Project Title

Production and pre-clinical testing of cGMP grade Leishmania donovani antigen for Leishmanin skin test (LST)

Collaboration
Partners

1. The Ohio State University (USA)
2. Institute of Tropical Medicine at Nagasaki University (NUITM) (Japan)
3. icddr,b (Bangladesh)

Disease

Leishmaniasis

Intervention

Diagnostics

Stage

Pre-clinical

Awarded Amount

JPY 670,108,468 (USD 4.2 million)

Status

Continued project

Summary

[Project objective]
The objectives of this continuation proposal are to: 1. Produce and characterize cGMP-grade Leishmania antigen (liquid or lyophilized) from L. donovani. 2. Test cGMP leishmanin antigen formulations (liquid and lyophilized) by performing LST in animal models. 3. Perform pre-clinical toxicology studies with cGMP leishmanin antigen formulation that is selected for further advancement based on results from LST studies in animals. 4. Analyze cytokine production in PBMCs or whole blood isolated from healthy individuals and cured VL patients following in vitro stimulation with the selected formulation of cGMP leishmanin antigen. 5. Prepare an IND package for clinical trials. 

[Project design]
During the previous funding period, the project team successfully accomplished goals of the project by 1) optimizing the protocol to produce and scale up production of leishmanin antigen from L. donovani parasites using a cost-effective, scalable and industry suitable osmotic shocklysis technique; 2) performed stability studies; 3) validated GLP leishmanin antigen using experimental animal models, and 4) completed manufacturing of cGMP cell bank of L. donovani at ATCC. In this project, three different formulations of leishmanin antigen will be produced from cGMP L. donovani cell bank. The formulations will be validated for safety and potency using preclinical animal models of vaccination and cured VL. One formulation will be selected for further advancement and scale-up of cGMP production on the basis of results from stability studies and LST studies in animals, and pre-clinical toxicology studies will be performed as per regulatory guidelines. To assess the immunogenicity of the product, cytokine production in PBMCs or whole blood isolated from healthy individuals and cured VL patients following in vitro stimulation with the selected formulation of cGMP leishmanin antigen will also be analyzed. IND package will be prepared for submission to regulators for clinical trials.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/226/en

Project Title

Lead optimization and preclinical studies of new antimalarial Gwt1p-inhibitors with a novel mechanism of action, improved efficacies and safety profiles

Collaboration
Partners

1. Eisai Co., Ltd. (Eisai) (Japan)
2. Medicines for Malaria Venture (MMV) (Switzerland)

Disease

Malaria

Intervention

Drug

Stage

Lead Optimization

Awarded Amount

JPY 680,010,000 (USD 4.3 million)

Status

Continued project

Summary

[Project objective]

The objective of this proposal is to investigate the new Gwt1p-inhibitor and find a back-up candidate with improved activity and safety profile. To deliver this goal, the project team will focus on the following specific objectives:

(1) Two chemical series will be chemically optimized and a frontrunner compound will be selected from each series, as precandidates.

(2) Two precandidates will be evaluated in multiple assays and the most favorable compound will be selected as a Late Lead.

(3) The synthetic route of Late Lead will be optimized and GLP manufacturing will be conducted.

(4) Non-rodent DRF study will be conducted and candidate selection will be scheduled following a successful outcome to this study.

[Project design]
In this project, chemical modification of two lead series will be conducted to improve anti-Plasmodium activity and safety profile while securing a long-half-life. Synthesized new compounds will be shipped to Eisai's Tsukuba Research Laboratories in Japan. They will be tested according to the defined screening cascade starting from the primary screening of anti-Plasmodium activity and cytotoxicity. Compounds which show good anti-Plasmodium activity and safety margin will be tested for solubility at neutral pH and stability against human and murine liver microsomes assays. Based on these results and other profiling, the most promising compound in each series will be selected as pre-candidate and will be further evaluated. Two precandidates will be evaluated in the in vitro/vivo anti-Plasmodium assay, a rat dose range finding (DRF) study, safety profiling, human dose prediction, salt selection, resistant risk assessment and parasite life-cycle assays. The most favorable compound will be selected as a Late Lead. The synthetic route for the Late Lead will be optimized and GLP manufacturing will be conducted. Non-rodent DRF study using the manufactured GLP material will also be conducted. The final goal of this project is the candidate selection in both Eisai and MMV and planned for September 2026.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/227/en

