Lead Discovery for Infectious Tropical Diseases

Annual Report 2008

Lead discovery for infectious tropical diseases

TDR Business Line 3

For research on diseases of poverty Lead Discovery for Infectious Tropical Diseases

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Design: Lisa Schwarb • Layout: Simon Fenwick Cover picture: WHO/TDR/Craggs Printed by the WHO Document Production Services, Geneva, Switzerland Lead Discovery for Infectious Tropical Diseases BL3

TDR/BL3.08

Table of contents

Overview and highlights...... 5 Contributions to leverage, empowerment and stewardship...... 7 Implications of progress/delays on 2008-2013 plans...... 8 1. Context, strategic objectives and framework...... 9 1.1. Context and rationale...... 9 1.2. Strategic objectives...... 9 1.3. Strategic framework/operational approach...... 10 2. Key stakeholders and partnerships: roles and responsibilities...... 15 3. Implementation plan 2008–2013 and progress...... 17 3.1. Plan, progress and key milestones...... 17 3.2. Implications of progress/delays and global context changes on 2008–2013 plans...... 24 3.3. Specific activities for 2009...... 24 4. BL leverage, contributions to empowerment and stewardship and synergies with TDR business lines...... 25 4.1. Leverage...... 25 4.2. Contributions to overall empowerment and stewardship and synergy with TDR business lines...... 26 4.3. Elements enhancing sustainability of BL outcomes...... 26 4.4. Synergies with work of TDR BLs...... 26 5. Critical issues and suggested solutions...... 27 Issues identified through STAC and EDAC reviews addressed...... 27 6. Annexes...... 29 Annex 1. List of publications, meetings, conferences or invited lectures attended by BL3 in 2008 and planned for 2009...... 29 Annex 2. Membership of EDAC (Expert Drug Discovery Advisory Committee) and Helminth Drug Initiative Task Force...... 31 Annex 3. Summary of BL3 activities and end-products for 2009...... 32 Annex 4. Details of revision of business plan...... 35 Annex 5. Responses to specific JCB and STAC requests on BL3...... 35 Annex 6. Report of EDAC (BL3 SAC)...... 38

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List of abbreviations

ADME Absorption, Distribution, Metabolism IP Intellectual property and Excretion LMPH Laboratory of Microbiology, AiBST African Institute for Biomedical Science Parasitology and Hygiene and Technology LSHTM London School of Hygiene and Tropical ANDI African Network for Drugs and Medicine Diagnostics Innovation MMV Medicines for Malaria Venture ASTMH American Society for Tropical Medicine MTS Medium-Throughput Screening and Hygiene NCDS National Centre for Drug Screening BL Business Line NIH-USA National Institutes of Health - United BMGF Bill and Melinda Gates Foundation States of America CDRI Central Drug Research Institute NPIMR Northwick Park Institute for Medical CRO Contract Research Organization Research CYP Cytochrome P NIPRD National Institute for Pharmaceutical DEC Disease-Endemic Country Research DMPK Drug Metabolism and PK Pharmacokinetics Pharmacokinetics PPP Public-Private Partnerships EU European Union QC Quality Control EDAC Expert Drug Discovery Advisory R&D Research and Development Committee SAC Scientific Advisory Committee DNDi Drugs for Neglected Diseases Initiative SOP Standard Operating Procedures GIBEX Global Institute for Bioexploration STI Swiss Tropical Institute HAT Human African Trypanosomiasis TB Tuberculosis HDI Helminth Drug Initiative TBRI Theodor Bilharz Research Institute HEOS Hit Explorer Operating System TDR Special Programme for Research and HIV Human Immunodeficiency Virus Training in Tropical Diseases HTS High-Throughput Screening UB University of Buea IC Inhibitory Concentration UK United Kingdom ICGEB International Centre for Genetic UNAIDS United Nations Joint Programme on Engineering and Biotechnology HIV/AIDS ICS-UNIDO International Centre for Science UW University of Washington and High Technology - United Nations WHA World Health Assembly Industrial Development Organization WHO World Health Organization IFPMA International Federation of Pharmaceutical Manufacturers and Associations IGWG Inter-Governmental Working Group (on Public Health, Innovation and Intellectual Property)

4 TDR BL3 • 2008 Report Lead Discovery for LInfectiousead Discove Trryopic fora Ilnfectious Diseases Tropical Diseases BL3

Overview and highlights

The gap in the availability of drug leads and compound evaluation through parasite screens in candidates to sustain the development pipeline vitro and in animal models in vivo; and iterative for infectious tropical diseases is well documented medicinal chemistry linked to drug metabolism/ through the work of TDR and others (Fig. 1). pharmacokinetics. The primary objective of the Lead Discovery The major strengths of this North-South drug Business Line (BL3) is to help fill this “translational discovery network include: 1) the strong technical innovation gap” through a North-South drug and financial leverage attained through in-kind discovery network. Established in 2005, this support provided by partners, for example access integrated drug discovery network is producing to compound libraries; 2) the potential for rapid significant results following the increasing focus, GO/NO GO decisions on projects due to closer coordination and external leverage achieved through monitoring and review process, helping to reduce TDR’s new strategy. In addition to the discovery cost and enhance chances of success; 3) the added of novel drug leads to feed the development advantage of promoting innovation in disease- pipeline, this business line is supporting the endemic countries through the network activities; empowerment and stewardship functions of TDR and 4) the potential for spin-off of mature activities through activities that include: target selection that would otherwise not be well-resourced from and validation in support of target-based screens; within TDR.

100.0 100 Expected program survival rate (%) 80 Target diseases ts Translational Chagas 60 innovation gap HAT Leishmaniasis Malaria 40 Helminths 30.0 TB

Number of projec 20 19.5 10.7 5.8 4.0 1.9 1.3 1.3 0 Screening Lead Lead Preclinical Phase I Phase II Phase III Registration Approved for hits identi cation optimization Phase

Fig. 1. Translational innovation gap in drug discovery for infectious tropical diseases. Sources: TDR, MMV, DNDi, TB Alliance and a number of academic institutions

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Highlights of progress made by BL3 in 2008 include: (DNDi) on implementation of two hit‑to-lead projects based on the TDR compounds for 1) Development of clear lead progression and Chagas disease. candidate selection criteria with input from network partners and our Expert Drug Discovery 3) Identification of about four lead structures for Advisory Committee (EDAC). various diseases from our industry collaborations that are now the subject of new medicinal 2) Development of interface with other partners, chemistry programmes within these companies. including public-private partnerships (PPPs) such Furthermore, many confirmed hits against as collaboration with the Medicines for Malaria various parasites have been identified and are Venture (MMV) on the TDR 15087 project at forming the basis for new lead identification the University of Cape Town, and an agreement programmes (Fig. 2). with the Drugs for Neglected Diseases Initiative

Genomics/ Screens/ Lead Lead HTS hits identi cation optimization

12847/ Chagas 2 USP 437

12847/ TDR20364 HAT 1 MerkSerono 226 series (OSU)

12951/ Leishmaniasis 98 rget Database) Ta 5 (Industry/ TDR 12845/ TDR15087 Malaria academic 741 series (UCT) TB ( centres)

8120/ 4 Chemtura Clorsulon Onchocerciasis 339 >1 P zer Emodepside rget prioritization across diseases Ta including

10765/ Schistosomiasis Ro 15-5458 913

Translational innovation

Fig. 2. TDR drug discovery portfolio

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4) Some lead identification and lead optimization Contributions to leverage, projects being implemented through the medicinal chemistry network are reaching GO/ empowerment and NO-GO decision points, with two projects stewardship transitioning into lead optimization while another four have been terminated (consistent BL3 made progress in advancing innovation in with the high attrition rate in the process). developing countries through a range of activities, including: 5) Finalization of contractual agreement between • Initiating the African Network for Drugs and TDR, NovoNordisk (pharmaceutical company) Diagnostics Innovation (ANDI) which was and the (Chinese) National Center for Drug launched in Abuja, Nigeria, 6–8 October, 2008. Screening Shanghai on the exploitation of NovoNordisk’s compound library in support of Funding support for participation of some TDR’s drug discovery efforts. African scientists in the meeting was provided by several organizations including the MMV and 6) Continued improvement of the TDR target IFPMA. Over 200 delegates from 21 countries database, which continues to generate global endorsed the ANDI concept as a means of interest. promoting innovation in Africa. ANDI also has On the other hand, difficulties in finalizing been described by many observers as a possible contractual agreements with two academic model that supports the implementation of institutions working on TDR projects due to the new Global strategy and plan of action on intellectual property (IP) issues resulted in public health, innovation and intellectual property withholding of funding from TDR. approved by the World Health Assembly in May 2008 (WHA 61.21) following the recommendations of an intergovernmental working group. • The Helminth Drug Initiative (HDI) has provided further stimulus to innovation in developing countries by identifying, funding and providing technical support for three helminth screening centres. These centres are the Central Drug Reasearch Institute (CDRI) in India, the University of Buea in Cameroon and the Theodor Bilharz Research Institute (TBRI) in Egypt. Several new drug hits* and leads are already emerging through this work. This progress follows a focused set of reports on the HDI in a 2007 Special Issue of Expert Opinion in Drug Discovery (http://www.who.int/tdr/about/press_ center/files/helminth.pdf).

