INFORMAL INFORMATION DOCUMENT

Follow-up of the report of the Consultative Expert Working Group on Research and Development: Financing and Coordination

This document reproduces (from the original proposal documents) the summaries of the 7+1 proposals identified as potential demonstration projects by the Global Technical Consultative Meeting of Experts

on the Identification of Health Research and Demonstration Projects, as well as the clarificatory addenda requested by Member States (with reference to EB134/27 – Annex 2: Report of the Global

Technical Consultative Meeting of Member States on the Identification of Health Research and Development Demonstration Projects). These addenda are reproduced as submitted to the Secretariat by the proponents of each proposal.

7+1 POTENTIAL DEMONSTRATION PROJECTS IDENTIFIED BY EXPERTS

1. The Visceral Leishmaniasis (VL) Global R&D & Access Initiative 2. Multiplexed Point-of-Care test for acute febrile illness 3. Demonstration of the potential of a single dose malaria cure of artemether-lumefantrine through reformulation in a nano-based drug delivery system 4. Exploiting the Pathogen Box: an international open source collaboration to accelerate drug development in addressing diseases of poverty. 5. Development Of A Vaccine Against Schistosomiasis Based On The Recombinant Sm14 A Member Of The Fatty Acid Binding Protein: Controlling Transmission Of A Disease Of Poverty. 6. Development Of Class D Cpg Odn (D35) As An Adjunct To Chemotherapy For Cutaneous Leishmaniasis And Post Kala- Azar Dermal Leishmaniasis (Pkdl) 7. Development for Easy to Use and Affordable Biomarkers as Diagnostics for Types II and III Diseases PLUS: Dengue vaccine development

LIST OF QUESTIONS FOR CLARIFICATION*

Describe, where relevant, how your project:

1. Intends to delink the price of the final product from the cost of the R&D. 2. Utilizes collaborative approaches, including open knowledge innovation approaches. 3. Utilizes licensing approaches that secure access to your research outputs and final products. 4. Proposes and fosters financing mechanisms including innovative, sustainable and pooled funding. 5. Fosters effective and efficient coordination mechanisms amongst existing organizations/initiatives. 6. Strengthens capacity for research, development and production, including through technology transfer, in developing countries.

*As referred to in EB134/27, Annex 2: Report of the Global Technical Consultative Meeting of Member States on the Identification of Health Research and Development Demonstration Projects

Project title: The Visceral Leishmaniasis (VL) Global R&D & Access Initiative

Project summary:*

This proposal recommends as a candidate demonstration Project the creation of the VL Global R&D &

Access Initiative that will demonstrate that VL R&D projects can be optimized through guiding principles such as cross-regionals collaboration of existing networks (see Annex 3), open-innovation

and sharing knowledge, equitable access to new products, and sustainable funding secured through existing and new funding mechanisms. Considering the current VL R&D landscape, the existing drug portfolio (see below) and the current treatments limitations mentioned above, for this project DNDi will focus on the following strategy over the next five years (see table below summarizing the objectives related to the treatment limitation):

Objective 1: to develop new safe and effective oral treatments as monotherapy and as early as possible as combination treatment (medical product) to prevent the risk of resistance development for the treatment of VL patients and a very safe, short-course one for asymptomatic carriers once their role in disease transmission has been better established:

Activity 1: to identify new series of compounds and to select candidates for promising NCEs from lead-optimization program to pre-clinical (class of Oxaborole; class of Nitromidazole; Dundee/GSK); Activity 2: to bring from preclinical to POC a new drug candidate (VL2098); Activity 3: to complete the clinical development of existing candidate up to registration (Fexinidazole or VL 2098) as monotherapy and as soon as possible as combination treatment.

Objective 2: to develop technology of diagnostic (xenodiagnoses coupled with a quantitative PCR) in order to evaluate the role in transmission of asymptomatic carriers and PKDL patients:

Activity 1: set-up of sand fly colonies and training on xenodiagnoses and quantitative PCR. Activity 2: small clinical study evaluating the infectivity of asymptomatic careers and PKDL patients.

Objective 3: to develop treatment for PKDL (medical product): Activity 1: start and complete clinical development of new regimen of treatments that demonstrate skin penetration for the current treatment of PKDL patient.

Objective 4: the contribution to the development of a shared, open-access data base that will allow identifying determinants of treatment effectiveness that will be based on existing ones developed for malaria. The project is based on an optimization and coordination of already existing initiatives in order to reduce the time, costs and efficiency necessary to achieve the goal of development new tools for the treatment of VL.

The guiding principles of the Initiative are defined as:

1. Sharing knowledge and Open innovation Open knowledge platform through the establishment of a Drug Accelerator Consortium -which could be supported by the Innovative Medicines Initiative (IMI)/Horizon 2020 - will be a key asset to speed up upstream research, avoid duplication of research and decrease cost of R&D development: partners within the Drug Accelerator platform will agree to screen their libraries together increasing chance to identify good hits for later optimization. Other institutions and researchers from different Initiatives and networks (listed in Annex 3) would agree ensuring open knowledge sharing, similar to the Open Source Drug Discovery (OSDD) set up in India3 part of the Council of Scientific and Industrial Research (CSIR).

2. Sustainable funding In addition to existing resources involved in the support of VL, new funding mechanisms would be needed to increase resources such as the European and Developing Countries Clinical Trials Partnership (EDCTP 2), Innovative Medicines Initiative (IMI), contributions from emerging economies countries affected by the disease (Brazil, India, Middle-East and North Africa) and Prizes.

3. Equitable access To ensure affordable access replicate the industrial model based on agreement signed with pharmaceutical company for one project for example contract signed with Sanofi for fexinidazole. It makes new therapeutic and diagnostic tools developed as public goods and ultimately available at affordable prices.

4. Coordination through collaborative approach Setting up the VL Global R&D & Access Initiative in partnership with the current VL consortia and research platforms from the different relevant regions (see Annex 3). Details about the functioning of the Initiative: The Initiative for VL would be composed of a steering committee selected among the representatives of the scientific community, key governments, main R&D partners, relevant regional WHO offices (SEARO, PAHO, EURO, AFRO), DNDi, and the existing VL Initiatives (LEAP; Consortium for VL treatment in India and Bangladesh; Consortium on HIV/VL in East Africa; Consortium on PKDL) supported by a secretariat housed in an existing institution. The Initiative would also work in partnership with relevant partners such as the EDCTP, IMI, the Council of Scientific and Industrial Research (CSIR) including OSDD. The Secretariat will need to be committed to minimizing overhead costs and achieving value for money. The responsibilities of the Initiative would be to: • Review and validate R&D priorities for VL disease • Define priority treatment candidates • Development and implementation of equitable access policy • Review and validate funding needs • Identify potential funding mechanisms at country, regional, and international levels • Review and validate proposals for innovative incentive mechanisms such as prizes • Review and propose regulatory, financial, and procurement policies to facilitate access to final products • Monitor project implementation and results • Review and validate financial reports • Facilitate information sharing with national programs and regional initiatives • Appoint and have oversight of delegated activities of the Secretariat

*As taken from original proposal template, question 5.

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ADDENDUM- CEWG Demonstration Projects

The Visceral Leishmaniasis Global R&D and Access Initiative

“Authors must send an addendum to their project which describes, where relevant, how the project:

1. Intends to delink the price of the final product from the cost of the R&D.

2. Utilizes collaborative approaches, including open knowledge innovation approaches.

3. Utilizes licensing approaches that secure access to your research outputs and final products.

4. Proposes and fosters financing mechanisms including innovative, sustainable and pooled funding.

5. Fosters effective and efficient coordination mechanisms amongst existing organizations/initiatives.

6. Strengthens capacity for research, development and production, including through technology transfer, in developing countries. “

Submitted by DNDi to the WHO PHI Secretariat on January 15th, 2014

How the project : ADDENDUM- The Visceral Leishmaniasis Global R&D & Access Initiative (1583 words)

1. Intends to de-link the price of the final product from the cost of the R&D

To address identified VL R&D gaps (cf. proposal Questions 4 and 5), the VL Global Initiative (hereafter ‘Initiative’) requires innovative incentive mechanisms that de-link R&D costs from product price. De-linkage particularly applies to activities of moving a new chemical entity from product pre-clinical to clinical development (Objective 1, Activity 2); completing clinical development of an existing candidate up to registration (Objective 1, Activity 3); and developing a new treatment for PKDL (Objective 3). De-linkage is ensured through:

1. DNDi’s intellectual property (IP) policy adopted in 2004, based on two criteria: ensuring that drugs are affordable and accessible in an equitable manner to patients who need them; and developing drugs as public goods whenever possible. This is the basis of contract negotiations with pharmaceutical partners to guarantee patient access to end products, in line with the Target Product Profile, which defines the ideal characteristics of the end product. Research and operations are not financed through IP rent revenues.

2. Contractual provisions with pharmaceutical partners. In practice, DNDi aims at securing licensing terms which ensure research and its outputs are considered public goods that advance public health. After ten years of experience, DNDi developed 6 new treatments and established ‘Gold standard’ licensing terms:

- Perpetual royalty-free, non-exclusive, sub-licensable licenses - Worldwide research and manufacturing rights; - Commitment to make the final product available at manufacturing

cost, plus minimal margin, in all endemic countries, regardless of

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income level; - Non-exclusivity, enabling technology transfer and local production to

multiply sources of production and decrease cost of product. As an example of de-linkage, ASAQ-FDC for malaria, developed by DNDi and Sanofi (2007), is available at-cost plus a small margin (under USD 1 for adults; under USD 0.5 for children). 3. PDPs as push mechanisms: The last decade, with new public and private donor commitments, has seen new push mechanisms, including PDPs, to finance R&D and pull mechanisms to attract new stakeholders. PDPs, with a model such as DNDi’s, by seeking diverse funding from private and public donors (cash donations, in-kind contributions, R&D grants), inherently de-link R&D expenditures from product price, financing R&D by sources other than IP rent revenues. For the Initiative, DNDi has already secured EUR 9 million of the EUR 36 million needed. To develop a diagnostic tool based on quantitative PCR (qPCR) (Objective 2) a milestone or small end-stage prize is a suitable incentive for partners to better evaluate VL transmission via asymptomatic carriers and PKDL patients. Because R&D incentives are weakened by insufficient market potential, they fail to stimulate innovation. A milestone or small end-stage prize would stimulate investments to rapidly adapt the existing qPCRs to specific transmission risk-assessment needs for the Initiative. The qPCR technique could help correlate parasite load with transmission risk in asymptomatic and PKDL patients. It detects and quantifies parasite DNA. Similar methodologies exist but show varying levels of sensitivity and specificity in clinical VL, CL, MCL and PKDL. Additional investments are needed to develop more accurate qPCRs adapted to the regional VL variations, sensitive enough to detect very low parasite DNA in asymptomatic, antibody-positive carriers. The VL prize would notably reward a group already invested in qPCR and stimulate developing countries’ research orientations and researchers, thus strengthening capacities. A small prize, up to EUR 500 thousands would attract small organizations, and shift some costs of failure to the prize-funder rather than researchers. As highlighted by the CEWG report, the success of the prize will depend on the suitability of its design, including targeted cost and technical requirements (e.g. sensitivity) for the intended purpose. The Initiative steering committee and scientific advisory committee will define the design and rules for the prize following key principles of de-linkage (i.e. availability and affordable access) and compliance with the initiative’s IP and licensing rules (including open source publication of findings).

