Lead optimization of the aminopyrazole series for visceral leishmaniasis
  • Awarded Year
    2014
  • Awarded Amount
    $4,022,552
  • Disease
    NTDs Leishmaniasis
  • Intervention
    Drug
  • Development Stage
    Lead Optimization
  • Collaboration Partners
    Takeda Pharmaceutical Company Limited, Drugs for Neglected Diseases initiative

Introduction and Background of the Project

Drugs for Neglected Diseases initiative (DNDi) in collaboration with Takeda Pharmaceutical Company Limited aim at delivering an anti-parasitic drug from the aminopyrazoles series that is orally active, safe, effective, short-course, and field-adapted for the treatment of visceral leishmaniasis (VL) – a drug that would have the potential to revolutionize the treatment of VL.

 

Leishmaniasis is a complex disease caused by more than 20 species of the Leishmania parasite.  VL is deadly if not treated and accounts for 200,000 to 400,000 new cases and 20,000 to 40,000 deaths each year.  While the last decade has seen improvement in the treatment, diagnosis, and prevention of leishmaniasis notably in South Asia, response to treatment differs among regions. 

 

Existing drugs for VL have serious drawbacks in terms of safety, resistance, stability and costs.  They have low tolerability, long treatment duration and are difficult to administer. The proposed approach is clearly differentiated from the existing therapeutics for VL. The partnership will develop a novel class of orally active aminopyrazoles with a presumed novel mechanism of action that demonstrate excellent in vitro and in vivo anti-parasitic activity. The intention is that a new aminopyrazole drug would be developed for use in combination with other oral therapies (i.e. miltefosine, fexinidazole, VL-2098 or other emerging candidates) for VL, providing a major step forward over existing monotherapies or combination therapies.   Such a drug could also provide a much needed treatment option for HIV-VL co-infected patients. If the safety profile of the new aminopyrazole drug allows, it could also be tested in other manifestations of leishmaniasisincluding post kala-azar dermal leishmaniasis (PKDL), treatment of asymptomatic individuals to reduce disease transmission, and cutaneous leishmaniasis (CL).

 

How can your partnership (project) address global health challenges?

DNDi in partnership with Takeda seeks to develop a new treatment that appropriately addresses the patient needs, specific to each affected region.  DNDi and Takeda will collaborate on lead optimization of this novel series which recently demonstrated a proof of concept in an animal model of VL.  Specifically, the goals of this lead optimization program will be to (1) fully profile the early aminopyrazole leads, (2) to identify 4-6 leads with the required in vivo efficacy (3) select a small group of 2-3 advanced leads for further profiling including exploratory in vivo toxicology studies from which (4) the best compound meeting the target candidate profile will be selected as the ‘optimized lead’ for further preclinical development.

What sort of innovation are you bringing in your project?

This partnership brings together DNDi’s experience of discovering and developing new treatments for Neglected Tropical Diseases with Takeda’s extensive experience, strong capabilities and depth of scientific knowledge in drug discovery and development – assets that will be invaluable to progress rapidly with this initiative.  DNDi was created to develop new treatments for the most neglected tropical diseases such as leishmaniasis.  Takeda is a leading international pharmaceutical company with a corporate mission to “strive towards better health for people worldwide through leading innovation in medicine.”Takeda will use its extensive and broad drug discovery experience to provide advice and guidance to the project team.  Takeda has more than 200 chemists and computational chemists who can aid design.  In particular Takeda scientists will contribute to the medicinal chemistry strategy, data analysis and compound design applying experience from other Takeda projects to help solve scientific problems faced by the project team.  For example Takeda can apply proprietary ligand based in silico molecular design technologies such as advanced similarity searching and also chemotype-hopping methods to extend the chemical space for design and identify lead contingency options. Additionally, to solve absorption, distribution, metabolism, and excretion toxicology issues, a knowledge-based Takeda original database can be applied. The in silico technologies were newly built or customized by Takeda computational chemists, which can point out different directions for optimization. Takeda will also provide advice on compound pharmacokinetics, safety assessments and exploratory toxicology which are critical to the development of a safe anti-parasitic therapy.