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• Transfer of hits and leads emerging from Implications of progress/ the BL3 network activities to institutions in developing countries for further progression. delays on 2008-2013 plans This is another key leverage because it is now The progress discussed above indicates that BL3 is helping to spur innovation in developing on track in achieving its yearly milestones, which countries. Examples include a successful lead ultimately will result in delivering the medium-term identification programme at the University of objectives for 2013. As a result of the momentum Cape Town, in collaboration with the African generated by ANDI in the African region, it has now Institute for Biomedical Science and Technology been agreed that the implementation of ANDI and in Zimbabwe. Also, TDR is supporting research initiation of other regional networks (for example on natural products at the Kenya Medical Asia and South America) form the the core of the Research Institute and the National Institute of activities of BL4, which focuses on innovation for Pharmaceutical Research and Development in products in developing countries. Nigeria. As an implementation strategy, BL3 will be synergistically linked with BL4. Leads, standard operating procedures and guidelines resulting from the North-South product discovery activities undertaken through BL3 and other relevant activities within TDR are to be channeled to BL4 to support a focused products innovation platform in developing countries. An integrated management of these two BLs will help to bring coherence to the work of TDR in the area of innovation, as well as improved linkage to WHO’s new global strategy and plan of action on public health, innovation and intellectual property. Indeed, BL3 is now leveraged to kick-start BL4 at reduced costs.

*Hit, compound with selective in vitro activity (IC50≤1uM) against whole parasite and /or proteins; lead, compound with drug characteristics, efficacious in disease animal model with no overt toxicity; drug candidate, optimized lead compound with in vitro and in vivo activity equivalent or better than drug standards, with acceptable pharmacokinetic and toxicity profile, amenable to cost-effective scale-up

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1. Context, strategic objectives and framework

1.1 Context and rationale 1.2 Strategic objectives

The gap in the availability of drug leads and BL3’s overall objective is to facilitate and support candidates to sustain the development pipeline the discovery of new drug leads for tropical diseases for infectious tropical diseases is well documented through networks and partnerships between (Fig. 1). pharmaceutical companies, academia and disease- endemic country (DEC) institutions. In recent years there has been an increase in product development activities for tropical diseases through The specific objectives include: a number of public-private partnerships (PPPs) for 1.2.1 Identify quality drug leads for tropical malaria, tuberculosis and certain neglected tropical diseases and facilitate the transfer of those diseases; examples include MMV, DNDi and TB leads to PPPs, industry, and other innovative Alliance. However, there is a dearth of credible drug partnerships for further development. leads to feed the development pipeline of these PPPs or in support of sustained product innovation 1.2.2 Identify drug candidates for helminth activities in developing countries. There is an infections (initially focusing on urgent need for a vibrant drug discovery initiative schistosomiasis, lymphatic filariasis and to produce such leads. Furthermore, for helminth onchocerciasis) through the Helminth Drug diseases there is currently no PPP for product Initiative, and transfer the candidates to development, and there is a need to go beyond lead appropriate partners for development. discovery and identify drug candidates that can be 1.2.3 Promote the global coordination of drug further developed by partners or within TDR. discovery activities through the network and TDR is well positioned to play the leading role partnership model. in the discovery of new leads. TDR also has 1.2.4 Promote technology transfer and innovative played a pioneering role in establishing win-win drug discovery in DECs through North/ agreements with industry, obtaining compounds South collaboration networks and from pharmaceutical and animal health companies partnerships. to support lead discovery through a coordinated network of compound assessment centres. 1.2.5 Support targeted fundamental research on Additionally, the recent availability of parasite generation of new tools to facilitate drug genome sequences presents an opportunity for de discovery. novo discovery of new chemical entities. The mandate of BL3 is helping to fill the innovation gap, and contributes to empowerment and stewardship functions, which furthers TDR’s vision of fostering an effective research effort on infectious diseases of poverty in which disease-endemic countries play a pivotal role.

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1.3 Strategic framework/ screens are assessed in whole parasites (in vitro) through the compound screening network. In operational approach addition, compounds (small molecules and natural products) are sourced and channeled into The implementation strategy (business model) the compound screening network for whole-cell for this business line is based on a coordinated network of partners from industry and academia screening, with actives subsequently tested in in developed and developing countries working animal disease models. Through iterative medicinal on different areas of the drug discovery process chemistry and DMPK network activities, leads are (Fig. 3). This innovative drug discovery identified. The leads are taken forward into lead network includes: 1) the drug target portfolio, optimization either in partnerships with other 2) in vitro and in vivo screening or evaluation, 3) institutions or handed off (Fig. 5). It should be medicinal chemistry and 4) drug metabolism and stressed that any such transfer of leads or hand- pharmacokinetics (DMPK) networks. off contractual agreements will ensure that public interest is protected; however, agreements may The TDR target database (www.tdrtargets.org) not always be reached to enable partnerships. The developed by the target portfolio network is closer alignment of Business Lines 3 and 4 makes already supporting target prioritization, high- BL4 the major pathway for hand-off of leads for throughput screening (HTS) and in silico further progression in DECs. screening efforts for infectious tropical diseases (Aguero et al., Nature Reviews in Drug Discovery, The integrated lead discovery strategy involves November 2008). Hits emerging from such experienced consultants and mentors who support

Pharmacokinetics/ metabolism network Compounds (known rationale, p diverse, natural rshi to products) n In e d

Capacity u Target In vitro/vivo M

t Quality

building/ r Drug portfolio screening y Optimization eads Hits Hits leads network network fellowships L candidates A HTS ca demia Interface with other players Validated drug targets Medicinal chemistry network

Fig. 3. An innovative lead discovery strategy for tropical diseases. Source: Nwaka & Hudson, 2006

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and provide guidance on various aspects of are managed by the BL3 staff, the Expert Drug the preclinical process – including support for Discovery Advisory Committee (EDAC) and research fellows from disease-endemic countries. consultants. A central drug discovery database These DEC fellows are trained in drug discovery known as the Hit Explorer Operating System methods at pharmaceutical and academic research (HEOS) supports BL3’s management of individual laboratories as part of BL3 activities supporting projects, as well as data and compounds exchange. ‘empowerment’ objectives of TDR. Interactions The milestones and end-products for BL3 (through between the different networks and quality control 2013) are presented in Table 1 and Fig. 4.

Signi cantly behind plan Upstream Downstream Slightly behind plan but BL3: Generic Basic Product Intervention Real-life Research likely to get on track Discovery activities research development development evaluation for access Well on track/ahead of plan

Generic stage Drug discovery stage

7. Candidates Candidate selection 2 Drug candidates between 2010–2013

6. Lead Screens, MedChem, 2 Lead optimization projects/year optimization DMPK, expl tox.

Lead selection 2 Leads/year 5. Lead identi cation Hits to lead 5 Ongoing hit-to-lead projects/year

Hits >50 Con rmed hits/year 4. Hit generation Assats, HTS >5000 Compounds screened/year Research stage

Prioritization, validation, curation 3. Targets Establish target network, database

2. Resource Funding support generation and logistics

1. Knowledge BL plan, SAC, review consultations

2007 2008 2009 2010 2011 2012 2013 2014

Fig. 4. Framework for monitoring drug discovery milestones and indicators

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Table 1. Indicators for end-products and outcomes (till 2013) Indicators BL objectives End-products Indicators for Expected for expected end-products outcomes outcomes

Strategic • Two leads discovered objective 1: every year Identify quality Six leads drug leads entering Ten leads • One lead transferred to a for tropical optimization Three leads (with novel partner every other year diseases and through transferred chemotypes) facilitate the partnerships to BL 4 or discovered for • A portfolio of projects transfer of including centres in one or more delivering leads (see Fig. 2) those leads to through BL4 the South TDR target PPPs, industry to support for futher diseases by • Open access database and other innovation in optimization 2013 containing drug targets in innovative developing support of high-throughput partnerships countries and in silico screening for lead for further discovery starting 2007 development

Strategic objective 2: • HDI fully functional, utilizing Identify drug existing network and candidates partnerships model (2006- for helminth 2008) infections Two drug (initially • HDI Task Force in place to Two drug candidates focusing on help further develop the One drug candidates meeting schistosomiasis, framework for the initiative, candidate identified target lymphatic including the development entering through the product filariasis and of a focused business plan development Helminth Drug profiles onchocerciasis) (2007-2008) pipelines by Initiative by based on through the 2013 2013 animal data Helminth Drug • Two new centres for helminth identified Initiative (HDI) screens identified and and transfer supported through funding the candidates and technical support to to appropriate contribute to sustainability partners for (2008) development

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Table 1 cont. Indicators for end-products and outcomes (till 2013) Indicators for Expected Indicators for BL objectives End-products end-products outcomes expected outcomes

• Coordinated drug discovery strategy based on networks and partnerships • Portfolio review published through the and Expert Drug publicized • Improved Discovery Advisory (2006-2013) coordination, Committee Strategic management (EDAC), Helminth objective 3: • Target and sharing of Managed portfolio Drug Initiative Promote product information of lead discovery Task Force and the global profiles and in support of projects with partners network meetings coordination of compound drug discovery available, delivering to promote drug drug discovery progression activities leads and transferring discovery for public activities criteria these to appropriate health starting 2007 through the as well as • Publications partners for further network and standard or processes development (Fig. 2) • Two product partnership operating contributing to innovation model processes harmonization publications in support of global of drug research efforts • Four meetings on discovery innovation in the established North and South • Web-based SOPs/ compound submission requirements

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Table 1 cont. Indicators for end-products and outcomes (till 2013)

Indicators BL objectives End-products Indicators for Expected for expected end-products outcomes outcomes

• North-South networks for drug discovery established and contributing to Strategic innovation in developing objective 4: Empowerment countries through Promote of DEC institutional strengthening Increased Ten technology scientists and and training capacity developing transfer and institutions to building country innovative drug participate in • Six fellows from DECs trained and training scientists discovery in North-South through drug fellowships of leaders trained or DECs through networks and in drug institutions North/South to produce • Workshops and training on discovery in strengthened collaboration leads (2006– innovative lead discovery in DECs networks and 2013) DECs including structure- partnerships based drug design, medicinal chemistry, in vitro ADME, whole cell screening, and natural products

• Continued management and TDR target Strategic curation of the TDR target database • Eight objective 5: database Support the maintained diseases Support translation of (supporting covered targeted • Three new targets validated genomics and target- in the fundamental and one assay developed basic research based drug database research on for at least one TDR target into product discovery and generation of disease leads and supporting • Two targets new tools to their further translation of progressed facilitate drug • One new in vitro or in development research into to HTS discovery vivo drug screening tool drug leads) developed by 2013