2. Utilizes collaborative approach: including open knowledge innovation approaches

Neglected diseases, where traditional market mechanisms do not attract investments and with limited funding resources, require open models for sharing knowledge and research data, particularly for upstream research, to identify promising new technologies/compounds.

The Drug Accelerator Consortium (hereafter ‘Accelerator’) proposed, based on current DNDi negotiations with several pharmaceutical companies, will be launched in 2014. It transcends existing approaches of bilateral agreements, and will pool resources, compounds, and expertise across companies,

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expediting identification and selection of candidates for promising new chemical entities from lead optimization to pre-clinical research (Objective 1, Activity 1). The Accelerator would collectively adhere to the licensing practices described above, and reduce costs and time of the discovery phase of R&D. Outcomes would be placed into the public domain (e.g. through the EU Open PHACTS Discovery Platform) to catalyse further research. Specifically, the Accelerator’s activity would comprise searching and screening multiple libraries simultaneously and pooling capabilities of companies to identify more rapidly expanded hit series to quickly establish Structure-Activity Relationships that the Initiative could take through lead optimization and the full spectrum of R&D to implementation. It would provide access to state-of-the-art compound profiling assays and expertise with other leaders in NTD lead optimization (e.g. Drug Discovery Unit of Dundee University) to increase the capacity to identify a large number of top quality preclinical candidates and avoid duplication. The Innovative Medicines Initiative (IMI), a public-private partnership between the European Union and the European Pharmaceutical Industries and Associations with a EUR 2 billion budget, within the Horizon 2020 (EU Framework Program) would be an adequate mechanism to promote collaboration among pharmaceutical companies, academic groups, SMEs, and a PDP. Additional funding could be sought through this mechanism (see below).

The Initiative will implement a Data Sharing Platform to identify determinants of treatment efficacy and effectiveness (Objective 4). Working with WWARN, it will develop, under the principles described above, an open clinical and biological database (including pharmacology, in vitro and molecular parameters) to resolve scientific questions emanating from single studies. This requires technical expertise and a legal-ethical framework to pool anonymized patient data for research. Such expertise has been extensively developed by WWARN and malaria partners.

3. Utilizes licensing approaches that secure access to research outputs, and access to final products

The Initiative will secure innovative licensing terms (see Question 1) to make research outputs global public goods. Timely access to newly-generated knowledge and data is crucial to neglected diseases with high mortality rates (e.g. VL). The Initiative will provide open access to knowledge generated, including that of the Accelerator. Data from the Initiative will be presented and published in open access journals and publicly accessible databases (e.g. ChEMBL; WIPO Re:Search). The Initiative will apply an equitable access policy to all new therapeutic and diagnostic tools, based on agreed-upon principles that ensure affordable pricing, sustainable production, and de-linkage (see Objective 1 Activity 2). To ensure sustainable access, the Initiative will regularly review and propose enabling regulatory, financial, and procurement policies by engaging endemic-country regulators in to accelerate the registration.

4. Proposes and fosters financing mechanisms including innovative, sustainable and pooled funding

Leveraging the EUR 9 million already secured by DNDi for the Initiative, other appropriate pooled mechanisms will be approached:

- European & Developing Countries Clinical Trials Partnership (EDCTP-2), which expanded its scope to clinical trials in Africa for all Neglected Infectious Diseases (global budget: EUR 248 million, 2014-2015) (for clinical-trial activities).

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- Innovative Medicines Initiative (IMI) co-funded by the European Commission and the pharmaceutical industry (in-kind contributions; to support the Accelerator).

- Global Health Initiative Technology Fund, initiated in 2013, co-financed by the Japanese government, the Japanese pharmaceutical industry and the Bill and Melinda Gates Foundation (global budget: USD 100 million, 5 years) for infectious disease R&D.

- Member States’ dedicated funding (including emerging economies that are endemic for VL, e.g. Brazil, India) for demonstration projects, managed as pooled funding for example via TDR.

New innovative funding sources (e.g. UNITAID; FTT), which require Member State decisions, protect long-term product development from shifting individual donor circumstances and priorities. The Initiative aims to constructively feed, by example, ongoing Member State discussions on such mechanisms.

5. Fosters effective and efficient coordination mechanisms amongst existing organizations/initiatives

The Initiative aims to demonstrate that R&D projects can be effective while strengthening coordination among multidisciplinary partners and through innovative R&D financing and coordination mechanisms, notably as VL affects EURO, SEARO, EMRO, AFRO, and PAHO. Seeking rapid health impact and a sustainable public health solution necessitates an integrated model for North-South and South-South collaboration. Constant strong involvement of endemic countries to define priorities and facilitate implementation of new tools, and innovative alliances with pharmaceutical and biotechnology companies and academia, are vital. DNDi, with no laboratories or manufacturing facilities, functions thanks to engagement of public and private partners (academia; public research institutions, particularly in endemic countries; pharmaceutical and biotechnology companies; NGOs; PDPs; and governments) by leveraging their assets, capacities, and expertise. The Initiative will partner with the LEAP clinical platform in Africa, EDCTP, IMI, CSIR and OSDD, in addition to DNDi’s pharmaceutical and academic partners. A steering committee elected among multidisciplinary partners, would embody these sectors.

6. Strengthens capacity for research, development and production, technology transfer in developing countries

- Technology transfer: Development of a new diagnostic technology for diagnosis of asymptomatics and PKDL patients by xenodiagnoses (Objective 2): Two steps: training courses and set-up of colony and infectivity experiments in Bangladesh, Sudan, India (2-year duration).

- Capacity Strengthening via the Prize for qPCR to evaluate the role of transmission in asymptomatics and PKDL. A pre-requisite for receiving the qPCR diagnosis Prize would be capacity-building.

- Clinical development of an existing drug candidate up to registration (Fexinidazole/VL2098) (Objective 1, Activity 3) with potential support of EDCTP and endemic countries, will enhance clinical trial capacity (including GCP, GLP, ethics, case management, regulatory capacity) in Asia, Africa, and Latin America, through DNDi’s platforms and other research networks. Fexinidazole for VL is now in clinical trial, driven by LEAP. With wide-range disease strains, the same GCP-standard clinical trials in different regions will differentiate geographical immune responses.

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Objectives Activities Incentive mechanisms

Partners (pending until discussion and agreement from suggested partners)

Region

Objective 1: Development of safe, effective, and field-adapted 1st-line treatments for East Africa and Latin America (and 2nd-line for the Indian sub-continent),

Activity 1 : Identifying new compounds from lead optimization to pre-clinical phase (class of Oxaborole, class of Nitromidazole) Activity 2:Moving an NCE from pre-clinical phase to POC (VL2098)

Open knowledge and open source, through Drug Accelerator Consortium De-linkage principle

Drug Accelerator Consortium partners (pharmaceutical companies), OSDD/CDRI, Dundee/GSK consortium, IMI/EU All

Global Global

Activity 3: Complete clinical development of existing candidates up to registration (Fexinidazole and combination)

De-linkage principle, capacity-building, Collaborative coordination, Innovative Regulatory pathways

LEAP platform, EDCTP, ICMR, Fiocruz, pharmaceutical partners

East Africa, Latin America, Indian sub-continent

Objective 2: Understanding of the role of asymptomatic and PKDL patients in the transmission of the disease

Xenodiagnosis Quantitative PCR

Capacity-building; transfer of technology; collaborative coordination; data sharing De-linkage principle; milestone and/or small end prize; capacity-building

University Utrecht, Institute of Endemic Diseases, University of Caracas, Ferrer Group, Salpêtrière Hospital, Stiefel GSK, SGS All

Sudan, Bangladesh, India Global

Objective 3: Development of safe, effective and field-adapted 1st-line treatment for PKDL patients

Research on skin penetration of existing drugs – clinical development

De-linkage principle; capacity-building; collaborative coordination

LEAP, EDCTP, ICCDRB, PATH, IMI

Sudan, Bangladesh, possibly later India

Objective 4: Tools to monitor the development of resistance to existing treatments

Build up a data sharing platform

Open source; data sharing

WWARN, MoHs, ITM-Antwerp, EDCTP/EU

Global

Project title: Multiplexed Point-of-Care test for acute febrile illness (mPOCT)

Project summary:*

Acute fever or acute febrile illness (a rapid onset of fever and symptoms such as headache, chills or muscle and joint pains) is common in the tropics and sub-tropics and can be caused by very diverse pathogens[1-3]. Differential diagnosis of these etiologies based on clinical criteria alone is not possible as clinical signs and symptoms of most of these infections are very similar and the correct diagnosis is only possible by using pathogen specific diagnostic tests. For patient treatment and management, differential diagnosis of causative agent is required [1-3]. In low income countries, many preventable deaths occur because of delayed or lack of correct diagnosis. In last few years, extensive efforts to control malaria are resulting in positive outcome. In fact, non-malarial febrile illnesses (NMFI) cause more deaths than malaria even in malaria-endemic countries and in the absence of accurate or available diagnostics for NMFI, many non-malarial fevers are treated as malaria which is contributing in the generation of artemisinin resistance [1, 2, 4, 5]. Based on these facts, availability of multiplex test which can quickly identify a pathogen from a group of pathogens that cause the similar symptoms is of paramount importance not just from medical standpoint but will also have much greater public health relevance[1]. There are many state of the art diagnostic platforms and techniques available which can be used for multiple target screening in a specimen e.g. advanced multiplex nucleic acid tests, array based immunoassays and bead/flow based assays [6-8]. Unfortunately, these platforms are not suitable for most of the developing countries as these tests tend to involve complex equipment, are expensive and not proven to be robust in field situation where constant power supply is problem and regular maintenance is a challenge. In the resource-limited settings, the impact of diagnostic tests that can be provided at immediate point-of-care is potentially even greater, because the alternative to a POC test (POCT) may be no diagnostic support at all [8]. Based on these facts, in this proposal, we have decided to use simple field deployable lateral flow formats, which with some innovation, can be used for the generation of multiplex test for at least 5-6 major high-burden pathogens responsible for AFI in tropical and subtropical regions of the world especially SEARO region. Based on literature search, infectious diseases which cause major burden of AFI and also amenable to multiplexing include Malaria, Dengue, Typhoid/Paratyphoid, Chikungunya, Leptospirosis and Scrub Typhus [1-3, 5, 9]. These are the diseases that are proposed to be targeted by multiplex POCT. Despite the strong need, no multiplex POCT is available in market which can be used in resource limited settings for the detection of multiple etiologies of AFI. Although, individual (singleplex) POCTs for the chosen infections (Dengue, Malaria, Typhoid/Paratyphoid, Chikungunya, Scrub Typhus, Leptospirosis) are commercially available but most of these tests are of poor quality. Only the POCTs for malaria (because of FIND/WHO extensive evaluation program), and to some extent Dengue NS1 Ag, fulfill WHO ASSURED criteria [1, 5, 10]. The POCTs for infectious diseases developed in developed countries are often imported by developing countries but these tests are generally very expensive and also do not perform to the mark in the developing countries. Major reasons for poor performance of available tests are: 1) Not sufficient financial incentive to develop high quality rigorously evaluated tests for developing countries; 2) Use of poor quality antigen/antibodies; 3) lack of knowledge about specific target(s) of particular pathogen which causes problem of cross-reactivity; 4) Lack of evaluation using local clinical specimen (inappropriate cutoffs) ([8, 10, 11]. Because of the problems in available singleplex tests, we also propose to generate high quality diagnostic intermediates/reagents for each pathogen. Here, we also propose to generate, affordable handheld mobile phone based test reader which will improve both the sensitivity and specificity of the test as the reader will remove the subjectivity involved in reading the test line or dot.