Project Title

Manufacture of clinical trial material for a monoclonal antibody to prevent P. falciparum malaria

Collaboration
Partners

1. Program for Appropriate Technology in Health (PATH) (USA)
2. GlaxoSmithKline Investigacion y Desarrollo, S.L. (Spain)
3. Eisai Co., Ltd. (Eisai) (Japan)
4. Ehime University (Japan)

Disease

Malaria

Intervention

Drug

Stage

Pre-clinical

Awarded Amount

JPY 585,190,112 (USD 3.7 million)

Status

Continued project

Summary

[Project objective]

The objective of this project is to complete GMP drug substance and GMP drug product manufacturing to support the future Investigational New Drug Application (IND) submission to the United States Food and Drug Administration (US FDA) for a proof-of-concept clinical trial that includes controlled human malaria infection. Our long-term goal is to secure a WHO recommendation for a mAb that prevents P. falciparum malaria in young children living in areas of seasonal transmission in sub-Saharan Africa.

[Project design]
The project is built on our successful completion of the following activities: 1) production and release of a pre-master cell bank for the candidate mAb; 2) development and optimization of the manufacturing process for the candidate mAb to confirm production conditions for Good Laboratory Practice toxicology studies and future scale-up; 3) formulation development to enable stability of the mAb at a high concentration to accommodate potential subcutaneous injection; and 4) a pre-IND meeting with the US FDA on the proposed nonclinical and clinical program, specifically on the adequacy of the nonclinical toxicology studies to support the FIH Phase 1 study.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/228/en

Project Title

Hit Validation of novel Daiichi Sankyo compounds with antimalarial activity

Collaboration
Partners

1. Medicines for Malaria Venture (MMV) (Switzerland)
2. Daiichi Sankyo Co., Ltd. (Japan)

Disease

Malaria

Intervention

Drug

Stage

Screening

Awarded Amount

JPY 4,000,000 (USD 25,292.44)

Status

Continued project

Summary

[Project objective]

The objective of the Hit Validation project is the synthesis and testing of a small array of compounds designed to investigate the minimum pharmacophore, key structural features required for activity and scope to address issues identified through the profiling of the hits identified from the earlier HTS campaign (S2020-113). If a compelling data package is obtained and the series clear potential for further development towards an Early Lead, a GHIT HTLP proposal will be submitted.

[Project design]
The focus of the array of analogs is to explore the key features required for activity and scope to address potential issues. A feature of the overall design of the array is focused on modifications with potential to improve the metabolic stability of the series in line with potential to deliver a long duration antimalarial (predicted human T1/2 > 120 h). The lipophilicity of the analogues covers a range of values from approximately 1.5 to 4.5 which will help to identify if data (potency, metabolism, cytotoxicity, etc.) correlates with either LogP or LogD.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/229/en

Project Title

Exploration of Novel Antiviral Compounds for the Development of Therapeutics Against Flavivirus Infections

Collaboration
Partners

1. Eisai Co., Ltd. (Eisai) (Japan)
2. Drugs for Neglected Diseases initiative (DNDi) (Switzerland)

Disease

Dengue and Zika

Intervention

Drug

Stage

Screening

Awarded Amount

JPY 12,653,193 (USD 80,007.54)

Status

New

Summary

[Project objective]

The project team aims to identify hit compounds that will serve as the starting point for new drug development by exploring novel compounds that exhibit antiviral activity against flaviviruses such as dengue virus and Zika virus.

[Project design]
To explore compounds that exhibit antiviral activity against dengue virus and Zika virus, the project team will screen two types of compound libraries, a focused library and a diversity library, using an image-based phenotypic assay system. In the phenotypic assay system, viral proteins and host cell nuclei are stained, and the antiviral activity of the compounds is determined by analyzing fluorescent confocal images. The focused library consists of compounds selected by a machine learning model developed using assay data accumulated by Eisai. By complementarily utilizing the diversity library, the project team efficiently explores compounds that exhibit antiviral activity. Ultimately, the project team aims to identify hit compounds that show activity against dengue virus and Zika virus to establish preliminary structure-activity relationships, physicochemical properties, and other relevant biological information.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/231/en

Project Title

Screening Project between RIKEN and MMV

Collaboration
Partners

1. Medicines for Malaria Venture (MMV) (Switzerland)
2. RIKEN (Japan)

Disease

Lassa Fever

Intervention

Drug

Stage

Screening

Awarded Amount

JPY 20,064,000 (USD 126,866.90)

Status

New

Summary

[Project objective]

The project aims to use a cell-based, infection-free platform to identify potential treatments against LASV using the RIKEN NPDepo library. Additionally, the project seeks to study the effectiveness of selected confirmed treatments against lymphocytic choriomeningitis virus (LCMV), Tacaribe virus (TCRV), and Junin virus (JUNV) in order to identify potential broad-spectrum antiviral compounds. This collaboration leverages the screening capabilities and drug development expertise of Japan's largest comprehensive institution, PDP, and academic investigators to achieve its goals.