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2. Key stakeholders and partnerships: roles and responsibilities

BL3 activities are implemented through There is also close interaction with PPPs such as the collaborations with several academic and industry MMV, DNDi and the Global Alliance for TB Drug partners, donors and government agencies. Development. MMV is partnering with TDR in two Table 2 lists current networks/partners and their antimalarial drug discovery projects (as co-funders roles. In addition, there is close cooperation of the projects) – one at Pharmacopeia and a second within WHO, especially with the Department one with University of Cape Town, for which a of Neglected Tropical Diseases (NTD) as well as contract is being finalized. BL3 also signed an with the Secretariat on Public Health, Innovation agreement with DNDI for hit-to-lead projects using and Intellectual Property (PHI) in support of screening hits identified by TDR for Chagas disease. the global strategy and plan of action of the TDR also interacts with philanthropic foundations Inter-Governmental Working Group approved such as the Bill and Melinda Gates Foundation through World Health Assembly resolution and the Wellcome Trust, and there is on-going 61.21 (WHA61.21). There is also very significant discussion regarding potential funding support to interaction between BL3 and the WHO legal leverage future BL3 network activities through these office in support of contractual negotiations with organizations. In addition to partnerships with partners. This major and sometimes time-sensitive specific pharmaceutical companies, there is ongoing contractual negotiation is mandatory for initiating collaboration with the IFPMA in support of drug new drug discovery projects with public and private discovery for tropical diseases.. institutions. In terms of national or multi-lateral agencies and institutions, BL3 also has ongoing interactions with the US National Institutes of Health (NIH) and the European Union’s drug R&D programme for malaria (TDR’s BL3 leader chairs this EU AntiMal Expert Scientific Advisory Committee).

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Table 2. List of network partners (implementors)

Network Partners Role

Swiss Tropical Research Institute, Basel; Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp; London School of Hygiene and Tropical Compound Medicine; Theodor Bilharz Research In vitro and in vivo whole Screening Institute, Egypt; University of Washington, parasite screens Network USA; University of Buea, Cameroon; Central Drug Research Institute, India; Kenya Medical Research Institute, Kenya; National Center for Drug Screening, China

Compound Chemtura, MerckSerono, Pfizer, Compound supply, storage Supply and LifeChemicals, NovoNordisk, RCC and ASDI and management Management

University of Cape Town, South Africa; St Jude’s Children’s Research Hospital, USA; Synthetic chemistry, Medicinal Ohio State University, USA; Pharmacopeia, molecular modeling, Chemistry USA; MerckSerono, Switzerland; University pharmacology to discover Network of Dundee, UK; University of Nebraska, and design new drugs USA; University of Sao Paolo, Brazil

Drug MerckSerono, Switzerland; Pfizer, UK; Metabolism and African Institute for Biomedical Science In vitro and in vivo DMPK Pharmacokinetics and Technology, Zimbabwe; Monash assessment (DMPK) Network University, Australia

Development and curation University of Washington, USA; University of TDR drug target of Pennsylvania, USA; Sanger Center, Drug Target database, discovery of new UK; Walter Eliza Hall Institute, Australia; Prioritization therapeutic targets through Biotech Institute, Argentina; Inpharmatica, Network modern approaches New England Biolabs and University of (genomics/proteomics/ California-San Francisco, USA bioinformatics)

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3. Implementation plan 2008–2013 and progress

Progress achieved in 2008 is described below chemistry efforts for lead identification in terms of each of the specific BL objectives (Fig. 2). This progress was largely due (Section 3.1). Please also refer to Figs. 3 and 4 to the successful compound acquisition and Table 1 for further details of implementation campaign of BL3 from industry partners strategy, timelines and specific end-products. and commercial sources as well as TDR medicinal chemistry centres. For example, 10 000 compounds were purchased this 3.1. Plan, progress and year from Life Chemicals. To maximize key milestones the chances for success, it should be emphasized that sourced compounds 3.1A Identification of drug leads and transfer are usually triaged and reviewed by BL3 to partners including PPPs, industry, and consultants before screens. Note that other innovative partnerships for further high-throughput screening (HTS) of large development. compound collections against molecular 3.1A.1 Clear lead and candidate progression targets is not part of the whole parasite criteria have been defined with input from screening described in this section; target- network partners and the Expert Drug based HTS is highlighted elsewhere in Discovery Advisory Committee. These this report. criteria are being finalized for publication 3.1A.4 In the context described in 3.1A.3, BL3 for the benefit of the wider international has completed the screening of selected community. compound libraries from Pfizer (e.g. 3.1A.2 There has been improved interface with focused anthelminthic, antiprotozoal, other partners including PPPs, such as and antibacterial libraries), Chemtura, collaboration with MMV on the TDR MerckSerono and also through focused 15087 project at the University of Cape SAR analysis at our medicinal chemistry Town and other TDR/MMV co-funded centres. From these screens, hits projects. were identified and triaged (>1000 in 2008) with several compounds already 3.1A.3 At least four potential lead structures progressed to in vivo testing (Tables 3 from industry collaborations identified and 4). Some hit-to-lead translation is in 2007, are now the subjects of new ongoing based on these screens. medicinal chemistry programs within these same companies, while over 10 3.1A.5 Several hit-to-lead and lead-optimization new compounds with confirmed activity projects implemented through the against parasites were identified in 2008 medicinal chemistry network are through the various network activities. In reaching GO/NO-GO decision points, some cases, these compounds have shown with two projects transitioning into lead promising in vivo rodent activity and optimization while another four have are forming the basis for new medicinal been terminated, consistent with the high attrition rate in the process. Examples of

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Table 3. Screens completed at the Compound Screening Network

Screening centre Number of compounds Screens performed*

STI 1818 6741

LMPH 1981 9617

UW 756 814

TBRI 2993 3245

LSHTM 1971 2056

NPIMR 2854 3257

UB 90 129

CDRI 105 396

* Includes MTS, IC50 and vivo assays for protozoans; motility (vitro) and worm reduction (vivo) assays for helminths; cytotoxicity assays

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Table 4. Hits* from screens

Number of compounds screened Number of hits

Chagas disease 2777 302

Human African 3351 165 trypanosomiasis

Leishmaniasis 2707 123

Malaria 3144 327

Schistosomiasis 4911 93

Onchocerciasis 2873 149

Lymphatic filariasis 104 32

TOTAL 1191

*Hit, a compound with selective in vitro activity against whole parasite and/or proteins; identified through screens of selected compound librairies and also through focussed SAR analysis at the medchem centres.

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compound series with confirmed in vivo training of two African scientists in China activity in 2008 are: in HTS (see press release on this project at: http://www.who.int/tdr/svc/news- • Chagas disease: Chemtura compounds: events/news/chinese-drug-screening). sterol biosynthesis inhibitors (TDR55247, TDR 70552, TDR70565, TDR66953) This again exemplifies the type of leverage show good activity @ 5×50 mg/kg orally TDR is achieving through BL3. (po) with significant extension of MSD BL3 works closely with the WHO legal compared to controls. office to finalize all necessary agreements • Malaria: Chemtura compounds: two including confidentiality, materials novel aminoquinoline series (TDR69153 transfer and partnership agreements and TDR691154) show about 98.26% to enable collaborations to take place. inhibition @ 1×30mg/kg po with This does not include the more routine significant MSD (mean survival days) technical services agreements for projects. compared to control; Pfizer compounds: This aspect of BL3 activity is sometimes TDR 63439 and 70803 have shown overlooked. The experience gained significant vivo activity by the ip route. through this negotiation is also critical for capacity development in DECs. Other compound actives currently being pursued through medicinal 3.1B Identification of drug candidates for chemistry projects are noted in Table helminth infections through the Helminth 5. Additional DMPK support for the Drug Initiative and transfer of the medicinal chemistry projects is provided candidates to appropriate partners for by Monash University (Australia). This development. includes support for in vivo PK studies for 3.1B.1 There has been good progress towards lead optimization projects and in silico meeting the specific BL objective of predictions (solubility, permeability) identification of two drug candidates and in vitro Absorption, Distribution, by 2013. Candidate selection criteria Metabolism and Excretion (ADME: for helminths has been finalized, solubility, metabolic stability, CYP target product profiles for helminths inhibition) at AiBST, Zimbabwe. are being finalized, and plans have 3.1A.6 New contractual agreements with industrial been made for further evaluation of partners: A three-way agreement with emodepside as a drug candidate for NovoNordisk, the National Center for onchocerciasis, pending additional data Drug Screening (NCDS), affiliated with and discussion with Bayer. There also the Chinese Academy of Sciences and has been prioritization of new compound TDR was implemented in 2008. This series with confirmed vivo activity for agreement represents the first time that onchocerciasis for further optimization. TDR has secured a collaboration with a Among those considered for further major pharmaceutical firm allowing the evaluation are four structurally unrelated transfer of a large compound collection compounds from Chemtura (TDR55132, relevant to screening against all TDR TDR55168, TDR55404, TDR55631) target diseases, including tuberculosis, and a number of Pfizer compounds (TDR51055, TDR51155, TDR51250, to an institute in a developing country. TDR51616, TDR51710, TDR52969). The molecular targets to support HTS are being provided through the TDR 3.1B.2. Three helminth screening centres are target network (www.tdrtargets.org). now fully operational in developing The collaboration also provides for the countries, including centres at the Central

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Table 5. Medicinal chemistry workstations

TDR- Disease target assigned Update compounds

Lead progressed into lead optimization University of Leishmaniasis, TDR15087 for malaria; funding support from MMV Cape Town malaria secured but awaiting contract

St Jude Children's Lead identification ongoing but TM A not Malaria TDR17516 Hospital signed by university Memphis

Series transitioned to lead optimization, Ohio State HAT TDR20364 but outstanding MTA not signed by University university agreement

Pharmacopeia Malaria TDR22093 Project co-funded by MMV.