Strategy: The strategy will involve parallel/simultaneous detection of IgM antibodies against particular pathogen and pathogen specific antigen in whole blood or serum. For Plasmodium falciparum and P. vivax, antigen will be detected. For Dengue, both antigen and IgM will be detected. For S. Typhi/ Paratyphi A, Leptospira spp., Orientia tsutsugamushi and Chikungunya virus only IgM antibodies will be detected. We will utilize fused strip approach for multiplexing as this approach allows incorporation or removal of any target from the panel, without affecting the performance for other targets. This is very important as the prevalence of different pathogens varies between regions. Another advantage of fused strip approach is that it’s an open system and can be manufactured by many diagnostic companies present in developing countries without any IP issues related to the platform. In this project, we will also develop a mobile based assay reader which will improve both the sensitivity and specificity of the test as the reader will remove the subjectivity involved in interpreting the results. The reader will also remove dependence on colloidal gold tracer which is not very sensitive. The proposed reader will also be capable of transmitting data to central server which will help in disease surveillance and will have greater public health significance. The high quality multi-country sera panel for major febrile illnesses will also be generated in this project. Evaluation of assay using clinical samples from developing world/SEARO region is prerequisite as regional background must be determined to tune the cut-off value [10]. The whole project will be guided by the WHO ASSURED criteria. THSTI, India will play role of coordinator (nodal point) for this project.

*As taken from original proposal template, question 5. References

1. FIND, Acute Febrile Syndrome Strategy. 2012. 2. Acestor, N., et al., Mapping the aetiology of non-malarial febrile illness in Southeast Asia

through a systematic review--terra incognita impairing treatment policies. PLoS One, 2012. 7(9): p. e44269.

3. Capeding, M.R., et al., Dengue and other common causes of acute febrile illness in Asia: an active surveillance study in children. PLoS Negl Trop Dis, 2013. 7(7): p. e2331.

4. Joshi, R., et al., Nonmalarial acute undifferentiated fever in a rural hospital in central India: diagnostic uncertainty and overtreatment with antimalarial agents. Am J Trop Med Hyg, 2008. 78(3): p. 393-9.

5. Crump, J.A., S. Gove, and C.M. Parry, Management of adolescents and adults with febrile illness in resource limited areas. BMJ, 2011. 343: p. d4847.

6. Reddington, K., et al., Advances in multiparametric molecular diagnostics technologies for respiratory tract infections. Curr Opin Pulm Med, 2013. 19(3): p. 298-304.

7. Ellington, A.A., et al., Antibody-based protein multiplex platforms: technical and operational challenges. Clin Chem, 2010. 56(2): p. 186-93.

8. Microbiology, A.A.o., Bringing Lab to the patient: developing point-of-care diagnostics for resource limited settings, A. Reid, Editor 2012: Washington, DC.

9. Chrispal, A., et al., Acute undifferentiated febrile illness in adult hospitalized patients: the disease spectrum and diagnostic predictors - an experience from a tertiary care hospital in South India. Trop Doct, 2010. 40(4): p. 230-4.

10. Yager, P., G.J. Domingo, and J. Gerdes, Point-of-care diagnostics for global health. Annu Rev Biomed Eng, 2008. 10: p. 107-44.

11. WHO, Increasing Access to Diagnostics Through Technology Transfer and Local Production. 2011.

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Addendum to candidate demonstration project titled “Multiplexed

Point-of-Care Test for acute febrile illness (mPOCT)” submitted by

THSTI, India

1. How the project intends to delink the price of the final product from the

cost of the R&D?

The Multiplexed Point-of-Care Test for acute febrile illness (mPOCT) project involves partners mainly from public space and not-for-profit organizations; as a result the cost of R&D will not flow on to final product. After successful R&D and testing of the product, proposed to be funded by innovative mechanisms including pooled fund, the product/technology will be transferred to private players in developing countries with bulk manufacturing capacity. Therefore, only the production and downstream costs will be part of the final product costs, for the sustainability and affordability of which we have proposed certain mechanisms mentioned in the main document and delineated in response to Question 4 of this submission.

2. How the project utilizes collaborative approaches, including open

knowledge innovation approaches?

This project seeks to foster collaboration and utilizes a Product Development Partnership (PDP) model to bring about connectivity between partners including leveraging strengths of international experts. Collaborative approaches are the backbone of this proposal as there are different work packages requiring technical expertise and resources for the various stages i.e. 1. Generation of well characterized sera panel; 2. Development of handheld reader; 3. Generation of pathogen specific reagents; 4. Field evaluation; 5. Manufacturing and marketing; 6. Evaluation of kits (product) manufactured by diagnostic companies.

This product development and deployment model brings together players with expertise from various domains globally in public, private, not-for-profit settings and government agencies to work together. Inputs from member states will be utilized to improve Target Product Profile (TPP) further to suit local needs. The project will seek information from manufacturers to accommodate their perspective on manufacturing feasibility/ practical issues.

All the collaborators will share/pool the IP with the consortium (among collaborators) as this will help keeping the price of the final product affordable. Thus the project will use an open-source approach to sharing non-

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confidential information from all partners through a platform that promotes networking and collaboration. Major technologies and processes behind the concept e.g. lateral flow, tracer/label, target discovery platforms, etc. are in public domain and expertise is available in the consortium. The reader prototype IP is also with consortium partner. This situation will allow the final product development without any need for in-licensing.

3. How the project utilizes licensing approaches that secure access to your

research outputs and final products?

Final product(s) will be licensed on non-exclusive basis to private players in both developed and developing countries to promote access to the mPOCT. This will prevent monopoly, generate healthy competition between the players and result in affordable, quality controlled tests in the market. Also, the consortium will be in a strong negotiating position because of their involvement with downstream product penetration into the developing country markets. As we propose to non-exclusively transfer the rights to commercial partners, we will secure access to research output and final product. This will also help the consortium to make further improvements in the product if required.

4. How the project proposes and fosters financing mechanisms including

innovative, sustainable and pooled funding?

Pooled funding is necessary to provide the crucial “push” to the project, thereby providing milestone based support for R&D of this product and support the delinking of final product price from the cost of R&D. Funding will be sought by presenting defined TPP (target product profile) information to all the possible sources for their contribution. In order to secure funding, contribution will be sought from: • Different Govts/member states: TPP information will be circulated in

different countries through WHO (regional offices) requesting for funds. • Potential Donors: Bill & Melinda Gates Foundation, Azim Premji

Foundation etc. • Other potential international institutions/agencies: Wellcome Trust,

UNITAID, The Global Fund, Finnish International Development Agency (FINNIDA), Swedish International Development Cooperation Agency (SIDA), Norwegian Agency for Development Cooperation (NORAD) etc.

Apart from this, funding will be leveraged from developing country government agencies such as Department of Biotechnology, Department of Science and Technology, Indian Council of Medical Research, Council for Scientific and Industrial Research etc. in India.

Given the invaluable benefits from the demonstration project, it is highly probable that mPOCT for acute febrile illness would be taken up by a

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number of national surveillance programs in developing countries, which will generate huge demand and thus enable in bringing down the cost of the product based on high volumes. In addition, country/ region specific retail price of product will be fixed based on the differential pricing policy as a sustainable financing mechanism, a strategy similar to GeneXpert MTB/RIF pricing.

5. How the project fosters effective and efficient coordination mechanisms

amongst existing organizations/initiatives?

Numerous coordination mechanisms, appropriate at different stages of development for the product, are proposed based on existing available expertise in the countries of India, Finland, Sri Lanka, Thailand etc. The chosen consortium partners have prior experience and good track record in respective field/ component and this project will bring respective technical expertise together. The strengths of main partners are mentioned in the main document. An appropriate multidisciplinary advisory body of global constituents/ experts/ technical partners, including agencies already working in the area of fever diagnostics e.g. FIND, WHO-TDR, MSF etc., would provide valuable inputs in the areas of biology, engineering and public health, at all stages of development and deployment of the product. The guiding principles for effective and efficient coordination will be understanding the public health needs in member countries, maintaining transparency in selection of collaborators, risk management, dissemination of information and managing potential conflicts of interest, while maintaining high standards of quality and ethics. It is proposed that THSTI will act as the nodal point to coordinate the research and funding activities. The project will have coordinators and administrative support staff for different work packages across institutions in different countries. Mechanisms /processes for information cross flow will be established.

6. How the project strengthens capacity for research, development and

production, including through technology transfer, in developing

countries?

The mPOCT for acute febrile illness addresses a real need in developing country diagnostics strategy. The project envisages a long term and sustainable solution through developing country participation in a collaborative framework mechanism and addresses local capacity building for diagnostic innovation, technology transfer, and local production. This PDP consortium will also provide training on latest technologies to scientific organization in less developed partner countries in this project. TDR and FIND could also be partnered with to provide training on ISO/GMP/GLP

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issues to the manufacturers/ licensees. In the proposed project, we are not only planning to transfer the final product to manufacturers in less developed countries but also plan to co-develop the product with input/support/expertise from different developing countries. This strategy will enable developing country capacity building for international norms and standards at every stage of diagnostic product development (discovery to production to dissemination) and will define a clear pathway for taking R&D products to market. This project will also create local expertise in developing country in quality-assured manufacture, packaging and distribution. As the prototypes and final products will undergo evaluation in many developing countries, it is likely to bring clarity and harmonization of standards in regulatory approval mechanisms, in sync with global/ regional standards.

