GHIT Fund Announces New Investments: A Total of 2.3 Billion Yen in Drugs for Malaria, Tuberculosis, Chagas Disease and Visceral Leishmaniasis, Vaccine for Malaria and Diagnostics for Tuberculosis

Project Title

First-In-Human Trial of the Pan-Malaria Transmission-Blocking Vaccine AnAPN1

Collaboration
Partners

Ajinomoto Bio-Pharma Services (Aji-Bio), CellFree Sciences Co. Ltd. (CFS), Centre de Recherches Médicales de Lambaréné (CERMEL), University of Florida (UF), University of Tübingen (UKT)

Disease

Malaria

Intervention

Vaccine

Stage

Preclinical to Clinical Development (Phase 1)

Awarded
Amount

¥648,622,379 (US$6,104,681)

Status

Continued project

Summary

[Project objective]

A very promising approach to reduce malaria transmission is the development of so-called "Transmission Blocking Vaccines" or "TBVs" that could block the transmission of the parasite from humans to the mosquito. Targeted vaccination of individuals in high transmission areas promise an immediate and effective reduction in the number of malaria cases. Although a TBV would not directly prevent immunized individuals from developing the disease, it has a clear, delayed clinical benefit for the population. Moreover, a TBV could provide effective means to prevent the spread of antimalarial drug-resistant parasites, and parasites that break through the most advanced malaria vaccine (Mosquirix™) to date. Thus, the development of new TBVs is one of the research priorities for a cost-effective intervention that can directly support the malaria eradication effort. The development of TBVs has mostly focused on P. falciparum ookinete surface protein 25 (Pfs25) and its P. vivax homolog Pvs25, for which Phase 1 clinical trials have been initiated, as well as gametocyte proteins such as Pfs48/45 and Pfs230. However, successful suppression of malaria transmission in most parts of the world will require TBVs that effectively block transmission of both P. falciparum and P. vivax, as the most common causes of disease. A parasite-centric approach requires the development of multiple TBVs using protein immunogens from different species. Instead, the partners focused our studies on developing a vaccine based on a highly conserved mosquito protein that acts as a receptor for the parasite and has the potential to block malaria transmission regardless of the Plasmodium species, i.e., a so-called universal malaria TBV.

[Project design]

The anopheline mosquito midgut-specific alanyl aminopeptidase N (AnAPN1) is a luminal midgut surface protein involved in blood meal digestion. At present, AnAPN1 is the only TBV candidate, which blocks parasite transmission of P. falciparum and P. vivax in different Anopheles species. Working with a mosquito protein further reduces the risk that the parasite could develop resistance against the intervention, potentially allowing for a long-term use of the vaccine under elimination settings.

AnAPN1 has been studied extensively in transmission-blocking experiments, where the protein induced very high titers in immunized animals. A detailed analysis of the protein structure and consecutive mapping of epitope domains identified critical transmission-blocking epitopes of AnAPN1 that can elicit antibodies that completely reduced parasite development in the mosquito. Since any TBV will require very high antibody titers within vaccinated individuals to be effective, it is mandatory to develop an optimized antigen to ensure transmission-blocking activity. The partners have achieved this goal, by re-designing the AnAPN1 antigen and immuno-focusing the humoral response to the key epitopes. The optimized AnAPN1 immunogen, UF6b, has no purification tags, and when formulated with the GLA-LSQ adjuvant elicits potent transmission-blocking activity in mice and non-human primates against natural P. falciparum strains.