MerckSerono HAT TDR22518 NO-GO decision as of August 2008

TDR22180 MerckSerono Malaria Lead identified TDR30317

University of Malaria TDR32750 Lead identification ongoing Dundee

University of Roche Schistosomiasis Lead optimization ongoing Nebraska compound

New medicinal chemistry centre; lead University of TDR26631 Chagas identification ongoing; in vivo activity Sao Paolo TDR30139 identified

TDR BL3 • 2008 Report 21 BL3 Lead Discovery for Infectious Tropical Diseases Lead Discovery for Infectious Tropical Diseases

Drug Research Institute (CDRI), India; resolutions, as well as formal meeting the University of Buea, Cameroon; and report, is contained in Annex 6. the Theodor Bilharz Research Institute Joint screening, medicinal chemistry (TBRI), Egypt. Several new drug hits and and DMPK network meeting: for the leads are already emerging through this first time in 2008, a joint meeting of work. the different networks in the TDR Drug 3.1C Promote the global coordination of drug Discovery Programme (Compound discovery activities through the network Screening, Medicinal Chemistry and and partnership model. DMPK) was held on 27–28 August 2008. The Drug Target Prioritization Network 3.1C.1 BL3 staff and associated strategic advisory did not participate in this meeting but committees (EDAC and HDI Task Force) will be included in subsequent meetings. are involved in the coordination and The purpose of this joint meeting was to quality control of the target database, enhance integration, coordination and screening, chemistry and DMPK networks strategic planning between the various as well as the Helminth Drug Initiative as areas of drug discovery. In line with an integrated set of activities. EDAC recommendations, the meeting Advisory committee meeting: the first included discussions on how to improve meeting of the Expert Drug Discovery turn-around time of data from one centre Advisory Committee (EDAC) was held to another, for example, from screens 31 March-3 April 2008 in Geneva. back to chemistry, and how to promote In the meeting, EDAC commended communications within the network. BL3 for excellent progress to date on Prior to the meeting, turn-around time implementation of the drug discovery of data was assessed and bottlenecks network concept, while recommending identified in a series of consultations improved measures in the following between TDR’s BL3 staff, EDAC areas: communication and strengthening representatives and consultants. The joint of teams across all networks; use of meeting also presented an opportunity the HEOS database system to enhance to finalize the hit-to-lead progression operations including compound criteria for both protozoan and helminth distribution/tracking and data/ drug targets. This constitutes a guiding knowledge sharing; recruit a new stream document for deciding on and justifying of industry collaborators and leverage further progression of compounds in the collaboration with IFPMA and other drug discovery pipeline. The next Joint industry associations; establish new Network Meeting is planned for August medicinal chemistry centres based in 2009. Africa in tandem with the establishment HEOS (hit explorer operating system) of ANDI; plan improvements in database: this is an important resource logistics of compound bank storage and for managing individual projects and management; rationalize and optimize the for processing/analyzing data and use of screening centres, thus improving compounds. Activities undertaken on turn-around time. The second EDAC through the database include: meeting is scheduled for 30 March- 1 April 2009 in Geneva, and will be held • QC of data, recapture and validation of in tandem with the meeting of the HDI historical data; Task Force. EDAC and HDI Task Force • Harmonization of assay and organism composition is detailed in Annex 2. names; A complete summary of all EDAC

22 TDR BL3 • 2008 Report Lead Discovery for Infectious Tropical Diseases BL3

• Custom functions to harmonize and 3.1D.3. The African Network for Drugs and assist in reporting biological and DMPK Diagnostics Innovation (ANDI). Several data; African centres participating in the North- • Improved data mining and information South drug discovery networks have sharing functions; successfully implemented drug discovery activities such as compound screening, • TDR Monthly Dashboard Report for medicinal chemistry and DMPK. For compound tracking and monitoring; example, the systematic implementation • Issue of turn-around time for data of a hit-to-lead project at the University addressed, analyzed and solutions of Cape Town over the past two years has implemented. led to the identification of an orally active A major challenge with the database is the lead compound for malaria based on question of sustainability, as the database animal data. This project has also trained is managed by Scynexis, a biotech four postdoctoral scientists from Africa. company based in North Carolina, USA. The DMPK centre at the African Institute for Biomedical Science and Technology 3.1C.2 Publications, meetings (see Annex 1) in Harare, Zimbabwe, supports in silico 3.1D Promote technology transfer and and experimental ADME assessment. innovative drug discovery in DECs The Kenya Medical Research Institute through North-South collaboration has been validated as a screening center networks and partnerships. for antimalarials, and has capacity for natural products chemistry as well as 3.1D.1 A number of DEC scientists and clinical pharmacology. The Theodor institutions are now participating in Bilharz Institute in Cairo, Egypt, has our North-South networks. These become a world-class screening facility include a centre for filariasis compound for schistosomiasis supporting the TDR screening at the Central Drug Research network in lead discovery. It also has Institute (CDRI) in India; a centre for strong pharmacology capacity. The onchocerciasis compound screening at National Institute for Pharmaceutical the University of Buea, Cameroon; and Research (NIPRD) in Abuja, Nigeria, medicinal chemistry, DMPK as well as has established a good screening compound screening for Chagas disease infrastructure for tuberculosis and malaria at the University of Sao Paulo, Brazil. supported with good natural products 3.1D.2 Two research fellows from developing chemistry as well as pharmacology countries completed training as part of expertise. The US National Institutes of TDR drug discovery activities and have Health recently established a chemistry returned to their respective countries. laboratory at NIPRD. One of these fellows, Dr Musonda The success of these North-South Chitalu, was engaged by a South African networks has provided the impetus for drug discovery company immediately the establishment of the African Network upon his return to his home country for Drugs and Diagnostics Innovation following two years of training at Pfizer. (ANDI). ANDI has generated significant Another fellow returned to a job in India interest following a very successful following two years of training at the inaugural meeting in Abuja, Nigeria, University of Dundee. Three other TDR 6–8 October 2008. The meeting was fellows from developing countries have attended by the vice president and health now joined the network projects for minister of Nigeria among other senior 2009. government officials.

TDR BL3 • 2008 Report 23 BL3 Lead Discovery for Infectious Tropical Diseases Lead Discovery for Infectious Tropical Diseases

A full report on the recommendations 3.2. Implications of progress/ emerging from the ANDI launch is available on the TDR website (http://www. delays and global context who.int/tdr/news-events/news/pdf/ANDI- changes on 2008–2013 plans minutes.pdf). The planned operations of the ANDI Task Force, established to As reflected inFig. 1, a significant innovation develop the organizational structure gap remains despite some ongoing activities in and business plan for ANDI, is detailed drug R&D for malaria, tuberculosis and some further in the BL4 report. neglected diseases through product development partnerships based in the North. At the same time, 3.1E Support targeted fundamental research on however, there has been increased donor interest the generation of new tools to facilitate in promoting early-stage innovation, e.g. through drug discovery. initiatives such as the BMGF Grand Challenges 3.1E.1 There has been continued management Grants. There also has been a major change in the and improvement of the TDR target past two years regarding intergovernmental support database (www.tdrtagets.com). The TDR for innovation as a result of the IGWG process and target database is already supporting the new WHO Global strategy and plan of action on target discovery in support of high- public health, innovation and intellectual property. throughput screening (HTS) and in silico These new interests reflect a forward-looking agenda screening efforts at various institutions. A that could contribute to sustaining long-term access high-impact publication on this database to health products within these countries. ANDI is a has just been published in Nature practical approach initiated by TDR in implementing (Aguero et al., Nature Reviews in Drug R&D initiatives in developing countries. Promoting Discovery, November 2008). Discussions innovation for products in developing countries is are ongoing with the Bill and Melinda likely to be the future terrain for many new product Gates Foundation (BMGF) to leverage R&D efforts for neglected diseases. additional support for improvement of the data and incorporation of chemical 3.3. Specific activities for 2009 structures in the database. 3.1E.2 This open-source TDR target database Please refer to Annex 3 for specific activities and has supported major grant applications planning for 2009. by external investigators. Targets are now increasingly being selected for further studies based on the criteria established for this database. 3.1E.3 In the area of in vitro drug screening assay development, the work of this BL has helped some centres within the TDR screening networks to leverage external funding for screens this year; for example, recent funding to the London School of Hygiene and Tropical Medicine for HTS assay development for schistosomiasis.

