership with Takeda. Medicinal chemistry optimization around the identified leads and further development plans have been prepared to support progression of at least one optimized lead to candidate status. The S07 series is synthetically tractable, the structure-activity-relationship is well-understood and extensive in vitro safety profiling has not highlighted any issues to date.
The overall objective is to deliver a pre-clinical candidate compound for VL from the chemical series S07 fulfilling the Target Candidate Profile (TCP) for VL developed and used by DNDi.
1. Expand current selection of compounds meeting candidate level efficacy
2. Investigate and determine PK/PD drivers for the S07 series
3. Support compound development with preliminary CMC activities
4. Nominate one compound for preclinical development IND enabling studies
The following activities will be undertaken as part of this project, but outside the scope of GHIT funding support.
1. Identify at least one potential back up series following scaffold scouting
2. Further characterization of the mechanism of action (MoA) for the S07 series
The overarching strategy for progression of the S07 series towards candidate nomination is to identify 3-5 optimized leads with potential to fulfill the TCP for in-depth profiling. From this optimized lead profiling, 2-3 of the most promising leads will be profiled in exploratory toxicology, and the best compound then nominated for progression to preclinical studies. The decision regarding which compound to progress will be made by a data review and candidate nomination meeting composed of all project members and external experts.
To identify 3-5 optimized leads we will:
a) complete profiling of the existing leads identified via the NTD Drug Discovery Booster program
b) use SAR knowledge from previous work to produce new leads for profiling
In parallel, following scaffold scouting, we will explore, design, synthesize and profile sub-series to identify at least one potential back up series outside the scope of GHIT funding support. Similarly, we will investigate the mechanism of action of S07 series.
How can your partnership (project) address global health challenges?
Worldwide, 1 in 7 people live in leishmaniasis endemic areas with an estimated 1 billion at risk of infection from VL and cutaneous leishmaniasis (CL). Every year, there are in between 50,000-90,000 new cases of VL responsible for around 10,000 deaths (5,710 in 2019).(1) The disease is highly endemic in the Indian subcontinent and in East Africa, with more than 95% of new cases reported to WHO in 2018 occurring in 10 countries: Brazil, China, Ethiopia, India, Iraq, Kenya, Nepal, Somalia, South Sudan and Sudan with a high rate of underreporting.(1)
Liposomal amphotericin B is currently considered as the standard treatment for the elimination of VL in India. However, this drug is not effective in East Africa and pentavalent antimonials remain a component of the primary first-line treatment in this region with significant drawbacks in terms of either parenteral route of administration, or length of treatment, toxicity or cost. Our priority is to replace the use of antimonials by developing at least one safe, effective, oral, short-course VL treatment which could be used at any healthcare level in all VL endemic scenarios.
What sort of innovation are you bringing in your project?
There has been progress in the past 20 years with new treatments being developed to replace the highly toxic antimonials used as monotherapy for VL, including combinations containing liposomal amphotericin B, paromomycin and/or miltefosine, with improved safety and tolerability profiles, as well as theoretically much lower propensity to resistance development. However, these drugs remain costly, are difficult to administer, often requiring long dosing/treatment duration, or are poorly tolerated and may not be adapted to high temperatures in endemic regions.
It is essential to add new drug candidates from novel chemical classes acting via not yet explored mechanisms of action to the R&D pipeline. Such candidate(s) will be investigated not only for standalone potential but also as part of DNDi’s extensive drug combination platform focused on VL. A new candidate based on the very promising S07 morpholine chemical scaffold will strengthen the early pipeline for VL and increase the chance of programme success by providing further options for combination with the other drug candidates in development.
Role and Responsibility of Each Partner
The project will be conducted by a team comprising the project director, scientists from Takeda and DNDi. The studies will be conducted in collaboration between Takeda/DNDi, the principal investigators and partner test centers.
- Compound design: Takeda, DNDi/Epichem (Australia)
- Compound synthesis: TCG Lifesciences (India), Epichem
- Synthesis route scouting for scale-up: Takeda, DNDi preliminary CMC studies and consultation: Takeda
- Compound scale-up: TCG Lifesciences
- Physicochemical properties, DMPK: Takeda, TCG Lifesciences, CDCO/Monash University (Australia), WuXi Apptec (China)
- Safety profiling: Eurofins Discovery (France)
- Toxicology: Contract Research Organization to be determined
- In vitro and in vivo parasitology (L. infantum, L. donovani and Leishmania cross-screening): DNDi in collaboration with its mandated screening center namely Laboratory of Microbiology, Parasitology and Hygiene at University of Antwerp (Belgium), All activities related to in vitro and in vivo efficacy studies will be managed by DNDi.
Others (including references if necessary)
(1) Leishmaniasis. WHO Fact Sheet; Updated 2 March 2020 http://www.who.int/mediacentre/factsheets/fs375/en/
Lead optimization and preclinical candidate selection from the NTD Drug Discovery Booster series S07 for visceral leishmaniasis