Approx. USD 4.0 M Invested in Product Development for NTDs – GHIT’s First Investment in the Development of Diagnostics for Trachoma

Project Title

A First-in-class, Fully TPP-compliant Rapid Diagnostic Test for Trachoma Surveillance: Delivering the Missing Piece in WHO’s Worldwide Trachoma Elimination Efforts

Collaboration

Partners

1. Drugs & Diagnostics for Tropical Diseases (DDTD) (USA)

2. Medical & Biological Laboratories, Co. Ltd. (MBL) (Japan)

3. The Carter Center (TCC) (USA)

4. Big Eye Diagnostics, Inc. (BEDx) (USA)

Self-funded Research Partner: Centers for Disease Control and Prevention (CDC) (USA)

Disease

Trachoma

Intervention

Diagnostics

Stage

Product Development

Awarded Amount

JPY 288,958,766  (USD 2.0 million)

Status

New project

Summary

[Project objective]

The overarching objective of this project is to deliver a rapid diagnostic test (RDT) to detect exposure to Chlamydia trachomatis, the pathogen causing trachoma. Our test will meet all key criteria of WHO’s Target Product Profile (TPP) for trachoma surveillance and will be delivered in both a dipstick and a cassette format.

[Project design]
The project team will pursue the following 6 specific objectives:

-Objective 1 (MBL): One key factor to ensure reproducible product quality is to have a constant, reliable source of the biological components of the test. MBL will be in charge of this key task and produce the C. trachomatis antigen.

-Objective 2 (DDTD): A functional prototype RDT has already been generated and validated by the CDC, and subsequently reproduced and partially optimized at DDTD. This test will now be fully optimized until it satisfies all key TPP criteria.

-Objective 3 (CDC): Once an optimized candidate test has been nominated by DDTD, CDC will provide an independent validation of TPP compliance in terms of sensitivity and specificity.

-Objective 4 (TCC): TCC will work with the Trachoma Monitoring Laboratory to further validate the RDT for diagnostic performance and user-friendliness (feasibility) in one of the intended use cases.

-Objective 5 (DDTD, BEDx): DDTD will develop a robust, ISO13485-compliant large-scale manufacturing process commensurate with the expected demand forecast of up to 700’000 tests/year and the ideal target pricing of <$5 per test required by the TPP.

-Objective 6 (DDTD): DDTD will liaise with a social anthropologist and a health economist with the goal to acquire socio-economic data on optimizing test acceptance by local populations and on testing costs of programmatic surveys.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/223/en 

Project Title

Generation of an Early Lead for a Novel Long-Acting-Injectable (LAI) Prophylaxis Anti-Malarial: Hit-to-Lead Optimization of Dimeric Alkaloidal Molecules

Collaboration

Partners

1. Institute of Tropical Medicine, Nagasaki University (NU-ITM) (Japan)

2. Department of Chemistry, School of Science, The University of Tokyo (Japan)

3. Shionogi & Co., Ltd. (Japan)

4. Medicines for Malaria Venture (MMV) (Switzerland)

Disease

Malaria

Intervention

Drug

Stage

Hit-to-Lead

Awarded Amount

JPY 149,816,440 (USD 1.0 million)

Status

New project

Summary

[Project objective]

The project aims to optimize the hit series, prioritize the best candidates, and deliver an early lead for intra-muscular chemoprevention that meets Medicines for Malaria Venture’s long-acting-injectable Early Lead Criteria. The investigation will focus on the medicinal chemistry potential of the unique natural-product-inspired hit series as novel anti-malarial agents, ensuring synthetic tractability, cost-effectiveness, and the potential for optimizing long-acting injectable relevant anti-malarial properties. Additionally, the project will explore and characterize the novel mechanism of action and access the propensity to induce resistance.

[Project design]

The project team will study the structure-activity relationship to define the essential features of the minimal three-dimensional pharmacophore structures, aiming to simplify their design. Scaffold diversification will be explored to enhance our compound library, with an emphasis on improving the properties of long-acting injectable compounds by maintaining low solubility, increasing metabolic stability, and achieving a balanced blend of potency, stability, and solubility. The team will continue evaluating promising leads based on established safety and effectiveness criteria and predicting their behavior in humans. This process includes assessing leads for pharmacokinetics/dynamics, potential off-target activities, and injection site reactions using animal models.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/224/en

Project Title

Design of a universal Rapid Diagnostic Test for the detection of chronic Trypanosoma cruzi infections.