24 TDR BL3 • 2008 Report Lead Discovery for Infectious Tropical Diseases BL3

4. BL leverage, contributions to empowerment and stewardship and synergies with TDR business lines

4.1. Leverage to collaborate and to negotiate win-win contractual agreements. The achievements described above and in the past 4.1.2 Economy of scale due to disease scope. It has years would not have been possible if not for the been argued that TDR’s focus on multiple significant leverage achieved through the network diseases, given the limited funds, signifies a model. This certainly includes the substantial in- lack of focus. However, in the case of early- kind contributions through various industrial and stage drug discovery through the network academic partners, the economies of scale achieved model, the focus on multiple diseases due to the scope of diseases, the support from presents a significant advantage both in EDAC and consultants who contribute their time terms of leveraging additional cost savings and efforts at far lower cost than commercial rates. and reducing overall compound attrition Selected examples of leverage achieved through BL3 (Nwaka and Hudson, 2006, Nature Reviews are: Drug Discovery). For example, the screening 4.1.1 Access to compound collection and industry for multiple diseases implemented by BL3 support. Although TDR purchases compound makes it easy to rapidly evaluate scarce collections from time to time for its drug compound collections across eight diseases discovery purposes, a significant proportion in a very short time. This, in turn, supports of the thousands of drug-like compound rapid decision-making for prioritization of collections used for screening are supplied compounds. by industry at no cost to TDR. Since the 4.1.4 The TDR target database (www.tdrtargets. cost of preparing, acquiring and maintaining org) is now a global resource leveraged by good compound libraries runs into the several investigators to get funding for work millions of dollars, TDR leverage achieved on infectious tropical diseases. The TDR is thus represented by comparable cost target network is exploring funding from savings. Examples of such leverage are the the Gates Foundation to support continued ongoing collaborations between TDR and maintenance of the database. companies including MerckSerono, Pfizer, 4.1.5 Additionally, BL3 is now leveraging its North- Chemtura and NovoNordisk. In addition, South drug discovery strategy to kick-start some of these companies perform medicinal regional innovation activities in DECs, e.g. chemistry and training of TDR-supported through ANDI. fellows from developing countries. It must, however, be acknowledged that achieving this leverage means significant investment in time and resources to identify partners willing

TDR BL3 • 2008 Report 25 BL3 Lead Discovery for Infectious Tropical Diseases Lead Discovery for Infectious Tropical Diseases

4.2. Contributions to overall ANDI, provides another important element of sustainability, as does the transfer of knowledge empowerment and steward- and leads from BL3 to BL4 for further develop- ship and synergy with TDR ment, particularly in DEC networks and business lines institutions. • Fig. 5 illustrates other interfaces and linkages As discussed earlier, this BL is supporting significant that support the sustainability of BL3. stewardship and empowerment functions (see 3.1C and 3.1D). These activities are now being enhanced through BL4. Other examples of the BL’s stewardship efforts include sharing of lessons with 4.4. Synergies with work the international community. This takes place, for of TDR BLs example, through the development of compound This BL provided very significant technical support progression criteria and target product profiles to the IGWG discussions that resulted in the Global and through the dissemination of information and strategy and plan of action on public health, innovation knowledge through publications, databases and and intellectual property. It also worked with the meeting presentations and attendance. Examples IGWG secretariat in preparing documents in of BL3’s participation in empowerment activities support of the IGWG deliberations. include training developing country researchers in As discussed, BL3 is leveraging ANDI to promote drug discovery in state-of-the-art pharmaceutical innovation in developing countries as part of BL4 company laboratories, as well as its initiatives activities. There also is close interface between BL3 supporting compound screening and medicinal and BL5 (Innovative Vector Control Interventions) chemistry centres in DECs. BL3 coordinates in sharing lessons through the networks and with with TDR’s Empowerment Function (BL2) in the BL6 (Drug Development for Helminths/NTDs) implementation of the training and fellowship through the Helminth Drug Initiative. BL3 also aspects of drug discovery and has worked with BL1 works with BL7 (Quality-assured Diagnostics) through TropiKa in the launch of ANDI. through various innovation activities, including the TDR target prioritization database which now also 4.3. Elements enhancing includes diagnostics targets prioritization. Finally, sustainability of BL outcomes BL3 harmonizes with BL8 (Evidence for Treatment of TB/HIV) through interaction on the identification The following activities and linkages help to ensure of needs for drug discovery, and with BL9 sustainability of the BL activities: (Antimalarial Policy/Access) on the desired product • The North-South discovery networks are already profile for new antimalarials. helping to stimulate recognition of DEC drug discovery research leaders and research centres and thus support sustainability of their activities. The establishment of product R&D networks in developing countries, as exemplified by

26 TDR BL3 • 2008 Report Lead Discovery for Infectious Tropical Diseases BL3

5. Critical issues and suggested solutions

Close interface and synergy Issues identified through STAC between BL3 and BL4 and EDAC reviews addressed Three years ago, we suggested that some of the hits and leads emerging from the BL3 network activities Interface between BL3 and other be transferred by TDR to institutions in developing initiatives including BL6 (Fig. 5) countries for further progression. We also suggested that this could be key in helping spur innovation in After discussions between BL3 and BL6 on the developing countries. Indeed, this is already proving product R&D for helminths, both BL leaders agreed to be the case; for example, the successful lead that under the current resource scenario, TDR alone identification work at the University of Cape Town, is not in a good position to successfully implement and other centres including those in sub-Saharan drug candidate transition into drug development. Africa. In light of this progress, the implementation Neither BL3 nor BL6 is resourced to undertake of ANDI and the planning for Asian and South such “interface” activities (e.g. safety pharmacology, American ANDIs is now the core of BL4 focusing on pre-formulation, formulation, animal toxicology, innovation for product development in developing scale-up chemistry). countries (see BL4 report). While BL3, through the Helminth Drug Initiative An implementation strategy involving the two (HDI), still requires considerable funding for lead interlinked BLs has been proposed as follows: 1) optimization that is currently unavailable, BL6 is leads, standard operating procedures and guidelines not in a position to do pre-clinical development on resulting from the North-South product discovery its own without considerable resources. Possible activities undertaken through BL3 and other scenarios to fill this gap are: relevant activities within TDR are fed into BL4 to 1) In the short term, BL3-identified development support a focused products innovation platform candidates belonging to Pharma are promoted for in developing countries. This strategy (see BL4 a TDR BL6/Pharma joint development strategy report) is exemplified by work of BL3 that led to the (e.g. moxidectin model). concept of ANDI. An integrated management of this 2) HDI secures additional funding support in the synergistic activity will help to bring coherence to short term to cover preclinical development and the work of TDR in the area of innovation, linking then interfaces with BL6 as appropriate. In the to WHO’s global strategy and plan of action as well meantime, there should be extensive promotion as leveraging the strength of BL3 to kick-start BL4 at and support of developing country R&D reduced costs, particularly of human resources. innovation platforms such as ANDI that cover discovery, pre-clinical and clinical development, as well as regulatory capacity.

TDR BL3 • 2008 Report 27 BL3 Lead Discovery for Infectious Tropical Diseases Lead Discovery for Infectious Tropical Diseases

This is now being achieved through BL4. In this context, HDI could become part of ANDI. ANDI (including HDI) may offer longer-term solutions, as both initiatives leverage external funding and seek industrial partners to support product R&D. Other challenges/issues for BL3 include: • Limited resources (both human and financial); • Need for continued access to quality compounds for screening requires proactive interaction with pharmaceutical companies and other compound suppliers; • Need for more resources to access commercially available collections and access to natural products in developing countries; • Slow implementation of funding to partners due to delays associated with WHO’s Global Management System; • Intellectual property issues with some partners, particularly medicinal chemistry partners.

BL4 DEC Innovation (ANDI) Targets: Screens: MedChem/ADME: selection, in vitro/in vivo, in vitro/in vivo • PPPs HTS cytotoxicity Protozoa • Industry Quality leads

s BL4 Lead DEC Innovation (ANDI) Targets: Screens: MedChem/ADME: optimization HDI selection, in vitro/in vivo, in vitro/in vivo and candidate HTS cytotoxicity • BL6

Helminths selection Quality leads

Drug candidate Drug • Industry

Fig. 5. Interfaces and hand-off of leads

28 TDR BL3 • 2008 Report Lead Discovery for Infectious Tropical Diseases BL3

6. Annexes

Annex 1. List of publications, meetings, conferences or invited lectures attended by BL3 in 2008 and planned for 2009

• Agüero F et al. 2008. Genomic- • Meeting of BL3 staff and • Visit to North Carolina for scale prioritization of drug consultants second week of training as backup for HEOS targets: the TDR Targets every month starting February database, Corie Alias, June/July database. Nature Reviews Drug 2008 (Geneva). 2008. Discovery. 7(11):900–907. • Joint Meeting of the Screening, • Visits to potential collaborators • WHO-TDR. 2008. African Chemistry/DMPK Networks, in China; for example, a Network for Drugs and held every year to review company developing database Diagnostics Innovation in progress, discuss SOP, for traditional medicines in Africa. Part 1: Health Product progression criteria, strategy Beijing (14 July 2008) and the R&D Landscape in Africa; and issues like turn-around Centre for Drug Screening in Part 2: Collection of Meeting of data: 27–28 August 2008 Shanghai, October 2008. Abstracts. ANDI Founding (Geneva). • MMV review meeting in Meeting in Abuja, Nigeria, • Visit to ASDI (CRO in USA), Pennsylvania/Boston (June/July 6–8 October 2008. a potential new partner in the 2008). • First EDAC meeting to review TDR Compound Bank and • Meeting of the organizing BL3 projects in a face-to-face med chem. Centre linked to committee for ANDI in Abuja, meeting with PIs from our other visit in the US such as Nigeria, July 22–24, 2008. drug discovery networks, 31 to the World Bank on African • Visit to Chemtura in US March–4 April 2008 (Geneva). Network: May 2008. and Canada (date to be • TDR Compound Bank • Visit to North Carolina determined). Stakeholders meeting, linked (Scynexis) to resolve data • Bamako ministerial meeting with first EDAC meeting. The storage and management issues (November 2008). goal is discussing the feasibility with support from Dr. Lean of establishing the TDR Chee (EDAC member) who • ANDI Task Force meeting, Compound Library as a public has considerable expertise in December 2008. resource and the funding database management logistics, needs, 3 April 2008 (linked to Bernadette Ramirez and Foluke above). Fakorede, July 2008.