Project title: Demonstration of the potential of a single dose malaria cure of artemether-lumefantrine through reformulation in a nano-based drug delivery system Project summary:*

The World Health Organization recommended the use of artemisinin and its derivatives as a partner drug in combination treatments, to replace artemisinin monotherapies in the treatment of uncomplicated malaria. Parasite resistance to artemisinins has now been detected in Cambodia, Myanmar, Thailand and Viet Nam (WHO 2012). However, despite the observed reduction in parasite sensitivity to artemisinins, Artemisinin combination therapies (ACTs) continue to cure patients provided that the partner drug is still efficacious (WHO 2012). Lumefantrine co-formulated with artemether has been the most widely used ACT. Lumefantrine and arthemeter continue to be efficacious in the treatment of malaria but have been faced with limitations such as poor bioavailability and multiple dosing, hence poor patient compliance. Bioavailability is the fraction of an administered dose of drug that reaches the systemic circulation. When a drug is administered intravenously, the bioavailability is 100 %, however this is not the case when administered orally as is the case with the antimalarials in this study. In the oral route of administration, the drug must first be absorbed in the intestine, and as the drug passes through the intestine and liver, metabolism occurs mainly by the cytochrome P450 (CYP) family of enzymes, (first-pass metabolism) and further excretion may take place thus reducing its bioavailability. Lumefantrine has a poor and erratic absorption with bioavailability of about 57%. Similarly, artemether has recorded poor bioavailability of about 35%. This limited absorption and poor bioavailability necessitates use of larger doses of drug to ensure appropriate plasma concentration. Moreover, any attempt to increase the dose administered to patients in order to augment the therapeutic dose in case of tolerance is likely to cause toxicity. The primary objective of this study, therefore, is to enhance the oral therapeutic effectiveness of lumefantrine and artemether in combination by entrapping them in nanomedicine drug delivery systems (NMDDS). The NMDDS will be designed in such a way as to improve the drug bioavailability and slowly release and hence enhance the circulatory time of the therapeutic agents in the blood.This may enhance the exposure of the plasmodium parasite to the antimalarials. Currently the two drugs of the fixed dose are taken twice daily for three days. NMDDS presents the ability to achieve single dose therapy. The potency of the drug could be maximised and patient compliance enhanced by reducing dose and dose frequency. Therapeutic agents will be comparatively evaluated in vitro and in a mouse model. The CSIR nanomedicine platform, a Centre of Excellence in nanomedicine, (COE), has preliminary data with the antimalarial tafenoquine delivered in NMDDS showing significant enhancement in bioavailability and half-life in mice. We plan to develop NMDDS for lumefantrine and artemether, by applying our technology, to enhance bioavailability, increase the circulatory time and maintain therapeutic concentrations for longer periods at the target site. *As taken from original proposal template, question 5.

Demonstration of the potential of a single-dose malaria cure of artemether-lumefantrine

through reformulation in a nano-based drug delivery system

1. Delinking the price of the final product from the cost of the R&D

Product development will utilize grants from public funding sources/ foundations, allowing us to ultimately delink R&D cost from product cost. Lead researchers are supported by government agencies/grants from public institutions/foundations. Dr Melariri and Prof. Swai (CSIR) are supported by the South African (SA) government, whereas Bernhards Ogutu (KEMRI) is supported by the Kenyan Government. Our product development model for poverty-related diseases (PRDs) is based on public-private-partnership (PPP) ensuring the ultimate product cost is affordable. This model is used by Medicines for Malaria Venture (MMV), Malaria Vaccine Initiative (MVI) and Drugs for Neglected Diseases Initiative (DNDI). Plans exist to engage foundations e.g. MMV, big pharma e.g. Norvatis at the onset of the project.

The prescribed mandate and strategic objectives of the public institutions (e.g. CSIR) owning the Intellectual Property Rights associated with the technology platform, and developed through public funding, is to improve quality of life, and to promote access to affordable healthcare. Project outcomes are designed for impact, linked to social-benefit indicators, and commercial arrangements (including PPPs) must incorporate such obligations and performance requirements by commercial partners. Commercial contracts will therefore include such considerations as the ‘price of final product’ in relation to the economic cost/benefit of the solution deployed. The business plan, informed by our impact strategy, must incorporate operational/revenue models from an understanding of the economic, industry and value chain analysis, to implement the successful procurement and roll-out (manufacture, marketing and distribution) of the therapeutic regimen via the public healthcare system. 2. Utilizing collaborative approaches, including open knowledge innovation approaches.

The project is based on a collaborative framework to build capacity on nano-technology as platform for drug development in Africa. The hallmark of this collaboration is to utilize/share the expertise within the African region with support of expertise of the nano-technology community globally. In this respect we have had two nano-technology for drug delivery workshops hosted by CSIR, attended by several African scientists and experts in nanotechnology across the world. We have also held nano-technology roadshows in Kenya, Tanzania, Ethiopia, Nigeria etc, to update the scientists on nano-drug delivery platforms and their potential for PRDs and to sensitize stakeholders like policymakers, funders and the public. Through these forums we received feedback informing our strategy. Two of the collaborating institutes, CSIR and African Institute of Biomedical Science & Technology (AIBST) are already ANDI centres of excellence (CoE) and we are engaged in training scientists/researchers as detailed in section 5. 3. Utilizing licensing approaches that secure access to your research outputs and final

products

The consortium, and especially CSIR, has preference for non-exclusive licensing. Licensing agreements are associated with due diligence and licensee selection procedures, which conform to a standard organizational approval and governance framework, and which seek to promote our impact strategy. A national IP law exists in South Africa, (No. 51 of 2008: Intellectual Property Rights from Publicly Financed Research and Development Act, 2008), which allows the State an “irrevocable and royalty-free licence, authorising the State to use/have the intellectual property used globally for the health needs of the Republic.” This law promotes and secures access to R&D outputs within the public interest. The program will effect mechanisms fostering collaborative R&D agreements with pharmaceutical companies within the framework of agreed and existing PPP understandings (e.g.

MMV), to allow ongoing access to and avoid undue monopolization of rights to the technology being developed. The program will pursue an attractive portfolio of intellectual property rights, filed and prosecuted in the name of the public institution (e.g. CSIR) to secure and protect such rights for the purpose of issuing licenses, following negotiations, with pharmaceutical companies/stakeholders.

4. Proposing and fostering financing mechanisms including innovative, sustainable and

pooled funding

The program will utilize WHO funding as core grant to leverage our current funding from the SA government. The proposed engagement of Novartis, MMV and EDCTP in this project will ensure long-term viability and transfer of sustainable solutions to patients. A detailed strategy to this approach will be devised in alignment with the WHO strategy for demonstration projects. A central entity such as BRICS (Brazil, Russia, India, China, South Africa) an independent international organization, via their strategy for health, drug discovery and development, may be approached for funding to take the work further, dovetailing with their strategies to stem the tide of communicable and non-communicable diseases. Our strategy for innovative, sustainable and pooled funding is based on the Sixty-six World Health Assembly (WHA66.22) resolution attributable to the recommendations made by Consultative Expert Working Group (EWG) on R&D: Financing and Coordination. This will involve mainly Push Models of funding and other unconventional financing mechanisms being explored owing to poor funding for PRDs such as malaria. R&D is more amenable to Push Mechanism of funding. These are mainly through innovation funding & grants, subsidies for research, tax credits on R&D, expedited regulatory review facilitation mechanisms and liability protection. The Pull Mechanism related to production capacity, regulatory approval, delivery and product access will become more important in clinical development. Our proposed mechanisms include:

(a) Attracting grants from funding agencies eg Bill and Melinda Gates Foundation, MMV (Switzerland), Wellcome Trust (UK), and NIH (US). In this regard we held discussions with MMV. We will solicit funding from national Science and Technology Innovation mechanisms of participating countries (South Africa, Zimbabwe, Kenya, Tanzania). The involvement of malaria-impacted governments will ensure negotiable market guarantees that will encourage product developers and manufacturers. (b) African countries and communities such as SADC, ANDI and NEPAD increasingly realize the need of R&D investment, and are providing funds albeit at modest levels. Plans exist to apply for funding from malaria-eradication-driven organizations/agencies. Working with these organizations will leverage the R&D cost and enhance public acceptance. (c) Though venture capital mechanisms of funding are relatively minor in Africa, their need is apparent. Mechanisms for science-based African health innovation, with opportunities for risk-tolerant investors to make financial and social returns will be explored in consortium host countries. Such funds could be structured to counter low R&D in Africa, be sustainable in the long run, attract for-profit private sector funds, and have measurable and significant health impact. 5. Fostering effective and efficient coordination mechanisms amongst existing

organizations/initiatives

The multidisciplinary project nature will enhance networking/collaboration between African institutions in product development and also act as a catalyst to African governments to engage in funding product development in the region.

Unique skills, infrastructure and instrumentation are consortium-complementary e.g. the CSIR designated an ANDI CoE in Nanomedicine with strength in the design and characterization of the nano-based drug delivery system for anti-malarials; AIBST: designated an ANDI CoE in pharmacokinetics and pharmacodymic studies will evaluate the data derived from studies assessing the effectiveness of the formulation conducted at partnering institutes such as KEMRI. The consortium partners house several African biomedical science students and researchers, who will have a unique opportunity to gain skills on the aspects of drug development, including drug formulation, efficacy and PK/PD studies in small animals. Several PhD and Postdoctoral students from Kenya and other African countries are benefitting from laboratory exchange programs in CSIR, aimed at scientists in Africa to acquire new skills and enhance their capacity in nanotechnology hence, training the next generation of scientists. These activities have been supported by different organizations such as constituted by scientific partnership between South Africa and other African governments and Consortium for National Health Research, Kenya. Dr Melariri (CSIR), will act as the consortium project coordinator. CSIR will act as project secretariat and the integrative point of platform responsibility. Progress report updates will be discussed monthly via skype and teleconferences and electronic mails as appropriate. Annual meetings at chosen venues will be held to discuss progress and a way forward. Financial management will be under the secretariat’s auditing requirements. The CSIR annually receives a clean audit from the SA Auditor-General for its strong corporate governance.

6. Strengthening capacity for research, development and production, including through

technology transfer, in developing countries

The program has built-in capacity development at MSc, PhD, Postdoc and technician level, involving scientists from different institutions across Africa. The collaboration between different institutions and countries serves as the vehicle for technology transfer. The annual nano-workshops will be sustained and the next will be hosted by CREATES (Kenya) in February 2014. This project is to be conducted in Africa, through a unique collaboration between partnering institutes/countries. These countries are plagued by malaria, and high on their intra-country agenda, is elimination thereof. Pharmaceutical R&D seldom occurs on the African continent, occurring mostly in the Developed World. This project will provide African biomedical researchers, a significant opportunity to conduct pharmaceutical R&D and develop a product solution to a local problem. This is unique on the African continent, and, through scientist communication, and joint supervision of students with potential student rotation/exchange, technology transfer of the R&D activities will occur. The general product portfolio of African pharmaceutical companies is several years behind that of couterparts elsewhere, with respect to the compound complexity/generation, and in most cases, the effectiveness of the drug produced. This has significant impact on health care provision on the continent, relying on procurement of locally produced pharmaceuticals. The technology being developed could provide a boost for the African pharmaceutical production industry. The technology proposed is translatable into existing pharmaceutical production equipment, and is readily scalable, yet will be innovative and able to secure IP protection. The innovativeness will ensure global attractiveness of the product, ensuring that the product is not restricted to the African continent alone. For skills enhancement members are sent for training at different centers around the world such as Massachusetts Institute of Technology and University College London.

Project title: Exploiting the Pathogen Box: an international open source collaboration to accelerate drug development in addressing diseases of poverty.

Project summary:*

The “Pathogen Box” is a MMV led project that has received 3 years of funding from the Bill & Melinda Gates’ Foundation. The Pathogen Box (PB) will make molecules pre-screened by MMV and its partners available to researchers to apply to their areas of disease investigation. From an initial library of some 4 million compounds, MMV will make available 400 of the most promising, free-of-charge to researchers and will publish full ADMET in vitro characterization of compounds as well as oral mouse exposure data. Consequently there will be an unprecedented wealth of compound data to aid researchers and drug hunters. The project initiates in November 2013 and the PB will be available to launch to the community in 2015. The objective of this proposal is to maximize and exploit the richness from the PB so as to maintain momentum towards discovery of drugs against a range of neglected diseases. The proposal would be to do this in an Open Source mode in collaboration with global partners so as to benefit the research and drug discovery communities and enhance the likelihood of products ultimately being delivered. The specific objectives for the project are as follows:

1. Identify the mechanisms of resistance and modes of action on up to 25 Pathogen Box compounds

2. To deliver, in open source collaboration, up to 25 robust “hit” series against relevant pathogens

Thus, the proposal leverages considerable current investment to deliver series that will be the foundation of future drug discovery projects for neglected diseases. This project builds upon a successful earlier project, the “Malaria Box”, which screened some four million compounds, making a set of 400 available to researchers. That resulted in 158 Malaria boxes being supplied to 27 countries across the world, encompassing both Malaria endemic and non-endemic territories, with a large spike of interest in the United States, Europe and Australia.