This project represents a joint effort by the University of Florida, CellFree Sciences, Ajinomoto Bio-Pharma Services, Center of Medical Research Lambaréné (CERMEL), and the University Hospital Tübingen. The partners envision that during the two-stage project they will complete preclinical manufacturing of UF6b and toxicology testing to obtain ethical approval for use of the vaccine and then enter directly into Phase IA/B clinical trials in Lambaréné, Gabon. As the end points of the clinical trial, safety and dose will be confirmed. Antibodies obtained from immunized individuals will be fully evaluated using a set of functional, immunological, and biological assays established at the University of Florida and CERMEL.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/185/en

Project Title

Product Development of LFA platform for improving sensitivity of Point-of-Care assays for infectious disease with main focus on Tuberculosis

Collaboration
Partners

Asahi Kasei Corporation, Biopromic AB

Disease

Tuberculosis

Intervention

Diagnostics

Stage

Product Design

Awarded
Amount

¥226,625,704 (US$2,132,948)

Status

Continued project

Summary

[Project objective]

The main objective is to validate a Rapid Diagnostic Test which is currently developed by Asahi Kasei and Biopromic for diagnosis of tuberculosis in TB patients irrespective of HIV status. Moreover, the test should meet the WHO TPP criteria.

[Project design]

Asahi Kasei´s and Biopromic´s RDT test will be evaluated by analysis of more than 1000 well-characterized clinical samples collected from South Africa and Uganda to determine the accuracy of the test.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/182/en

Project Title

Lead optimization and preclinical candidate selection from the NTD Drug Discovery Booster series S07 for visceral leishmaniasis

Collaboration
Partners

Takeda Pharmaceutical Company Ltd., Drugs for Neglected Diseases initiative (DNDi)

Disease

Leishmaniasis

Intervention

Drug

Stage

Lead Optimization

Awarded
Amount

¥225,744,281 (US$2,124,652)

Status

New project

Summary

[Project objective]

The overall objective is to deliver a preclinical candidate compound for VL from the chemical series S07 fulfilling the Target Candidate Profile (TCP) for VL developed and used by DNDi.

Specific Objectives:

1. Expand current selection of compounds meeting candidate level efficacy

2. Investigate and determine PK/PD drivers for the S07 series

3. Support compound development with preliminary CMC activities

4. Nominate one compound for preclinical development IND enabling studies

[Project design]

The overarching strategy for progression of the S07 series towards candidate nomination is to

identify 3-5 optimized leads with potential to fulfill the TCP for in-depth profiling. From this

optimized lead profiling, 2-3 of the most promising leads will be profiled in exploratory

toxicology, and the best compound then nominated for progression to preclinical studies. The

decision regarding which compound to progress will be made by a data review and candidate

nomination meeting composed of all project members and external experts. To identify 3-5 optimized leads, the partners will:

a) complete profiling of the existing leads identified via the NTD Drug Discovery Booster

program

b) use SAR knowledge from previous work to produce new leads for profiling

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/186/en

Project Title

Structured-based approach to develop a novel mechanism-of-action antimalarial with multistage activity

Collaboration
Partners

Eisai Co., Ltd., Broad Institute, International Centre for Genetic Engineering and Biotechnology (ICGEB), The Scripps Research Institute

Disease

Malaria

Intervention

Drug

Stage

Lead Optimization

Awarded Amount

¥412,723,601 (US$3,884,457)

Status

Continued project

Summary

[Project objective]                                                               

The goal of this proposal is to leverage structural data on the target parasite protein to guide the design of next-generation antimalarials with higher efficacy, with potentially lower costs of treatment, and improved safety profiles.

[Project design]

We will use a combination of structural biology and computational chemistry to guide the design of novel antimalarials, which will be synthesized and profiled in vitro and in vivo. Promising compounds will be advanced to in vivo safety studies with the goal of selecting a preclinical development candidate.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/169/en

Project Title

Optimization of multistage inhibitors of Plasmodium falciparum lysyl t-RNA synthetase for the treatment of malaria

Collaboration Partners

Eisai Co., Ltd., Medicines for Malaria Venture (MMV), University of Dundee

Disease

Malaria

Intervention

Drug

Stage

Lead Optimization

Awarded Amount

¥353,873,865 (US$3,330,578)

Status

New project

Summary

[Project objective]

The aim of this project is to discover improved compounds with potential to treat human infection. In particular we want to identify a compound suitable for single dose treatment of malaria.