TDR BL3 • 2008 Report 29 BL3 Lead Discovery for Infectious Tropical Diseases Lead Discovery for Infectious Tropical Diseases

Invited lectures in 2008 • ICS-UNIDO: invited to deliver Scheduled meetings keynote at drug discovery • Drug Discovery and Design for 2009 meeting for developing meeting: invited as speaker and • Visit to CDRI India countries, 3–5 July 2008 to chair a session, 4–8 February (a collaborating centre), (Trieste). 2008. as well as Advinus and • Natural products meeting, • Visit to National Institute for other companies to discuss Mississippi (Bernadette Pharmaceutical Research, collaboration, 1Q 2009. Ramirez), April 2008. Abuja, to give a lecture and • Drug target network meeting: advise on drug discovery • Drug discovery meeting held twice per year to take activities. Also participate in in Beijing: invited speaker stock of work re: database the opening of laboratories (October 18–22; cancelled). optimization, incorporation of supported by NIH, 17–21 • Hope College Michigan: invited helminth data and continued February 2008. speaker (November 2008; curation of targets: 1Q 2009, • BioVentures meeting on cancelled). Seattle. Innovation: invited as speaker • Invited talks at ASTMH, New • The African Network for in a session and to represent Orleans (December 2008). Drugs and Diagnostics the director in another • Invited talk at GIBEX Africa Innovation (ANDI) meeting session: 10-12 March 2008 natural products meeting, in Africa: October 2009, (DC, USA). University of Cape Town Cape Town, South Africa. • Malaria postgenomics (November 2008). • Visit to new med chem and meeting, invited as speaker • Meeting with African screening centre in Brazil, April 7–8 (Wellcome Trust Development Bank on ANDI, 1Q 2009. London). Tunis, November 2008.

30 TDR BL3 • 2008 Report Lead Discovery for Infectious Tropical Diseases BL3

Annex 2. Membership of EDAC (Expert Drug Discovery Advisory Committee) and Helminth Drug Initiative Task Force

See also: http://www.who.int/tdr/ • Dr Ken Duncan (drug • Dr Valerie Mizrahi (genomics) svc/research/lead-discovery-drugs/ discovery) Global Health MRC/NHLS/WITS Molecular management Program, Bill and Melinda Mycobacteriology Research Gates Foundation Unit, ST/NRF Centre of Expert Drug Discovery • Dr Simon Efange (medicinal Excellence for Biomedical Advisory Committee chemistry, natural products) TB Research, National Health Laboratory Service • Dr Frank Douglas, chair University of Buea, Cameroon and University of the (innovation, research and • Dr Timothy Geary (helminths) Witwatersrand, South Africa development) Ewing Marion Institute of Parasitology, McGill Kauffman Foundation, USA University, Canada • Dr Alexis Nzila (parasitology) Kenya Medical Research • Dr Susan Charman • Professor Andrew Hopkins Institute/Wellcome Trust (pharmacokinetics, (informatics) Division of Collaborative Research metabolism) Department Biological Chemistry and Drug Program, Kenya of Pharmaceutics, Victorian Discovery, College of Life College of Pharmacy, Monash Sciences, University of Dundee, • Dr Philip Rosenthal (biology, University, Australia United Kingdom medicine) San Francisco General Hospital, USA • Dr Gaik-Lean Chee • Dr Ivan Idea-Mensah (chemistry) Crompton Co./Cie, (medicinal chemistry) • Dr Rakesh Tuli (biology) Chemtura Company Research Department of Chemistry, Central Drug Research Laboratories, Canada University of Ghana, Ghana Institute, India • Dr Alan Cowman (molecular • Dr Collen Masimirembwa • Dr Michael Witty (drug biology, genomics), Walter and (drug metabolism and discovery, medicinal chemistry) Eliza Hall Institute of Medical pharmacokinetics) African Pfizer Animal Health, United Research, Australia Institute of Biomedical Science Kingdom and Technology (AiBST), • Dr Carlos Zanni (natural Zimbabwe products) Instituto Oswaldo Cruz, FIOCRUZ, Brazil

TDR BL3 • 2008 Report 31 BL3 Lead Discovery for Infectious Tropical Diseases Lead Discovery for Infectious Tropical Diseases

Helminth Drug Initiative • Dr Bertram Nwoke (helminths, Observers epidemiology) Imo State Task Force For both EDAC and the HDI Task University, Nigeria • Dr Graham Mitchell, chair Force, observers from several • Dr Yves Ribeill (medicinal (helminths) FOURSIGHT interested parties and stakeholders chemistry, industry) Scynexis Associates Pty Ltd, Australia are usually invited, including: Chemistry and Automation, • Dr Sanaa Botros • Bill and Melinda Gates USA (pharmacology) Pharmacology Foundation • Dr Vincent Titanji (helminth Department, Theodor Bilharz • European Union Research Institute, Egypt biology) University of Buea, Cameroon • Country and national institutes • Dr Clotilde Carlow of health (parasitology) New England • Dr Juerg Utzinger • African Programme for Biolabs Incorporated, USA (parasitology) Swiss Tropical Institute, Switzerland Onchocerciasis Control • Dr Kelly Chibale (medicinal (APOC) chemistry) Department of • Dr Michael Witty (helminth • Organisation for Economic Chemistry, University of Cape research and development) Cooperation and Development Town, South Africa Pfizer Animal Health, United Kingdom • International Federation of • Dr Timothy Geary (helminths) Pharmaceutical Manufacturers Institute of Parasitology, McGill and Associations (IFPMA) University, Canada • WHO’s Neglected Tropical Diseases department • WHO regional offices

32 TDR BL3 • 2008 Report Lead Discovery for Infectious Tropical Diseases BL3

Annex 3. Summary of BL3 activities and end-products for 2009

Overall objective: To facilitate and support the discovery of new drug leads and candidates for tropical diseases through networks and partnerships between pharmaceutical companies, academia and disease- endemic country (DEC) institutions

Components Deliverables and of objectives Proposed activities/milestones end-products

• Two leads/year • 5000 compounds screened/ • Compound acquisition, storage and management year • Manage ongoing screening and hit-to-lead activities • Two high-throughput screens • Identify new medicinal chemistry centres especially in DECs initiated/year 1. Lead for hit-to-lead projects • 50 confirmed hits/year identification • Develop a generic intellectual property (IP) strategy for • At least 5 ongoing hit-to-lead compound supply and medicinal chemistry activities projects/year • < 30% of hit-to-lead projects stopped early for lack of promise

• Lead optimization plan • Transfer leads to primarily to BL4 but also through other established for Chemtura 2. Lead partners for further optimization and development compounds for malaria and optimization including PPPs, pharma, innovative partnerships in the Chagas South • One lead transferred to partner/year

TDR BL3 • 2008 Report 33 BL3 Lead Discovery for Infectious Tropical Diseases Lead Discovery for Infectious Tropical Diseases

Components Deliverables and Proposed activities/milestones of objectives end-products

• TPPs developed for schistosomiasis, filariasis • Implement lead optimization for helminths through network and onchocerciasis. activities 3. Helminth • Additional funding for HDI • Establishment of minimally acceptable target product profiles Drug • Reach decision point on (TPP) building on the available generic TPPs Initiative emodepside as a drug • Identify new partners, especially animal health companies, for candidate (Dec. 2009) lead optimization and toxicology • Two drug candidates between 2010 and 2013

4. Drug • Continued curation and optimization of the drug target database • High-impact accessible target and • Advance diagnostics target prioritization and selection work publications fundamental • Promote the extension of the target portfolio and selection • Two targets supporting research work to vaccine discovery through other organizations HTS

• Managed portfolio of • Organize and attend meetings to promote innovation network projects • Coordinate drug discovery activities through network activities • Two fellows trained per like open source databases, publications, standard operating year in a part of drug 5. Steward- procedures and the HDI discovery ship and em- • Fellowships and training for scientists from developing countries • One meeting organized power-ment through North-South and South-South network activities to promote innovation activities • Promote natural products and traditional medicine as a source • Two scientists/institutions of leads in developing countries from developing • Promote medicinal chemistry and drug discovery activities in countries identified for Africa and other developing countries North-South and South- South partnerships

• Implement joint meeting of the EDAC and HDI Task Force 6. Project • BL3 portfolio reviewed • EDAC and HDI Task Force to review all projects and provide coordination • Recommendations strategic input to BL3 strategy and review implemented • Implement recommendations

34 TDR BL3 • 2008 Report Lead Discovery for Infectious Tropical Diseases BL3

Annex 4. Details of revision Annex 5. Responses to of business plan specific JCB and STAC requests on BL3 A major change that has occurred in the planned BL3 activities is the transitioning of the African The STAC recommendations from 2008 have been Network for Drugs and Diagnostics Innovation addressed in the various sections of the report, (ANDI) concept to BL4 and the closer alignment of but below is a summary of BL3 responses for easy BL3 and BL4 under one business line leader. This reference. is now also paving the way for the establishment of Asian and American ANDIs as part of BL4 activities. 1. BL3 was asked to survey the drug discovery landscape for infectious tropical diseases to identify gaps and TDR’s comparative advantage As presented in Fig. 1, BL3 has surveyed R&D activities, especially drug discovery, to identify gaps and new opportunities in support of TDR’s work in drug discovery and innovation. This information builds on the rationale presented in the BL3 business plan as well as on the report from the BioVentures for Global Health and is due to be published more widely. The creation of public-private partnerships (PPPs) such as the Medicines for Malaria Venture, the Global Alliance for TB Drug Development and the Drugs for Neglected Diseases Initiative as well as the Institute for One World Health, all focusing on drug development for a select number of infectious tropical diseases in the late 1990s and early 2000s, has led to an impressive portfolio of products in development for some of these diseases, especially malaria and tuberculosis. Despite this progress, recent reports have shown that PPPs are focusing primarily on taking available leads or drug candidates into the development phase of the value chain, with limited activity in the high- risk and innovative lead discovery process or in the translation of basic research into product leads

TDR BL3 • 2008 Report 35 BL3 Lead Discovery for Infectious Tropical Diseases Lead Discovery for Infectious Tropical Diseases