158 Malaria Box shipped in 27 countries (3Q2013)

North America

Europe

Australia

Asia

Africa

South America

The costs involved in distributing the “Pathogen Box” are relatively low and the potential benefits huge. All results will be placed in the public domain so will be available for the whole community to exploit. To minimise excessive duplication, a requestor will be notified if more than three groups have already requested the box for screening in a specific assay. This approach has proved successful in managing the Malaria Box. *As taken from original proposal template, question 5.

Areas of Studies

Malariarelated

Non-malariarelated

Malaria

Target-basedassays

Phenotypicassays

Non-malaria

Target-basedassays

Phenotypicassays

Project Addendum: Exploiting the Pathogen Box: an international open

source collaboration to accelerate drug development in addressing diseases of

poverty

This document represents MMVs response to the follow request:

WHO Member States have requested that the secretariat seeks further elaboration from the original proposers

of the short-listed proposals on innovative aspects of their projects. More specifically, please send us an

addendum to your project which describes, where relevant, how your project:

1. Intends to delink the price of the final product from the cost of the R&D.

2. Utilizes collaborative approaches, including open knowledge innovation approaches.

3. Utilizes licensing approaches that secure access to your research outputs and final products.

4. Proposes and fosters financing mechanisms including innovative, sustainable and pooled funding.

5. Fosters effective and efficient coordination mechanisms amongst existing organizations/initiatives.

6. Strengthens capacity for research, development and production, including through technology

transfer, in developing countries.

Descriptions should be no more than 1500 words (in total for the 6 questions) and should be submitted at latest

by the end of the day on 15 January 2014. These will be submitted to the Executive Board along with the

original proposals, and will be instrumental for the final identification of a few demonstration projects by the

Executive Board and the World Health Assembly in May 2014.

1. Intends to delink the price of the final product from the cost of the R&D.

The deliverables of the “Exploiting pathogen box” project are early series (i.e. a robust Hit-to-Lead

series). In most disease areas the clinical development of such a product will take over 7 years, and

require substantial investment. For malaria these clinical development costs are known to be above

$50m. This development process would then fall into the normal drug development process

managed by Product Development Partnerships (PDPs) such as Medicines for Malaria Venture

(MMV) and Drugs for Neglected Diseases Initiative (DNDi). Such PDPs already have developed

collaboration structures for deploying the final product for the public health at a suitably low cost for

patients in low and middle income countries. We already have good examples of this with the fixed

dose Artemisinin Based Combination Therapies (ACTs) for malaria from both organisations, and the

fact that the new molecules in the MMV anti-malarial pipeline have pricing constraints built into late

stage contracts, fitting well with the de-linkage concept.

2. Utilizes collaborative approaches, including open knowledge innovation approaches.

As stated in the original application, the project is based on a multi-centre collaboration with the

MMV team as a central hub in a global network of scientists across many different neglected disease

areas. In addition, the project is Open Source and seeks to exploit publicly disclosed hits from the

“Open Source Pathogen Box”. This means that our goal is to make all the data publicly available as

early as possible. One part of the project involves acquiring, synthesizing and testing new chemical

analogues to build new Hit-to-Lead series. This type of project involves a ‘design-make-test’ cycle

that can only be achieved through working with our parasitology partners as well as the

contributions from a worldwide synthetic chemistry network. As much as possible we would like to

ensure that the synthetic chemistry helps to build sustainable intellectual capacity in disease

endemic countries. MMV has been working with groups in India, Africa and South America for

several years now, and would aim to make the best use of such networks for giving the best global

footprint to our project.

A second workstream will focus on identifying modes of action of compounds, again with partners

having the necessary expertise, who in this case will be largely in the academic centres. Given the

aim to prosecute multiple “Active to hit” and “Target identification” sub-projects for each year of the

grant over a range of different pathogens the extent of collaboration is likely to be truly diverse and

global. Already we have parasitological partners that cover the range of neglected pathogens and

which have representation from Africa, Asia and South America, as well as groups in the Pacific Rim,

Europe and North America. We see Open Innovation as a key strength of the proposal and a way to

build knowledge and experience as well as stimulating interest in the research for neglected

diseases. It is a fundamental part of the proposal to ensure that key data is published and uploaded

into publicly accessible databases. We will work with our existing open source partners and

processes, including ChEMBL, the Structural Genomics Foundation and the Royal Society of

Chemistry whilst applying learnings from the Synaptic Leap (our Open Source Antimalarial drug

discovery project) and our collaboration with OSDDm India.

3. Utilizes licensing approaches that secure access to your research outputs and final

products.

The Pathogen Box would be provided on request, free of charge, and not subject to license. All that

would be asked in return of Pathogen Box users is for the resulting data to be published and placed

in the public domain within two years of its generation to help continue the virtuous cycle of

research. The output of the “Active to hit” and “Target identification” projects outlined in the

proposal will be published and made available to researchers. MMV would not seek upfront rights in

the output of research - or any resulting products - conducted by Pathogen Box users.

As discussed above, the chemical series that emerge from this collaborative network would form the

basis of clinical candidates. We are proposing that the standard MMV or DNDi contract structures

would be in place for the investment in the lead optimization and clinical development which would

ensure that subsequent financial commitments are linked to ensuring the maximum access to any

final medicine.

4. Proposes and fosters financing mechanisms including innovative, sustainable and

pooled funding.

The Pathogen Box project is an open source catalyst that will accelerate the drug discovery process

leading to potential breakthroughs across a broad catalogue of neglected diseases.

This will be achieved by providing the recipients with 400+ screened compounds with the associated

wealth of in vitro and oral mouse exposure data. The researchers will have access to the data and

materials free of charge. This minimises the risk of duplication of effort, since such experiments will

only need to be performed once. This approach will reduce the financial risk for early stage drug

development; accelerating the process considerably as well as stimulating interest in exploring drug

development for neglected tropical diseases.

This reduction in early stage risk is also what leads to an improvement in the sustainability of the

model. As the collaboration structure takes off, then there will be a constant increase in the

efficiency of drug discovery, leading to either a lowering of the overall costs, or more likely an

increase in the number of disease areas which can be approached.

5. Fosters effective and efficient coordination mechanisms amongst existing

organizations/initiatives.

An innovative component of the original BMGF Pathogen Box grant is the Selection Committee, a

group of key opinion leaders selected from across the neglected disease community that will

oversee both the selection of compounds for inclusion in the box and any follow up work on

emerging leads. The selection committee will comprise a diverse group of senior scientists with

experience in neglected disease research, with representation from PDPs, industry, academia and

funding bodies. Given the nature of the project so far, then this group will have a wide geographical

diversity, since the consortium already has several different members from each continent. The

selection committee structure will provide a mechanism to rapidly link investigators wishing to

exploit particular Pathogen Box hits with the organisations best placed to provide assistance and/or

funding.

Therefore at the heart of the Pathogen Box project sits a group with the remit of fostering

collaboration within neglected disease arena and enabling the efficient coordination of follow-up

work. The project will also develop other tools to facilitate cooperation between researchers. These

include plans to detail groups who have requested the PB on the project website, thereby offering a

simple means to foster collaborations between scientists and avoid duplication of experiments.

6. Strengthens capacity for research, development and production, including through

technology transfer, in developing countries.

The project proposal is to both identify new mechanisms of action and to generate multiple, robust

chemistry start points that could be the basis of new neglected disease drug discovery projects. We

already have partners in South America, Africa and Asia who have collaborated with us on the MMV

Malaria Box. We will engage with these teams in the context of this proposal in the hope that we

can collaborate with them to deliver attractive chemical start points that justify further funding and

investment.

MMV offers considerable experience in drug discovery for anti-infectives and has a network of

advisors and experts who we can draw upon. This expertise will be offered freely in any “Active-to-

hit” process with a partner. The overall aim is, naturally, for partners to be able to optimize series so

as to deliver candidate drugs that can be developed further to launch. The expectation is that the

delivery of successful drug discovery projects will promote the additional necessary investment for

further research, development and manufacturing as well as a natural development of local

expertise and experience. This mirrors our experience with the University of Cape Town where the

first delivery of an African candidate drug for malaria between MMV and University of Cape Town

(UCT) has triggered considerable and courageous investment from South Africa and extensive

increase in local capabilities. We plan that with the new investment in the Pathogen Box that we

can repeat the success we have seen in South Africa, in other disease endemic countries. This will

help to foster a drug discovery culture closely aligned with an understanding of the needs of the

patient population.

Date: 14th January 2014

Project title: Development of a Vaccine Against Schistosomiasis based on the recombinant Sm14 a member of the fatty Acid Binding Protein: Controlling transmission of a disease of poverty.

Project summary:*

The development of an anti-Schistosome vaccine started at FIOCRUZ in the 1980’s. In the beginning of the 1990’s, with the use of Molecular Biology platform, one component of the previous protective mixture of antigens was cloned, sequenced and characterized as the Sm14, a member of the Fatty Acid Binding Protein (FABP) family (J. Biol. Chem., Vol. 266 nº 13: 8447-8454 -1991). The Brazilian Sm14 Schistosomiasis Vaccine Platform was launched and strongly pushed in the context of a formal WHO program, specifically structured towards the Development of Anti Schistosomiasis Vaccine. Main outcome of this initiative was the selection of 06 priority antigen candidates out of which Sm14 continued to be developed. With strategic support of WHO, Fiocruz move forward, to final development of Sm14. The rSm14 molecule was selected from a mixture of adult schistosome components obtained from living worms, previously shown to protect mice against infection. It was identified on the basis of a long-term investigation focusing on vaccination experiments in populations of out-bred animals. Specifically, two distinct animal models (SW mice and NZ rabbits) were developed with the parasitological approach of high and low susceptibility to cercarial infection; vaccination schedule parameters that influence protection were assessed in the strict context of animal models and minimum protection levels were established to optimize experiments and define immunization route and scheme (number of doses, dosage of antigen protein, adjuvants). Innovative methodology was used for protection assessment and we believe this has been critical for the selection not only of native rSm14 but also the identification of a mutant form which was constructed by site directed mutagenesis selected for its higher stability as compared to the native protein sequence. Phase 1 clinical trial has been recently successfully accomplished with the Sm14 vaccine in 20 healthy male volunteers. The vaccination schedule, based on Hepatitis B vaccine, consisted of 03 IM injections of GMP -Sm14 +GLA vaccine protein produced at the Ludwig Institute for Cancer Research –Cornell Univ facility ,Ithaca , NY, in monodosis presentation. Results, attested safety with almost no side effects . Immunogenicity was evaluated by Elisa with anti IgG ab also showed vaccination to be highly immunogenic mostly after the second dose. In collaboration with IDRI, we have assessed the immunological signature of vaccination by screening cells and sera from the human volunteers sent to IDRI. The main objective of this project is to move forward on the development for r-Sm14 as the molecular basis for an anti Schistosome and potentially a multi-valent anti-helminth vaccine. The demonstration project seeks to address the challenges for moving forward include funding for next phase II and III clinical trial in Brazil and Africa and ensuring access. *As taken from original proposal template, question 5.

