GHIT Fund Announces New Investments: A Total of 230 Million Yen in Drugs for Malaria and Chagas Disease

Project Title

Prolyl tRNA Synthetase Inhibitors for New Antimalarials

Collaboration Partners

Takeda Pharmaceutical Company Limited, Medicines for Malaria Venture (MMV)

Disease

Malaria

Intervention

Drug

Stage

Hit-to-Lead

Awarded Amount

¥54,726,800 (US$526,929)

Status

Continued project

Summary

Malaria, a mosquito-borne disease caused by Plasmodium parasites, still infects over 228 million people per year. There were an estimated 405,000 malaria deaths worldwide in 2018 (1). Novel classes of antimalarial medicines targeting different parasite stages are urgently needed to provide both effective alternatives when resistance to current therapies will inevitably progress and the tools needed to meet the malaria eradication agenda (2). The project team is now working on prolyl tRNA Synthetase (PRS) Inhibitors with the aim of identifying a potential new antimalarial drug. This PRS chemical series was directly repurposed from the Takeda Pharmaceutical Company Limited (Takeda) portfolio. At the beginning of the collaboration between Takeda and Medicines for Malaria Venture (MMV), screenings were performed at MMV testing centers in the USA (Prof. Elizabeth Winzeler – University of California, San Diego) and in Australia (Prof. Vicky Avery – Griffith Institute for Drug Discovery, Griffith University) against the liver (3), blood asexual (4) and sexual (5) stages of the malaria parasite. Data gathered showed that the Takeda PRS chemical series has activity against both the asexual blood and liver stages of the Plasmodium lifecycle.

The main objective of the project is to transform PRS Inhibitors into Lead series with proven in vivo efficacy in relevant animal disease models so as to identify at least one compound as an early lead molecule that meets the GHIT/MMV criteria for progression to Lead Optimization stage for prophylaxis.

This project will follow the current hit-to lead activity that will end in October 2020. In this new phase the project team will perform medicinal chemistry activity to optimise the PRS chemical series in terms of DMPK and physicochemical properties to meet GHIT/MMV early lead criteria. The most promising compounds will be evaluated in rodent PK experiments and in a relevant model of malaria to demonstrate in vivo efficacy/protection. After further optimization of their properties, the goal is to select a couple of lead molecules which will be the basis of a new proposal to GHIT for a Lead Optimization program.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/175/en

Project Title

Screening project between Daiichi-Sankyo and MMV

Collaboration Partners

Daiichi Sankyo Company Limited, Medicines for Malaria Venture (MMV)

Disease

Malaria

Intervention

Drug

Stage

Hit Identification

Awarded Amount

¥12,201,320 (US$117,479)

Status

New project

Summary

This is a screening project between Daiichi-Sankyo and MMV.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/178/en

Project Title

Pioneering antisense oligonucleotides as long-acting malaria prophylactics

Collaboration Partners

Eisai Co., Ltd., University of California, San Diego (UCSD)

Disease

Malaria

Intervention

Drug

Stage

Hit Identification

Awarded Amount

¥92,297,284 (US$888,670)

Status

New project

Summary

Malaria continues to inflict a devastating burden on low-income countries, and development of effective new liver-stage prophylactic agents is a priority for the antimalarial field. Antisense oligonucleotides (ASOs) are well-matched to this unmet need, offering the possibility of long-duration activity and benefiting from effective delivery to hepatocytes using well-established conjugation technology. Furthermore, ASOs are a platform technology that enable highly selective targeting of essential Plasmodium genes, with the potential to access previously undruggable targets and accelerate development of additional drugs following initial validation. Eisai has developed proprietary nucleic acid technologies that enhance these advantageous properties.

This project will undertake a rigorous investigation as a novel antimalarial strategy, with the goal of demonstrating in vivo proof-of-concept for ASOs as long-acting malaria prophylactics.

Well-validated malaria target genes will be examined for tractability, and ASOs against the selected target will be optimized using high-throughput cell culture assays at UCSD and Eisai's nucleic acid technologies. High-potency optimized ASOs will be tested in a causal prophylaxis animal model to assess in vivo efficacy.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/172/en

Project Title

Target validation and AI-guided identification of Trypanosoma cruzi phosphodiesterase inhibitors for the treatment of Chagas disease.

Collaboration Partners

Eisai Co., Ltd.,Universidad Nacional de La Plata (UNLP)

Disease

Chagas Disease

Intervention

Drug

Stage

Target Identification

Awarded Amount

¥71,007,750 (US$683,687)

Status

New project

Summary

There is an urgent need for new treatments for Chagas disease. Existing medications lack effectiveness against chronic infection, require long regimens, and have several adverse effects. Given their integral roles in trypanosome signaling and low homology with human counterparts, phosphodiesterases (PDEs) have been posited as drug targets for Chagas disease. Given the paucity of identified targets and critical need for new mechanism-of-action drugs, these enzymes merit definitive evaluation followed by efficient identification and development of inhibitors.

This project aims to validate PDEs as drug targets for Chagas disease and identify selective inhibitors using a computationally-enhanced screening cascade.

An accelerated drug development path will be sought by focusing on repurposing opportunities that can be rapidly progressed to clinical trials, complemented by screening for new chemical matter from Eisai's compound library. Candidate inhibitors identified in machine-learning based virtual screens will be profiled experimentally and promising compounds advanced to animal studies.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/171/en