(Nwaka and Widdus, 2004). In addition, analysis of focus, but from the perspective of BL3, and by the drug discovery group of TDR between 2005 judging from the success of the network approach, and 2006, including a survey of the global screening it is evident that the advantages of this approach and early drug discovery activities (Pink et al. 2005, far outweigh its disadvantages. The network Nwaka and Hudson 2006), shows that there is a model is a better way forward in addressing lead significant gap in lead and drug candidate discovery discovery needs of multiple neglected diseases as it for infectious tropical diseases ranging from malaria saves money, reduces attrition and ensures greater to tuberculosis, leishmaniasis, trypanosomiasis and success. As exemplified by ANDI, the network helminthiasis. These analyses, coupled with broad model is supporting innovation in developing consultative and TDR committee meetings held countries. The availability of a coordinated in 2006 and 2007, have helped in the finalization screening network that utilizes strict compound of a focused business plan for lead discovery for progression and prioritization criteria makes it more infectious tropical diseases (BL3) as an area of need efficient to evaluate compounds across a spectrum where TDR has a strong comparative advantage. of disease assays in vitro and in animal models in The objectives, needs and opportunities, as well as vivo within a reasonable time frame. One potential TDR comparative advantages for drug discovery, are challenge is the very close coordination required clearly defined in the BL3 business plan approved for large networks, but this challenge can be by STAC and JCB (http://www.who.int/tdr/research_ overcome with more human and financial resources lines/bl3_fin.htm). that support the deployment of new collaborative tools to promote rapid data sharing/exchange and Indeed, through its innovative drug discovery communication. networks, BL3 is in a unique position to identify leads that will feed into the pipeline of other 2. Entry and exit points of screening downstream players, including PPPs and innovative partnerships in developing countries. In the area centres need to be clearly defined of helminths, where there is no independent PPP The selection and review of screening centres are pursuing product discovery and development, based on an established set of criteria implemented the work of BL3 extends into drug development through the EDAC review process. TDR has been through the Helminth Drug Initiative (HDI). The successful in the past two years in selecting new establishment of the HDI, initially focusing on centres like the CDRI in India and in terminating drug discovery for schistosomiasis, filariasis and protozoal screening at the London School of onchocerciasis, signifies a growing emphasis on this Hygiene and Tropical Medicine due to poor highly neglected research area. A recent publication performance. and analysis by Hopkins, Witty and Nwaka (Nature 449: 166-169, 2007) highlights the magnitude of 3. Additional strengthening of compound the drug discovery gap for neglected diseases while screening in DECs: special focus on stressing the potential of the network model for natural products and screening against filling the gap. helminths is recommended Some may argue that tackling drug discovery for As described above, BL3 has made a major effort multiple neglected tropical diseases signifies a lack in identifying additional screening centres in

36 TDR BL3 • 2008 Report Lead Discovery for Infectious Tropical Diseases BL3

developing countries in the past two years. The a) Leads for malaria, tuberculosis, contractual agreement between NovoNordisk and HAT, leishmaniasis, Chagas the National Center for Drug Screening (NCDS) in Shanghai, China, allows the transfer of a large For these diseases, where considerable external compound collection from NovoNordisk to the efforts for lead optimization and development NCDS for screening against TDR target diseases exist, BL3 aims to transition projects at or including tuberculosis. Three helminth screening before lead optimization phase to BL4 and other centres are in developing countries are now part of partners like PPPs. BL3 is continually seeking the the screening network: CDRI in India, University engagement of partners at the screening and hit to of Buea in Cameroon and TBRI in Egypt. In lead phases through financial and/or intellectual addition, TDR also provides support for work input into this risky phase of the drug discovery at the Kenya Medical Research Institute and the process. This would guarantee such partners a National Institute of Pharmaceutical Research and right of first refusal to take forward leads that Development in Nigeria on natural products. This emerge from BL3 for a disease or project. This trend of identifying additional screening centres concept is depicted in Fig. 5 (upper segment) and in developing countries will continue and is also possible partners are shown. Current collaboration helping support regional ANDI efforts. with MMV on a malaria hit to lead project exemplifies the approach where a PPP engages 4. Strategy for hand-off of leads and in hit to lead projects with a view to taking the drug candidates project into lead optimization and development. Clearly, hand-off of projects to partners is not as As shown in Fig. 5, BL3 is employing a two- simple as it sounds; any hand-off has to consider pronged strategy for the hand-off of leads and drug existing agreements and intellectual property candidates emerging from its activities. arrangements, including those with industry concerns on particular projects, for example, screening or specific compound agreements. In addition, the receiving partner has to commit to developing the product as a public good to be made widely available to DECs at appropriate pricing as required by WHO. An agreement would cover such hand-offs. Another but preferred avenue for hand-off is to transfer TDR-owned leads or drug candidates to suitable DEC R&D centres or partnerships, to help spur innovation in developing countries while helping to achieve sustainability and economic development. Examples include possible transfer of leads to BL4 or to African Network for Drug Discovery and Innovation.

TDR BL3 • 2008 Report 37 BL3 Lead Discovery for Infectious Tropical Diseases Lead Discovery for Infectious Tropical Diseases

b) Interface between BL3 and other Annex 6. Report of EDAC initiatives including BL6 (Fig. 5) (BL3 SAC) After discussions between BL3 and BL6 on the 1st Meeting of the Expert Drug Discovery Advisory product R&D for helminths, both the BL leaders Committee (EDAC 1) Geneva, 31 March to agreed that under the current resource scenario, 3 April 2008 (31 March–1 April – Kofi A. Annan TDR alone is not in a good position to successfully Conference Room (UNAIDS Bldg.); 2 April 2008 implement drug candidate transition into drug – WHO Library; 3 April 2008 – Salle G, WHO development. Neither BL3 nor BL6 is well- Main Building) resourced to undertake such “interface” activities (e.g. safety pharmacology, pre-formulation, I. Attendance: The meeting was attended by the formulation, animal toxicology, scale-up chemistry). following: 1) Expert Drug Discovery Advisory Committee (EDAC) members, 2) Principal While BL3, through the Helminth Drug Initiative Investigators (PIs) of the various projects within (HDI), requires considerable funding for lead the Drugs Discovery Network, 3) Consultants, optimization which is currently not available, BL6 4) Observers and 5) Business Line 3 (BL3) team. is not in a position to do pre-clinical development on its own without considerable resources. Possible II. Agenda and meeting format. The meeting format scenarios to fill this gap are: 1) in the short term was as follows: introduction of the TDR New BL3-identified development candidates belonging Strategy, BL3 activities, role of EDAC, review of to pharma are promoted for a TDR BL6/pharma ongoing/new projects within the Drug Discovery joint development strategy (e.g. moxidectin model). Network and strategic discussions on BL3 2) HDI gets significant funding support in the activities. Progress reports were presented by short term to cover preclinical development and the respective PIs of the various projects. Each then interfaces with BL6 as appropriate; and 3) presentation was followed by an open discussion the third and most promising option is through and an EDAC closed session. For each project/ BL4 with its extensive promotion and support of proposal, a summary of the EDAC discussion developing country R&D innovation platforms was prepared by the assigned discussant. This such as ANDI that cover discovery, pre-clinical and summary contained specific recommendations clinical development as well as regulatory capacity for the project and justification for approving or may offer a longer-term sustainability. The capacity rejecting a proposal, and/or recognition of major to do clinical development in Africa established strengths or weaknesses of a project. through TDR and other organizations should be III. EDAC evaluation criteria. The reports and used to promote the above R&D model. Several proposals were grouped as follows: A) Industry screening hits owned by TDR are now available and collaboration, B) Compound screening centres, could benefit from this approach if successful. C) Drug Target Database Network, D) Medicinal chemistry centres, E) DMPK network, F) New medicinal chemistry centres, and G) Other projects. The projects/proposals were ranked by a voting score based on the following criteria:

38 TDR BL3 • 2008 Report Lead Discovery for Infectious Tropical Diseases BL3

1. Compound screening centres/DMPK centres participants to the meeting. He presented an • Progress to date overview of the new TDR strategy on behalf of Dr Robert Ridley, TDR director. This was • Throughput/turn-around time: number of followed by the EDAC chair, Dr. Frank Douglas, compounds screened, type of assays, data leading everyone in the introductions. Dr. reporting (considering staff time and budget) Douglas then presented the meeting objectives • Data quality/reporting: reproducibility, use of and provided clarity regarding the role of EDAC. agreed protocols, data results Finally, Dr. Nwaka presented a report on the • Effective collaboration: good communication, progress of BL3. priority given to TDR compounds The discussion highlights from the presentations • Future work plan including how identified by the PIs for the industry collaborations and challenges were resolved Compound Screening Centres are summarized below. 2. Drug Target Database Network Industry collaborations: TDR collaboration with • Progress to date: prioritization of targets for TDR Pfizer, Merck-Serono and Chemtura target diseases, curation • Collaboration moving forward with several • Clarity of future plans and strategy: actives in the protozoan and helminth screens incorporation of new data, how identified • Need to prioritize compound actives to progress challenges will be resolved, sustainability work towards selection of leads of database and curation, and publications • Potential synthesis resource limitation and need and dissemination of information about the for partnership in downstream lead pursuit database (Chemtura) 3. Medicinal chemistry centres (industry and • Go/no-go decisions defined for HTS and academia) medicinal chemistry projects (Merck-Serono) • Progress to date • Need for target validation (Merck-Serono) • Clarity of chemistry rationale • Collaboration will require improved turn-around • Throughput/data quality: number of times for screens in support of medicinal chemistry compounds synthesized, SAR • Challenges identified in post-doc selection and • Staff time devoted to TDR project training (Pfizer and Merck-Serono) • Effective collaboration/reporting: good • Direct interaction with screeners (by Pfizer communication and Merck-Serono) viewed as valuable for the collaboration • Future work plan, including how identified challenges were resolved • Significant number of hits and potential leads available from collaboration, including in vivo actives for protozoans and helminths (Pfizer and 4. New medicinal chemistry centres Chemtura) • Track record and expertise in synthetic chemistry • Pfizer is encouraged to focus the work of TDR • Ability to guide post-doctoral chemists funded post-doc chemists on optimization • Availability of basic infrastructure for synthetic/ of hits emerging from the screens instead of medicinal chemistry literature leads • Access to basic parasite screens an added Compound Screening Centres advantage • STI – reached maximum screening capacity IV. Highlights of the Meeting: Day 1: The meeting in reporting year; turn-around time affected; opened with an Introduction session. Dr. requested for HEOS access on screens done at Solomon Nwaka, BL3 manager, welcomed the other screening centres