[Project design]

The initial part of the project will be further optimization studies to identify an improved molecule with potential for single dose treatment. Work will then focus on profiling the compound to understand it in more detail. This will include a raft of experiments in "test-tubes" and disease models to try and understand if it should be possible to obtain sufficient levels of compound in the body to treat the malaria infection (pharmacokinetics) and experiments to make sure that toxicity is not seen at the levels at which the compound will be given.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/180/en

Project Title

Hit-to-lead development of new antimalarial compounds from DDI library

Collaboration Partners

The University of Tokyo, Medicines for Malaria Venture (MMV)

Disease

Malaria

Intervention

Drug

Stage

Lead Identification

Awarded Amount

¥116,744,280 (US$1,098,770)

Status

Continued project

Summary

[Project objective]

The University of Tokyo and MMV will generate structurally optimized lead compounds effective against malaria parasites, based on the hit compounds identified by the partners in the previous screening campaign in 2018-2020, supported by GHIT Fund. In the preceding project, the partners identified a number of hits that kill the malaria parasites under micromolar concentrations, by phenotypic screening of 210,000 structurally defined compounds from Drug Discovery Initiative, Japan. In the present project, the partners will conduct structural optimization of the selected six series to develop new antimalarial leads. The partners aim at new compounds with a novel scaffold, mechanism of action, and improved efficacy and safety.

[Project design]

The University of Tokyo and MMV will work together to generate a few series of new compounds that kill malaria parasites by structural modifications of the initial hit series. The new compounds will be further tested for efficacy against both drug-sensitive and resistant malaria strains and also for in vitro safety. It will be also elucidated how the new compounds kill the parasites. Malaria parasites are transmitted between humans and mosquitoes. The partners will also evaluate what developmental stages of parasites the new compounds are efficacious to, e.g., parasites in the human liver, erythrocytes, mosquito gut, and the salivary gland.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/189/en

Project Title

Hit-To-Lead development for Neglected Tropical Diseases

Collaboration Partners

Mitsubishi Tanabe Pharma Corporation, Drugs for Neglected Diseases initiative (DNDi)

Disease

Chagas disease, Visceral leishmaniasis

Intervention

Drug

Stage

Lead Identification

Awarded Amount

¥117,066,370 (US$1,101,801)

Status

Continued project

Summary

[Project Objective]

The objective of this project is to identify at least one series meeting DNDi lead stage criteria for Chagas disease and/or visceral leishmaniasis in line with DNDi published Target Product Profiles (TPPs) for new chemical entities. Medicinal chemistry efforts will be carried out in priority on the three most promising series.

[Project Design]

Screening cascade defined by DNDi for both diseases will be used to assess and progress T. cruzi and Leishmania active series. Compounds will be designed to address the identified liabilities of the series and explore the most promising chemical subset of activity based on structure activity relationship (SAR) identified to date. Any new compound qualifying as a hit in line with the in vitro activity and selectivity criteria will be considered for further profiling and progression in ADME in vitro assays and eventually PK studies assuming favorable ADME profile in vitro is confirmed. Plasma and culture medium protein binding measurements will be performed on promising compounds to evaluate the levels of drug available as free fraction and eventually correlate in vitro activity with drug plasmatic concentration in vivo. Compounds associated with sufficient drug exposure levels will be submitted to secondary assays as well as submitted in parallel to PD studies in acutely infected Chagas disease or leishmaniasis animal models to establish a PoC of in vivo efficacy. Compounds meeting the DNDi lead stage criteria are set as the final milestone of this 2-year project.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/190/en

Project Title

Hit-to-Lead Development of Hits Identified in the Phenotypic Screening against Mycobacterium tuberculosis (Mtb)

Collaboration Partners

Astellas Pharma Inc., TB Alliance

Disease

Tuberculosis

Intervention

Drug

Stage

Lead Identification

Awarded Amount

¥80,136,368 (US$754,225)