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Project: Development of a Vaccine against Schistosomiasis based on

the recombinant Sm14, a member of the fatty acid binding protein:

controlling transmission of a disease of poverty

Answers to the six questions from the Global Technical Consultation (3-5 December

2013 at the WHO headquarter in Geneva) for further consideration by the 134th

session of WHO Executive Board in 2014

1) Intends to delink the price of the final product from the cost of the R&D

The broad application of the Sm14 FABP family member as vaccine antigen for helminthic parasites of humans and animals and the decision of FIOCRUZ to develop Sm14 as the molecular basis for both anti Fasciola veterinary vaccine and human anti Schistosome vaccine was the strategic plan and opportunity to create foster mechanism to help the development of the human noncommercial anti Schistosomiasis vaccine with the pull forces from the veterinary axis,a strategy in which partners interested in the veterinary market of food safety and quality could also pull the development of the vaccine against schistosomiasis, as an humanitarian vaccine, in order to be accessible and affordable for the affected population in developing countries.

All critical steps that most commonly defeat new products at the laboratory bench level were accomplished and the decision to move ahead with Sm14 vaccine through a public-private partnership (PPP) was strategic and proven to be of outmost importance to a public institution as Fiocruz, in a country like Brazil, with very little tradition and experience in bioproduct development in contrast to a strong culture of acquiring vaccine technologies from multinational companies.

Major pharmaceutical companies have shown interest in the Fasciola vaccine and Fiocruz entered in two pre-licensing contracts that ended in frustrated experiences. The interest was exclusively in the veterinary product and the fact that no interest has been shown in the development of the Schistosomiasis vaccine stimulated the leading scientists to seek for an alternative and more efficient path that could ensure the human vaccine to reach final steps as well.

The choice for a private partner was a Brazilian company called Alvos SA Biotechnology, which had the mission to help pre-mature technologies from Institutions in the Academic sector to bridge the gap from the bench to the market.

In 2006, the partnership Alvos-Fiocruz received significant funds for final development of Sm14 as an anti Schistosomiasis vaccine from FINEP, a governmental financial agency, under a specific call for public-private partnership (PPP) projects in the Schistosomiasis area. Under this grant, Fiocruz and Alvos established an Agreement for Technological Cooperation in 2007 for the final development of the human vaccine, including scaling-up the production process, GMP batch preparation and the implementation of clinical trials phases I and II. In 2010, Alvos was acquired by the

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100% Brazilian company Ourofino Animal Health, leading industry in the veterinary field.

When phase I study was concluded in 2012 and during a joint press conference with Fiocruz, Ourofino publicly committed to ensure that the human vaccine would become a humanitarian vaccine ensuring access to the population of endemic areas all over the world, mostly poor countries.

In terms of pursuing lower costs for the human vaccine, Fiocruz also developed an optimization process which reduces the cost of production to reach a low final cost close to marginal cost pricing.

Additionally, from the production perspective, Ourofino is able to manufacture the protein (active ingredient) in bulk (large-scale), applied for both vaccines, which will surely contribute to the reduction of the final cost of production.

De-linkage has been also pursued considering that most of the funding for the development of the human vaccine were public-fund. In the current stage of the development, discussion are undergoing on the strategy for production and supply of the Sm14 vaccine, the development of a framework to ensure access (including architecture, availability, affordability and adoption) is being prepared1 as well as a Target Product Profile (TPP).

2) Utilizes collaborative approaches, including open knowledge innovation

approaches

The Brazilian Sm14 Schistosomiasis Vaccine Platform emerged from a public governmental scientific institution, the Oswaldo Cruz Institute/FIOCRUZ/Ministry of Health of Brazil. This project has been conducted in the context of academic/scientific traditional values with constant publication of results, up to date presentations at scientific meetings in all regions of the world, and being the subject for PhD thesis development at Fiocruz, specific post-graduation programs of Tropical Medicine, Molecular and Cellular Biology and Parasite Biology.

There are five families of patents covering technologies related to this project. The protection strategy was to ensure Fiocruz’s control on the technology in relation to partners and ensure access to the product.

The development of the human vaccine involved different partners in different stages, such as presented in question 11 of the original template.

1 Frost, L.J. & Reich, M.R., 2008. How do good technologies get to poor people in poor countries?

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3) Utilizes licensing approaches that secure access to your research outputs and

final products.

Access to the final product

As mentioned in item 1, in order to reflect current stage of development of the human vaccine in the licensing agreement, Ourofino and Fiocruz have agreed to review the Agreement on Technological Cooperation:

1) To ensure a production and supply strategy for the human vaccine led by Fiocruz principles as a public government organization: licensing and technological transfer to public and/or private partners from endemic countries;

2) To strength de-linkage by considering access clauses related to affordable prices.

Access to research outputs

The major multinational pharmaceutical companies have shown interest in the Fasciola vaccine and Fiocruz entered in two pre licensing contracts that ended in frustrated experiences. The interest was exclusively in the veterinary product and the fact that no interest has been shown in the development of the Schistosomiasis vaccine stimulated the leading scientists to seek for an alternative and more efficient path that could ensure the human vaccine to reach final steps as well.

Fiocruz has been developing the Sm14 vaccine in collaboration with partners from the different countries from the North and negotiations are ongoing with the South targeting to set cooperation for the access of final product. Fiocruz, as one of the biggest health research institution in the Americas , has close to 100 international collaborations and following this tradition ,the Brazilian Sm14 Vaccine Platform Schistosomiasis was developed since the very initial phase, under the scope of a net of collaborators at the scientific , operational, administrative and financial support levels.

Fiocruz and Ourofino are in the process of reviewing the agreements for the Schistosomiasis vaccine production/distribution, considering the present opportunity of Fiocruz´s participation in the production chain of the human vaccine in its new vaccine facility in Rio de Janeiro, Brazil and considering the CEWG report. Open approaches to research and development and innovation will be further explored for the current case.

One interesting possibility is the production of the protein in bulk at Ourofino facility and distribution to Fiocruz and an African company for fill finish and local distribution.

Ourofino has already declared publicly the interest in helping the development of the human vaccine against Schistosomiasis in an humanitarian platform and policy.

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4) Proposes and fosters financing mechanisms including innovative, sustainable

and pooled funding.

The Brazilian Sm14 Schistosomiasis Vaccine Platform is being developed in the context of an integrated net of collaborators, strategic partnerships and multiple sources of financial agencies and mechanisms under an effective innovative, sustainable and polled funding including public governmental funds direct from FIOCRUZ/Ministry of Health, FINEP, CNPq, Faperj, Fapesp, as financial agencies in Brazil. Current strategy includes starting a process for funding by the National Bank for Development (BNDES) for the support of next clinical trial phases.

5) Fosters effective and efficient coordination mechanisms amongst existing

organizations/initiatives.

Answered in question 18 of the original template.

6) Strengthens capacity for research, development and production, including

through technology transfer, in developing countries.

Strategy for strengthening capacities

Based on the potential broad application of Sm14 as the vaccine antigen for other helminthes that were identified with FABP homologous protein family members amongst the vast majority of human helminthes, the possible strategy to strengthen capacity for research , development and production, is to extend the access to Sm14 technology through a well-defined technological platform –an anti-helminthic vaccine matrix lato sensu - that may foster/provide the basis for launching specific vaccine projects in different endemic countries.

Development

The development of the human vaccine is moving to Phase II clinical trial, in collaboration with the Swiss Tropical and Public Health Institute. The implementation plan includes one site in Brazil and another in Africa.

Production and technology transfer

- Brazilian public manufacturers: (a) Instituto Butantan and (b) Biomanguinhos/Fiocruz, in preliminary conversations open to assess the technological/ economic feasibility to undertake production. Biomanguinhos today is the largest public biologics manufacturer in Brazil and besides providing most of the vaccines for the National Immunization Programme, exports Yellow Fever vaccine worldwide and has exported meningococcal vaccine by request of WHO.

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- Other endemic country manufacturer: the Biovac Institute, in South Africa, is open for discussions on the production and or fill finish of final product and distribution to African countries according to preliminary conversations.

South-South cooperation will be pursued in all levels of this process within the principle of public interest.

Project title: Development of Class D CpG ODN (D35) as an Adjunct to Chemotherapy for cutaneous leishmaniasis and Post Kala-Azar Dermal Leishmaniasis (PKDL)

Project summary:*

The project proposed aims to combine the use of antimonials with a novel innate immune modulator that activates the immune cells embedded in the skin. The project has 4 phases: 1) Production and characterization of GMP-grade D35; 2) Pre-clinical studies in 2 species (rat and primates) to assess potential toxicities; 3) Proof of concept clinical trials for D 35 and the combination of D35 with antimonials establishing safety profile and optimal dose, and 4) Establishing efficacy across L. major species and licensing. 1) Product synthesis and characterization: over 20 lots of D35 have been successfully produced in small scale at the core facility of the Food and Drug Administration. Its simple production is amenable to manufacturing at affordable cost and the technology to produce it is easily transferable. Two different contract manufacturers, Girindus in USA and Gene Design Inc in Japan have provided estimates of the cost to produce the 10 grams of the oligonucleotide needed for pre-clinical and phase I-II clinical studies. Their estimated time to deliverable for 10g of product including CMC characterization: 8 months. 2) Pre-clincial studies: Although there is vast positive experience with synthetic CpG ODN in clinical trials, this particular CpG ODN sequence has had limited testing in humans, therefore all preclinical requirements must be met. D35 stimulates Toll like receptor 9 (TLR9) of pigs and primates but is not active on TLR9 from small rodents. Previous studies using synthetic phosphorothioate ODN show that mice routinely tolerate single doses of CpG ODN of up to 400 ug, and repeated doses of 100ug (i.p. 4 days apart) as compared to reported therapeutic doses of 5-50 ug. The most common histopathological findings in safety toxicology studies were modest splenomegaly and lymphoid hyperplasia with an accompanying accumulation of mononuclear cells (B cells, monocytes). In macaques studies performed in Dr Verthelyi’s laboratory no significant changes in body weight, temperature, behavior, CBC or metabolic panel at effective doses were observed (Figure 12). Additional studies to establish NOAEL in mice and primates (Figure 13) will entail dose escalation studies. Planned studies include a single and a multi-dose study in mice using 30, 100 and 300 ug of D35 (SC dose/week x 5). Readouts will include clinical signs, body weight, food consumption, hematology and blood chemistry, PK and PD on 1st and 5th dose, and histopathology. Single and multi-dose studies in rhesus macaques will use doses of 1, or 3 mg/kg SC. Clinical signs, body weight, food consumption, hematology, urinalysis, and blood chemistry, immunogenicity, pharmacokinetics and histopathology on 1st or 4th dose. Estimated time to deliverable: 12 months. 3) Phase I-II clinical studies : In all these studies D35 will be used as an adjunct therapy to the local standard of care chemotherapy which consists mostly of antimonials (20mg/kg) for 21 days. D35 will be administered SC on day 1 of treatment.

a) A Phase Ia, randomized, double blind, placebo-controlled single dose escalation study will be conducted to establish safety in humans for D35 in 35 treatment naïve patients with cutaneous leishmaniasis due to Leishmania braziliensis using a 4:1 design. The anticipated starting dose will be at 0.01mg/kg (1:100th of a known safe dose in macaques) and will escalate to 1 mg/kg. The site of the study has not been selected but would likely be in Peru, Brazil or Colombia.

b) b. A randomized, double blind, placebo-controlled, dose escalation, repeated administration Phase Ib study with PKDL patients receiving 3 doses of 0.3 and 1mg/kg 2 weeks apart (8:2 per dose cohort for a total of 20 patients). Safety monitoring will be performed in days 1, 3, 7, and 14 after each dose. Exploratory PK & PD data will be collected. Monitoring of immunological parameters will include serum levels of IFNa, CXCL-10 and IFNg. Results will be compared with pre-treatment samples for each subject. The site of the study has not been selected but Bangladesh

or Sudan, where the incidence of PKDL is higher, would be desirable. Estimated time to deliverable: 12 months.

c) c. A phase II studies to collect additional safety data, PK, PD and initial efficacy in CL patients (extended to include Leishmania amazonensis, L. guyanensis etc.)