Collaboration

Partners

1. Nagasaki University School of Tropical Medicine and Global Health (Japan)

2. Tulane University School of Public Health and Tropical Medicine (USA)

3. Barcelona Institute for Global Health (ISGlobal) (Spain)

Disease

Chagas disease

Intervention

Diagnostics

Stage

Target Research

Awarded Amount

JPY 69,989,878  (USD 0.49 million)

Status

New project

Summary

[Project objective]

The ultimate objective is to achieve a prototype RDT to detect chronic T. cruzi infections that renders a very good performance regardless of the geographic origin of the clinical samples to analyze. For that, we envisage the following specific objectives: 

(1) To sequence and assemble the whole genome of underrepresented T. cruzi isolates from Mesoamerica. 

(2) To analyze, with the assistance of computational methods, all available T. cruzi protein sequences for prioritization of diagnostic antigens.

(3) To address the reactivity against those selected antigens by arraying them with plasma/serum samples originating from multiple Chagas disease endemic countries. 

(4) To print the ultimately prioritized antigens on immunochromatographic (IC) strips for their analytical evaluation, and qualification, as a prototype POC RDT.

[Project design]

To reach the goal of analytically validating a new RDT prototype that hypothetically works in all regions, the project team will first need to obtain the whole genome sequences of under-represented isolates circulating in Central America and Mexico, where it is acknowledged that currently available tools have a poor performance. Then, responding to the second specific objective, the team will analyze all the sequences with the aid of computational methods in order to identify the antigens, or epitopes within them, of diagnostic interest. In search of the antigenic sequences that could encompass a pan-American, or regionally tailored, serological tool, we will consider evolutionary conservation as a major feature. For evaluating the prioritized peptide sequences derived from the computational analysis, the team will use a collection of samples from T. cruzi-infected individuals, and geographically matched non-infected controls. For the sake of time, this collection will be retrospective, and it will encompass two sets of samples: one for the exploratory part of the project, and another for the validation of the sequences.

The teamr will address the reactivity of the samples over the distinct peptide sequences by means of peptide microarrays. These will render the necessary throughput to be able to check hundreds of peptides. Those supporting the widest geographical coverage and yielding the highest signal will be selected. Finally, the best will be taken to generate the RDT prototype in the shape of a lateral flow assay.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/225/en

Project Title

Fragment and structure-based hit generation platform for new malaria targets

Collaboration

Partners

1. University of Tokyo (Japan)

2. Medicines for Malaria Venture (MMV) (Switzerland)

3. University of Oxford (UK)

4. University of Dundee (UK)

Disease

Malaria

Intervention

Drug

Stage

Target Research

Awarded Amount

JPY 69,962,310 (USD 0.48 million)

Status

New project

Summary

[Project objective]

The goal of the project is to generate high quality hit compound series against two highly validated malarial targets, by applying, for the first time in malaria, the state-of-the-art XChem fragment approach of X-ray structure-accelerated, synthesis-aligned lead discovery. The targets, Pf DPCK and Pf KRS are essential, novel Plasmodium targets prioritized by the malaria drug discovery community. There is a need for high quality chemical matter to serve as starting points for further optimization.

[Project design]

Crystallization conditions on the two selected biological targets will be optimized to enable large-scale production of protein crystals (~1000) that consistently diffract to a high resolution (preferably <2.5 Å).  Each crystal will then be soaked separately with a fragment from a library that was optimized to cover chemical space and designed to allow rapid, cheap follow-up synthesis to provide quick structure activity data. Solving the crystal structure of fragments that bind to the target gives an understanding of how that compound binds to the target and allows the team to then apply AI and medicinal chemistry techniques to design, then synthesize new compounds that will bind more tightly to the target. Through application of these design-make-test cycles the team will optimize the selected hits to deliver high quality drug discovery starting points.  A suite of biochemical and biophysical tools will be used to characterize the hit compounds, with advanced compounds being fully profiled for malaria lifecycle activity.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/222/en