Status

Continued project

Summary

[Project Objective]

Astellas in collaboration with TB Alliance have identified two chemical series in our screen of the 20,000-compound library offered by Astellas. The partners intend to develop them in a hit-to-lead phase by preparing a set of analogues for each to finetune their structure-activity relationships (SAR) and to acquire data on their pharmacokinetic (PK) properties and safety profiles. Consolidating the cumulative data, the partners aim to identify candidate compounds, ideally from both series, to test in a mouse acute infection model of TB. If successful, this project will provide a candidate for the lead optimization (LO) phase.

[Project Design]

New analogues in the two series will be synthesized and tested for the in vitro activity against Mtb and any promising analogues will be evaluated for PK and toxicity. Analogues selected after the PK and toxicity studies will be scaled up to test them in a mouse acute infection model.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/191/en

Project Title

Screening project between Daiichi Sankyo RD Novare and TB Alliance

Collaboration
Partners

Daiichi Sankyo RD Novare, TB Alliance

Disease

Tuberculosis

Intervention

Drug

Stage

Hit Identification

Awarded
Amount

¥11,830,099 (US$111,342)

Status

New project

Summary

This is a screening project between Daiichi Sankyo RD Novare and TB Alliance.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/192/en

Project Title

Evaluation of a malaria vaccine candidate comprised of full-length recombinant CSP formulated with SA-1 adjuvant, using RTS,S/AS01 as a benchmark

Collaboration Partners

Ehime University, Sumitomo Dainippon Pharma Co., Ltd., PATH

Disease

Malaria

Intervention

Vaccine

Stage

Antigen Identification

Awarded
Amount

¥99,973,317 (US$940,925)

Status

New project

Summary

[Project Objective]

The overall objective of T2020-252 project is to rigorously test a novel vaccine candidate, flCSP/SA-1, comprised of a full-length recombinant CSP adjuvanted with a novel toll-like receptor 7 (TLR7) agonist, SA-1, for superiority to the RTS,S/AS01 benchmark vaccine, to inform whether to advance flCSP/SA-1 to preclinical development. The partners will examine two aspects of the vaccine, adjuvant (SA-1 vs AS01) and antigen (flCSP vs RTS,S), independently and in parallel.

Our specific objectives are:

1. Test whether flCSP/SA-1, compared to flCSP/AS01, for induction of improved durability of antibody responses in NHP model.  NHPs are used as the test species because rodents do not adequately model the rapid decline of antibody titer observed with RTS,S/AS01 in humans.

2. Test whether flCSP antigen, compared to RTS,S, for induction of stronger protective efficacy in well qualified rodent challenge model.

[Project Design]

Activity 1. Evaluate antibody response durability in NHP model. Cynomolgus monkeys will be used as the primary animal model for immunogenicity because of their responsiveness to the TLR7 agonist in SA-1 and the similarity of induced functional antibody pharmacokinetics (PK) seen in humans. Monkeys will be immunized with of flCSP formulated with SA-1 or with AS01.

Activity 2.1. Evaluate protective efficacy of antibodies induced by flCSP/AS01 and by RTS,S/AS01.  The partners will next compare the quality of the antibody response induced by flCSP or by RTS,S. Each immunogen will be tested in the same adjuvant, AS01, which is known to be active in mice. The experimental design will be closely based on our previously published qualification of in vivo models.

Activity 2.2. Evaluate protective efficacy induced by flCSP/SA-1.  To assure that the combination of flCSP with SA-1 adjuvant results in protective efficacy in the mouse model, the partners will conduct active immunization followed by challenge with sporozoites and measure protection from parasitemia.

At completion of T2020-252 the partners will conduct a Go/no go decision to recommend preclinical development of flCSP/SA-1. A go decision will require evidence of superior, durable protection.

Project Detail

https://www.ghitfund.org/investment/portfoliodetail/detail/187/en