4) Multicenter pivotal clinical trials to continue to collect safety data and establish efficacy in CL and PKDL populations and Licensure application in target countries under a concerted effort with National Medicines Regulatory authorities *As taken from original proposal template, question 5.

Development of Class D CpG ODN (D35) as an Adjunct to

Chemotherapy for cutaneous leishmaniasis and Post Kala-Azar Dermal

Leishmaniasis (PKDL)

1. Intends to delink the price of the final product from the cost of the R&D.

Delinking is the fundamental principle on which this proposal is based. FDA publishes the results of the basic scientific research in peer reviewed journals so they can be accessed by the public. The US-FDA does not contemplate recovering the investment in R&D as part of the Agency’s mission. One of the agency’s goals is to foster fundamental creative discoveries, innovative research strategies, and their applications to protect and improve human health. Indeed, for licenses on inventions coming from the Health and Human services (HHS) intramural program, HHS promotes commercial development of technologies in a way that provides broad accessibility. This project will put in practice the effective use of equitable or humanitarian licensing as a means to improve global access to essential products by ensuring affordability of the final product. The US-FDA developed and holds the patents for D35and Pro-D35 and can license them to a WHO consortium. Thus, the R&D costs and the price of the product will be fully delinked under this proposal. 2. Utilizes collaborative approaches, including open knowledge innovation approaches.

The objective for this demonstration project is to develop a short, safe, affordable and field-friendly treatment that are efficacious for CL and PKDL using a collaborative approach governed by a WHO based consortium that will coordinate Member States representatives (in particular, national regulatory and health authorities from developing countries where leishmaniasis is endemic and that may benefit from the R&D), scientific institutions, donors and other relevant stakeholders convened by WHO. While necessary R&D may be conducted in an array of institutions both in developed (US-FDA, Osaka University for example) and developing countries (additional testing and clinical trials should be conducted in developing countries), the consortium will ensure that results and knowledge produced during the course of the project is open and transferable. This approach will enable any result that emanates from this project to reach the public domain and where information can be used as the basis of more ideas and new developments. The establishment of such a development path may enable future joint development efforts that follow the same principles. For example, similar approaches might be useful for treating similar entities and results from these trials may open the door to new applications of the proposed technology. 3. Utilizes licensing approaches that secure access to your research outputs and final products.

The US-FDA holds the patents for both D35 and PRO-D35, the alternative chemistry of the oligonucleotide backbone discussed above with similar intentions of development. FDA, like NIH, has Non-Profit License Agreements available for patented inventions and non-patented biological materials from intramural laboratories. The available license scope includes vaccines, drugs, therapeutics and diagnostics (or enabling technologies to produce such products) to prevent, diagnose or treat neglected tropical diseases (“NTDs”, as defined by WHO), HIV, TB and malaria in humans or animals. The Agreement establishes reasonable terms, including patent cost reimbursement and royalties that would be acceptable to most non-profit institutions. The license is available to non-profits with a demonstrated commitment to diligence in providing broad global access to technologies, products and services consistent with the submission of an acceptable product development plan to bring the technology to practical application. For example a license could have a $2,000 up front fee and modest royalties on sales of 1.5% for exclusive licenses and 0.75% for non-exclusive licenses, excluding sales to public sector institutions or institutions using public-sector funds (such as PEPFAR or Global Fund). If the

licensee sublicenses the technology to another institution to bring it to market, the sublicense fee for exclusive licenses will be 15% of the value received if NIH or FDA has provided in vivo model data and 10% if such data have not been provided. For non-exclusive licenses, the sublicensing fees would be half these amounts. Additional research on the patented products performed by the FDA is made available without restrictions.

4. Proposes and fosters financing mechanisms including innovative, sustainable and pooled

funding.

The proposal includes the development of a WHO-based consortium that will be in charge of managing and coordinating the project and will include stakeholders from key institutions and Member States. The funds that sustain the cost of implementing the necessary R&D could come from pooling monies within the global health community. The resources needed for this project include not only funds but expertise (clinical trials, laboratory testing, manufacturing capacities among others) for a sustainable and efficient implementation. The mechanism chosen to pooled these resources is beyond the scope of this proposal and should be the subject of an in-depth analysis of Member States and/or the coordinating consortium

5. Fosters effective and efficient coordination mechanisms amongst existing

organizations/initiatives.

This project would be coordinated by a WHO-based consortium that includes representatives from the Member States and including those countries affected by Leishmaniasis. Other stakeholders that can bring expertise and knowledge to the project should also be including in the coordinating mechanism and are

by no means limited to the authors of the proposal. This multi-stakeholder body will ensure proper coordination and an open knowledge approach of all relevant institutions. Importantly, because the technology to produce the product is easily transferable and manufacturing could eventually take place at facilities in the affected regions, the consortium could oversee that technology transfer does effectively take place. Scientists form FDA and Osaka University could provide technical expertise at different points in the R&D process, however the FDA would not play a role in the design or implementation

of the clinical trials as this would be construed as a conflict of interest. If clinical trials are deemed successful, the WHO-based consortium would supervise the selection of the manufacturing site as well as coordinate and audit the pre-clinical and clinical trials following current Good Pre-clinical and Clinical Practices guidelines. Further, the expectation is that WHO consortium will not only include public health representatives from the countries affected by CL but also involve the corresponding regulatory authorities of these countries early in the process thus facilitating regulatory approval, adoption and deployment of the D35 by health systems.

6. Strengthens capacity for research, development and production, including through

technology transfer, in developing countries.

The manufacturing platform for D35 is easily transferable and the expectation is that one or more manufacturing sites would be chosen in the affected regions to produce the material for clinical trials and then after licensure WHO would provide support by pre-qualifying additional manufacturing sites to ensure affordability of the product for countries that require it and/or implement a UN /donor based medicine procurement mechanism that ensures access to the product. As mention before, the US-FDA licensing arrangement allows sublicensing and the coordinating consortium will be responsible for selecting and overseeing these agreements in a way to ensure that maximizes access to an affordable, safe, quality and effective product.

Project title: Development for Easy to Use and Affordable Biomarkers as Diagnostics for Types II and III Diseases

Project summary:*

Schistosomiasis, echinococcosis, vivax malaria and sleeping sickness are among the most Neglected Tropical Diseases (NTDs) in China or Africa today. Lack of simple, affordable, sensitive, and specific assays for field diagnosis make the prevention and control program for these diseases face many challenges. Landscape analysis showed that novel technologies and new tools are urgently needed in the diseases diagnosis. This project will leverage a well-established high-throughput screening platform based on OMICS technologies developed by China NDI research group, which will be applied to discover novel biomarkers and process them to development. For better understanding of humoral immunity to clinical schistosomiasis, echinococcosis, vivax malaria and sleeping sickness as well as comprehensive analysis of humoral immuno-epidemiology, we will screen biomarkers of the four different parasitic diseases with genome-wide scales of 8000-10,000 proteins, using the samples from 2,000-4,000 human subjects. The biomarkers associated with these parasite infections will be indentified as well. The diagnostic kits identified by high-throughput platform will be translated into field and population based use. This will be the first time to develop such sensitive, specific and affordable new tools into the control and elimination of Neglected Tropical Diseases program. Specific aims of the project, 1) Development of protein microarrays containing 8000-10,000 selected antigens for individual diseases. 2) Probe well-characterized infected human sera from China and Africa and identify serodiagnostic antigens．3) Develop, evaluate, validate and optimize field deployable tests for each agent applicable to each region. 4) Seek regulatory approval and promote use of products in endemic area. The key deliverables of the project in first five years include the following: 1. 8000-10,000 gene clones of 4 parasitic diseases; 2. 8000-10,000 recombinant proteins of 4 parasitic diseases; 3. Four kinds of biochips of parasitic diseases; 4. 4-7 diagnostic kits which can meet the current challenges in diseases control and prevention; 5. 4 registered diagnostic products based on multicentre evaluation and registration.

*As taken from original proposal template, question 5.

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Addendum: Development of Easy to Use and Affordable Biomarkers as Diagnostics for Types II and III Diseases This addendum provides more information on how our project will address the following key

elements of the call for demonstration projects:

1. Delink the price of the final product from the cost of R&D.

2. Utilizes collaborative approaches, including open knowledge innovation

approaches.

3. Utilizes licensing approaches that secure access to research outputs and final

products.

4. Proposes and fosters financing mechanisms including innovative, sustainable and

pooled funding.

5. Fosters effective and efficient coordination mechanisms amongst existing

organizations/initiatives.

6. Strengthens capacity for research, development and production, including

through technology transfer, in developing countries.

1. As outlined in our proposal, the project intends to demonstrate a robust and verifiable

delinkage of the price of final product(s) from the cost of R&D. Firstly, the starting

point for our project is the availability of the sequence of relevant pathogen genomes,

which the international community supported over the past years, and the cost of which

will not influence price of product(s) resulting from this project. Secondly, our project

have leveraged these sequences to obtain a mass of parasite transcriptomics, proteomics,

genomics and metabolomics (OMICS) information and integrated them into a

ChinaPathDB Biomarker Screening Platform (comprising 22 genomes, 24 transcriptome

and 7 proteomes), covering different Types II and III diseases (see Fig 1, 2, 3 of our

proposal). The potential of this innovative high-throughput screening platform vis-a-vis

diagnostic development has been published in leading international journals such as

Nature, Nature Genetics and others (see our proposal). Again the costs associated with

developing this platform will not influence the cost of resultant product(s). Through this

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publicly supported platform, a series of the colloidal gold immunochromatography assay

(GICA) strips for diagnosis of parasite infection based on parasite recombinant proteins

have been developed in collaboration with a small Chinese Biotech company which is a

partner in this proposal. Through ANDI, several African institutions have engaged with

their Chinese counterparts to advance this project, and we intend to engage other public

and private partners. If selected as a demonstration project with appropriate financing,

this project will demonstrate and ensure that the price of any resulting product is

delinked from the cost of R&D. This approach is consistent with an integrated Push and

Pull mechanism being developed by ANDI, which considers different financing models for

both R&D and manufacture/access (Fig.1). Our project is geared to deliver quality

assured, easy to use, accessible and affordable diagnostics that will support control and

elimination programs for specific neglected diseases.

