Awarded Amount$4,022,552DiseaseNTD (Leishmaniasis)InterventionDrugDevelopment StageLead OptimizationCollaboration PartnersTakeda Pharmaceutical Company Limited , Drugs for Neglected Diseases initiativePublication
Van den Kerkhof M, Mabille D, Chatelain E, Mowbray CE, Braillard S, Hendrickx S, Maes L, Caljon G. In vitro and in vivo pharmacodynamics of three novel antileishmanial lead series. Int J Parasitol Drugs Drug Resist. 2018 Apr;8(1):81-86. doi: 10.1016/j.ijpddr.2018.01.006. Epub 2018 Jan 31. PMID: 29425734; PMCID: PMC6114106.
Van den Kerkhof M, Mabille D, Hendrickx S, Leprohon P, Mowbray CE, Braillard S, Ouellette M, Maes L, Caljon G. Antileishmanial Aminopyrazoles: Studies into Mechanisms and Stability of Experimental Drug Resistance. Antimicrob Agents Chemother. 2020 Aug 20;64(9):e00152-20. doi: 10.1128/AAC.00152-20. PMID: 32601168; PMCID: PMC7449183.
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.
1. Project objective
The goal is to develop 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. We intend that a novel class of orally active aminopyrazoles drug would be developed for use in combination with other oral therapies for VL, providing a step forward over existing monotherapies or combination therapies. In the project, we aim to optimize a novel series of aminopyrazoles with excellent in vitro and in vivo activity against Leishmania donovani and infantum.
2. Project design
State-of-the-art medicinal chemistry strategies are applied to efficiently optimize the aminopyrazole series, addressing identified and perceived risks early, to advance only molecules with profiles consistent with the requirements of DNDi’s published TPP. In addition to routine assessment of in vitro and in vivo parasitological efficacy, we carefully assess physicochemical properties, in vitro ADME (Absorption, Distribution, Metabolism, and Excretion) properties and in vivo pharmacokinetics, in vitro and in vivo safety, synthesis and formulation to ensure early de-risking and effective risk management of lead molecules.
3. Results, lessons learned
DNDI-5561 was selected as the best compound meeting the target candidate profile for further preclinical development. The compound displays pharmacological and physico-chemical properties consistent with the requirements of DNDi’s published TPP. Further experiments conducted during the preclinical phase will establish whether this compound has a high probability to fully meet the TPP minimum requirements when tested in clinical trials. Activities for four back-up candidates continue in parallel.
The successful conclusion of this stage of the project has been achieved through a highly collaborative partnership between Takeda, DNDi and its consortium of partners including universites, companies and research institutes. DNDi and Takeda plan to continue the further development of DNDI-5561 through preclinical stage, and if the results are promising, into clinical studies. This project was made possible through the generous support of the GHIT Fund to which the project partners express their appreciation.
Lead optimization of the aminopyrazole series for visceral leishmaniasis