[Project design]
The primary screen will use LASV-vRNP/293mRFP to assess a subset of the RIKEN NPDepo library. The screen will be in a 384-well plate format with a single compound concentration of 10 µM. Compounds will be evaluated for their antiviral activity and impact on cell viability. Approximately 200 compounds will be selected for further confirmation studies based on specific criteria. Confirmed actives will undergo broad-spectrum antiviral testing and prioritization for further profiling. Selected hits meeting specific criteria will be considered for future development.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/232/en

Project Title

Screening Project between RIKEN and MMV

Collaboration
Partners

1. Medicines for Malaria Venture (MMV) (Switzerland)
2. RIKEN (Japan)

Disease

Rift Valley fever

Intervention

Drug

Stage

Screening

Awarded Amount

JPY 23,712,000 (USD 149,933.61)

Status

New

Summary

[Project objective]

The project aims to use a live virus platform to identify potential compounds active against the Rift Valley fever virus (RVFV) using the RIKEN NPDepo library. Furthermore, the project intends to investigate the activity of selected compounds against the Punta Toro virus and La Crosse virus in order to identify potential broad-spectrum anti-bunyavirus compounds. This collaboration leverages the screening capabilities and drug development expertise of Japan's largest comprehensive research institution, PDP, and academic investigators to achieve its goals.

[Project design]
The initial screening will involve using the MP-12 strain of RVFV to infect human hepatocyte cells. A subset of the RIKEN NPDepo library (20,000 compounds) will be screened in a 384-well plate with a single compound concentration of 10 µM. The results will be evaluated for antiviral activity and cell viability, and potential hits will be chosen based on specific criteria.

About 100 compounds (assuming a 0.5% hit rate) will be selected from the screening for further confirmation studies. These studies will involve testing the compounds at three different doses in cultured cells infected with RVFV, similar to the initial screen, and assessing cytotoxicity. From the confirmed compounds, RIKEN and MMV will prioritize up to 5 hits for further evaluation.

To assess the potential for broad-spectrum anti-bunyaviral activity, the confirmed compounds will be tested against Punta Toro virus and the more distantly related La Crosse virus.

The hit series meeting MMV and GHIT criteria for further development (hits with confirmed EC50 < 5 µM against live viruses and a selectivity index (SI = CC50/EC50) of ≥10, with progressable chemotypes) will form the basis of a future GHIT HTLP application. 

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/233/en

Project Title

Screening Project between RIKEN and MMV

Collaboration
Partners

1. Medicines for Malaria Venture (MMV) (Switzerland)
2. RIKEN (Japan)

Disease

Ebola and Marburg

Intervention

Drug

Stage

Screening

Awarded Amount

JPY 22,800,000 (USD 144,166.93)

Status

New

Summary

[Project objective]

The project aims to use a multi-filovirus "rainbow" system that can simultaneously test for EBOV, MARV, and SUDV using a single cell line to identify potential treatments against filoviruses using the RIKEN NPDepo library. Additionally, the project seeks to study the effectiveness of selected confirmed hits against other filoviruses (Tai Forest, Reston, Bundibogyo, Lloviu) in order to identify potential broad-spectrum antiviral compounds. This collaboration leverages the screening capabilities and drug development expertise of Japan's largest comprehensive institution, PDP, and academic investigators to achieve its goals.

[Project design]
The primary screen will be performed on a subset of the RIKEN NPDepo library (20,000 compounds). The screen will be in a 384-well plate format with a single compound concentration of 10 µM. Compounds will be evaluated for their antiviral activity and impact on cell viability. Approximately 200 compounds will be selected for further confirmation studies based on specific criteria. Confirmed actives will undergo broad-spectrum antiviral testing and prioritization for further profiling against live Ebola virus. Selected hits meeting specific criteria will be considered for future development.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/234/en