Fig.1: proposed mechanisms for managing/financing R&D, transition to downstream manufacture/access. Illustration also demonstrate delinkage of R&D cost from price of final product.

2. One objective of ANDI and other regional networks such as China and ASEAN networks

is to utilize different collaborative approaches, to enhance the development of

products for diseases that disproportionately affect developing countries. Such

approaches include organized networks, consortia and public-private partnerships that

promote South-South and North-South collaborations as well as open innovation and

knowledge sharing. This proposal exemplifies the potential and power of such innovative

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and inclusive inter-and intra-regional collaborative approaches to solve the health

challenges of developing countries. Analysis of the Pan-African Centres of Excellence

undertaken by ANDI (Nwaka et al 2012) shows that there is limited South-South

collaboration for R&D and local production for neglected diseases including in the area of

financing. Indeed, our unique diagnostics development platform for neglected diseases

is a global open innovation resource that will be more widely accessible through this

project. Furthermore, all relevant protocols and data will be shared through platform

databases to be used for data management and knowledge exchange.

3. The project will manage IP and licensing to secure research outputs and final products

as follows: i) ANDI and its Chinese partners are already working to document any

background IP associated with this project. The project team has agreed that such

background IP will reside by the institution(s) that developed them but must be made

freely available to all partners for the purposes of R&D, manufacture and public access.

This includes the platform and all technologies associated with it, ii) through the

coordination framework for the project (see original proposal), all background and

program IP will be implemented through appropriate licensing agreements that ensure

public access to research results, unhindered manufacture and access to final products.

This type of licensing modality is well known to the project partners. We will establish

appropriate monitoring and evaluation mechanisms for all phases of the project to

ensure that access is not hindered.

4. We propose an interlinked financing approach to support demonstration projects: i)

immediate implementation of voluntary pooled financing scheme by government and

private entities, ii) implementation of government approved taxes on specific

products/services in the medium-term to complement the pooled financing, and iii) to

leverage the fund (pooled and/or taxes) to support R&D through grants and innovation

award schemes, and at the same time support appropriate guaranteed loans or social

venture initiatives or prizes to address unique R&D/manufacture and access issues. The

combination of grants with guaranteed loans and social venture support is consistent

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with delinkage of the cost of R&D from price of the final product. This approach will also

promote technology transfer, South-South and North-South collaboration for sustained

R&D, local production and access to finished product. Such fund can be established as a

professionally managed, Trust Fund (TF) or Innovation Fund or Endowment Fund,

through a regional and/or global body, such as a Development Bank/Work

Bank/WHO/UN body. A number of developed and developing countries have TFs for

various developmental issues, however, the concept of interlinked or integrated Fund as

described here for R&D and access is innovative and can easily be implemented. The

Fund host shall disburse funds under the directive of a coordinating body for approved

project(s). This approach will promote sustainability, scalability, transparency and

accountability. Our project covers the various parts of the diagnostics value chain and is

well suited as a demonstration project to illustrate these financing approaches. We will

establish a global advocacy/communications/fund-raising effort through our

coordination machinery to support agreed financing mechanisms.

5. Analysis undertaken by ANDI and others show that lack of coordination and financing

(fragmentation of efforts) are major bottlenecks in the implementation of robust

collaborative product R&D and access initiatives for diseases that affect developing

countries. The good news is that the issue of coordination and financing are recognized

as important for the success of WHO demonstration projects. Through ANDI and

partners, we intend to identify and work with other relevant global parties. This will be

achieved proactively and through regular global calls for additional

technologies/partners. ANDI has already reached out to PATH -Seattle US as potential

partner, and discussions are ongoing with the EDCTP, SD Diagnostics (major producer of

malaria RDTs) and Infopia in Seoul for R&D, manufacture and capacity building. Please

note that our project platform can handle multiple Types III and II diseases, thereby

presenting unique advantages in the context of demonstration projects than single

disease/product focused projects. These advantages include: i) the opportunity to

develop robust pipeline of products with better prospect for success, ii) our approach

provides for learning and sharing of resources across diseases, with the prospect of

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developing the much needed integrated/ multiplexed diagnostics for several neglected

diseases, iii) the opportunity for the project team to initiate regular open and global calls

for complementary technologies/partners to join the project. This will promote

coordination/linkages with other players and make it possible for interested parties such

as PDPs/FIND, companies and institutions from developed and developing countries with

relevant expertise to join the project. Please note that coordination includes direct

management of the project(s), such as preparation/implementation of project budget,

portfolio/pipeline management, approval/disbursement of funds to project partners,

M&E and reporting. These will be effectively implemented through the project

coordination mechanism.

6. Strengthening capacity for research, development and production, including through

technology transfer, in developing countries was highlighted in our original proposal

and above. We believe that this is critical in sustaining access to health products in the

long-term. As a deliverable in our submission, we defined the approximate number of

individuals/institutions that will be trained/strengthened as part of this project. Capacity

building will span all parts of the project from R&D to regulatory to manufacture and

access. This will include multi-center evaluation in the field and clinical trial of the

developed diagnostic products. Reference laboratories, product registration and QA/QC

of the product by manufacturer will be other areas for capacity building and technology

transfer, especially in Africa. Our goal is to incorporate/integrate developed diagnostics

into modern devices i.e. remote/mobile control system with data transfer capabilities to

enable easy and real time access to information and test results. This will support m/e-

Health system in developing countries.

Finally, our proposal is innovative, scalable and sustainable with potential transformational

outcomes – it meets the key criteria for demonstration project as outlined in WHA66.22,

and earlier resolutions on the Global Strategy and Plan of Action on Public Health

Innovation and IP.

Project title: Dengue vaccine development

Project summary:*

Dengue hemorrhagic fever is an important vector-borne disease with an increasing disease burden in many tropical and subtropical countries worldwide. Akthough the mortality is low with proper diagnosis and treatment, high incidence in Thailand and and many other countries has made it an important public health problem. Many approaches for vector and disease control have been attemped and failed. An effective dengue vaccine is urgently needed. Despite all the effort and investment, effective dengue vaccine is not yet available. Thailand has been engaging in dengue vaccine research and development for more than two decades. There is now a national dengue vaccine pipeline with live-attenuated, DNA, and viral-like particle vaccine candidates. All preclinical developments have been committed and supported by key governmental granting agencies expecially the Thai BIOTEC, the National Science and Technology Development Agency (NSTDA). Some of these candidates are being tested in primates and should be ready for clinical trials within 1-2 years. They are being tested in combinations in a novel prime-boost strategy, which has shown very promising results. The prime-boost approach should solve many of the problems currently faced by other dengue vaccine candidates. Newer strains of 4 serotypes have also been used for the vaccine designs in DNA and VLP vaccines. This project proposes to move forward this vaccine R&D program by producing clinical lots of tetravalent vaccine candidates and conducting phase I clinical trial. In addition, immunological assays are being developed and evaluated for their correlation with immune protection. Two potential GMP production facilities have been collaborated: one private vaccine company, the other is the naitonal GMP pilot facility. Capacity building for vaccine R&D and production has been set as a national agenda for Thailand. Dengue vaccine development is among the top priorities, not only because dengue vaccine is badly needed but also it can be used as a model for capacity and human resource development. With promising vaccine products to be launched, production capacity can be purposefully established and maintained. It will strangthen national vaccine capacity and self reliance. This will also provide affordable vaccine to the developing world and Thailand will collaborate with other developing countries to maximize access to the vaccine. In term of regional collaboration, we are currently collaborating with the Bogor Prmate Research Center, Bogor Agricultural University, Indonesia on non-human primate vaccine testing. If this proposed program is funded, through the adivce from WHO, more scientific imput and collaboration will be expanded such as from the Pediatric Dengue Vaccine Initiative (PDVI; the IVI, and SEA researchers that actively involve dengue researches. And additional regional GMP facilities canbe further explored if needed. *As taken from original proposal template, question 5.

Dengue Vaccine Development

1. Intends to delink the price of the final product from the cost of the R&D.

The dengue vaccine R&D program is being managed and funded by governmental organizations

of Thailand, which are non-profit organizations. The main objectives of the program are to make

available effective vaccine that is accessible for developing countries and to build up capacity for

vaccine R&D and production in the country. The program will seek more partners and funding

support from national and international public sector to move forward the vaccine candidates to

clinical trials, which will be the more costly part of the program. Although partnership with private

sector is also encouraged, the term of collaboration will not aim at getting financial return on

investment from the public sector. In contrary, in addition to a co-development of the vaccine, the

program will also aim at facilitating development of vaccine producers in Thailand by sharing the cost

of vaccine R&D to the public sector. It is therefore, in principle, the more funding the program can get

from public sector, the less of R&D cost will be linked to the final product price.

2. Utilizes collaborative approaches, including open knowledge innovation approaches.

The program is a collaboration among 3 universities (Mahidol, ChiangMai, and Chulalongkorn),

and 3 national research funding/management agencies (NSTDA, NVI, and HSRI) in Thailand.

Distribution of knowledge from the program via scientific publication and other academic interaction

is encouraged. Intellectual properties will be managed in the manner that will not hinder scientific

progress.

3. Utilizes licensing approaches that secure access to your research outputs and final

products.

As mentioned above, the program’s objective is not to get financial return. Licensing terms will

be designed to maximize access and licensing fee will be applied only to ensure commitment of the

private partner. Although it is difficult to predetermine the licensing terms, strategy to secure access

may include non-exclusive licensing, licensing with conditions on product pricing and access.

4. Proposes and fosters financing mechanisms including innovative, sustainable and pooled

funding.

The funding will be sought from several possible sources. Because the program is already a

collaborative network managed by national research funding agencies, several sources of funding can

be effectively managed as a pool. We are exploring to get pooled funding supports at least from 3

national funding organizations: NSTDA of MOST (Ministry of Science and Technology), the

National Research Council (NRCT), and the National Vaccine Institute (NVI) to help us plan for

phase 1 clinical trial in the next 2 years.

5. Fosters effective and efficient coordination mechanisms amongst existing

organizations/initiatives.

The initial R&D program is being managed by a team at NSTDA. Further development will be

coordinated by a working group as a collaboration of NSTDA, NVI, HSRI and the participating

universities. NVI is a newly established organization. Dengue vaccine development has been set as a

main agenda of NVI and will be used as a working platform to facilitate capacity building on project

management and coordination. The program will foster close collaboration and development of

coordinating mechanisms among these partners.

6. Strengthens capacity for research, development and production, including through

technology transfer, in developing countries.

Thailand has a reasonably good capacity for vaccine R&D at the level of discovery, vaccine

design and clinical trial. However, it lacks most of the capacity required to close the gap between the

early developmental phase and the clinical trial. This includes clinical lot production of the vaccine

candidates in GMP condition, preclinical testing in GLP condition. Vaccine production capacity is

also a weakness of Thailand. This dengue vaccine R&D will comprehensively strengthen vaccine

R&D and production in Thailand. We thus want to get a strong support via this WHO facilitating

mechanism to strengthen these capacities needed.