TDR BL3 • 2008 Report 39 BL3 Lead Discovery for Infectious Tropical Diseases Lead Discovery for Infectious Tropical Diseases

• UA – turn-around time affected by initial four- collaborations and determine what needs to be dose testing; may have to consider single-dose taken forward by company in-house and what testing to improve throughput and turn-around needs to be handed over to TDR time; expand use of HEOS for better interaction 4. Greater interaction and communication between between screeners and medicinal chemistry medicinal chemistry and screening centres centres • LSHTM – underscored the benefit of biologist- 5. Define lead and candidate target profiles chemist communication; presented data 6. Ensure TDR-funded post-docs in industry are on a promising new screening assay using contributing significantly to the collaboration schistosomula with higher throughput and 7. Despite some important recent initiatives better turn-around time (recommendation to – including those by National Institutes and aim for a 384 well assay); further validation of Gates Foundation, as well as some companies schistosomula assay recommended by EDAC. – major gaps remain in TB drug discovery. BL3 Other recommendations by EDAC: In vitro IC50 is encouraged as appropriate to play a catalytic determination may now follow after compound role through targeted activities such as the triaging, possibility of using LSHTM for TDR Drug Target Database and by promoting mechanistic studies (including RNAi studies) partnerships in this area through relevant • TBRI – data from screens at LSHTM and TBRI strategic partnerships; for example, ongoing are comparable; focus on using one strain collaborative discussion with NovoNordisk and (Egyptian strain); single-sex worm killing the National Drug Screening Centre in Shanghai, as parameter for in vivo follow-up may be China, which includes TB screens. In these important; EDAC suggestion to use TBRI centre instances BL3 is encouraged to interface with for routine schisto vitro and vivo screens while other relevant players in the TB area willing to schistosomula assay development is ongoing at support the activities. LSHTM 8. Define end of value chain in BL3: hand-off/ • NPIMR – presented data on vitro/vivo actives progression of candidate compounds. (particularly from Pfizer and Chemtura); significantvivo data from Emodepside and Day 2: Discussion highlights from PIs’ Clorsulon; Clorsulon currently being tested presentations for the Drug Target Database in the Brugia vivo model; use of cattle for in Network, Medicinal Chemistry Network and vivo evaluation not endorsed by EDAC, EDAC DMPK Centres recommended that BL3 define next steps for Drug Target Database Network recognized by Emodepside and re-contact Bayer EDAC as a valuable resource in drug discovery and • New screening centres – SOPs currently commended BL’s 3 catalytic role in establishing this in place, vitro/vivo activity criteria defined, network; need to address sustainability and curation flowcharts for compound evaluation prepared, and how to transition management of the database access to HEOS database provided, initial to the next stage and to consider other partners and batch of compounds sent to University of Buea external funding. (oncho vitro/vivo), CDRI (Brugia vitro/vivo) and Medicinal Chemistry Network and DMPK University of Washington (protozoan screens Centres. Good progress has been achieved in the vitro/vivo) various hit to lead programmes. Communication Strategic issues arising from day 1 between DMPK and medicinal chemistry centres 1. Need to improve assay turn-around time crucial so that DMPK centres can better address the needs of med chem centres and propose better tests; 2. Prioritization of screens for med chem projects identify complementary roles for DMPK centres 3. Prioritization of actives from industry (AiBST and Monash)

40 TDR BL3 • 2008 Report Lead Discovery for Infectious Tropical Diseases BL3

Strategic issues arising from day 2 Natural Products Research at KEMRI: EDAC 1. Closer interaction between screeners, med chem recommended continued funding for 2008 and DMPK centres encouraged with a caveat that KEMRI be integrated into the Drug Discovery Network and work along clear 2. Planned joint meetings for screeners, med chem deliverables. Current 2008 funding is provided by and DMPK centres to discuss common issues and the RCS unit of TDR, but a subcommittee of the share knowledge. Select EDAC members to be EDAC will review the programme and suggest ways invited to the meeting as appropriate. of moving forward for next year. 3. Integrate the concept of teams within network approach to drug discovery for better efficiency New medicinal chemistry centres. EDAC (modules within network of knowledge-sharing discussions on ranking of proposals for new nodes) medicinal chemistry centres were based on the following: capability, capacity, budget/cost, strategic 4. Strategic investment in centres with different fit and delivery focus as well as the need to identify focuses: lead generation vs. optimization and engage more centres from disease-endemic 5. IP strategy for TDR compounds countries, especially from Africa. 6. Need to leverage additional external resources for Strategic issues arising from day 3 the drug discovery network 1. Propose HEOS as an IT solution to improve Day 3: The discussion highlights from the management process and communications within presentation on the HEOS database are summarized Drug Discovery Network below. Discussions on Day 3 were also focused on the review of other projects (including compound storage 2. Knowledge/info-sharing is important across at RCC, the proposal on natural products at KEMRI networks (screeners, med chem and DMPK) and proposals for new medicinal chemistry centres 3. Need to leverage external funding sources and other ongoing projects identified as external to Day 4: The morning was spent on finalizing EDAC the TDR drug discovery network). The remainder conclusions and recommendations (see below). The of day 3 was spent finalizing EDAC decisions and TDR Compound Bank and Tropical Disease SARfari funding recommendations on all projects/proposals. Database were discussed, and synergy with the Drug HEOS database was recognized by EDAC as the heart Target Database was highlighted. The meeting was of knowledge-sharing within the Drug Discovery adjourned at noon. Network and as such should be exploited to its V. Conclusions and recommendations full potential. Scynexis, developer of HEOS, had leveraged TDR collaboration to include other users EDAC commended the BL3 leader and the rest so that the HEOS system is also used at DNDi and of the team for excellent performance in the discussion ongoing with MMV; Scynexis has also implementation of the Drug Discovery Network secured free access to key R&D software from sources concept. EDAC further conveyed its recognition of such as Accelrys, for neglected disease projects. BL3’s catalytic role in new initiatives (especially the HEOS (for neglected diseases) may have to explore TDR Drug Target Database) and encouraged TDR to shifting to being a “not-for-profit” initiative to ensure leverage further support for these new initiatives by sustainability and to access funds from donors. identifying more partners. RCC was recommended by EDAC to be retained EDAC made special note of BL3’s significant in the interim; TDR was encouraged to seek productivity within a short time, particularly alternative compound archiving companies with in consideration of limited funding. It further additional infrastructure and capabilities to better encouraged the team to build upon the impressive manage compound collection and develop the TDR achievements and take the lessons learned from the Compound Bank idea. network collaborators and partners to the next level of focused activities through improved management operations.

TDR BL3 • 2008 Report 41 BL3 Lead Discovery for Infectious Tropical Diseases

Specific recommendations from EDAC were as example, ongoing collaborative discussion with follows: NovoNordisk and the National Drug Screening Centre in Shanghai, China, which includes TB 1. Implement team concept across networks and screens. In these instances BL3 is encouraged intensify communication. Transition from to interface with other relevant players in the service concept to teams with closer interaction TB area willing to collaborate and support the across networks (screeners, medicinal chemistry/ activities. DMPK) 10. Support existing medicinal chemistry centres. 2. Design a HEOS-based operational plan for Encourage Ohio State University to apply compound distribution/tracking and data/ for funding from the Gates Foundation for knowledge sharing. Continue to invest in HEOS continuation of project. Support the selected and encourage other investment strategies new medicinal chemistry centre in Brazil and (including interaction with other PPPs) to ensure others in developing countries depending on sustainability as an important knowledge- funding availability. sharing resource for the Drug Discovery Network 11. Recommend a new call for applications for medicinal chemistry centres based in Africa. 3. Maintain present industry collaborations and Proposed African Network for Drug Discovery with the help of EDAC (as appropriate) recruit and Innovation welcomed and select EDAC a new stream of industry collaborators and members invited for the October meeting in leverage collaboration with IFPMA (International Abuja. Federation of Pharmaceutical Manufacturers and Associations) and other industry associations. 12. EDAC-appointed subcommittee to evaluate natural product centre in Africa to recommend 4. Consider support for post-doc training at next steps Chemtura 13. Continued support and additional funding 5. Plan improvements in logistics of compound recommended for current DMPK centres (AiBST bank storage and management and Monash). Encourage closer alignment of the 6. Maintain present screening centres and two DMPK centres in support of hit-to-lead and strengthen participation of new centres into the lead optimization activities network 14. Seek an alternative partner specialized in 7. Rationalize the use of screening centres and compound archiving that can better deliver identify a strategy for optimizing use and on the requirements for the storage and improving on turn-around time (higher management of TDR’s compound collection; throughput primary screens vs. focused screens develop further the idea of the TDR Compound in support of medicinal chemistry) Bank. Ongoing discussion with ASDI, BioFocus and academic centers should be expedited 8. Promote continued improvement and development of the TDR Drug Target Database 15. Explore the establishment of a TDR/EDAC while also encouraging TDR to identify new Award for excellent achievements in network partners for possible hand-off and for longer- projects and training term sustainability VI: Next EDAC Meeting: 30–31 March & 9. Major limitations still remain in TB Drug 1 April 2009. Discovery despite some significant recent initiatives. BL3 is encouraged as appropriate to play a catalytic role through targeted activities such as the TDR Drug Target Database and by promoting strategic partnerships; for

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For research on diseases of poverty

TDR/World Health Organization 20, Avenue Appia 1211 Geneva 27 Switzerland Fax: (+41) 22 791-4854 [email protected] www.who.int/tdr

The Special Programme for Research and Training in Tropical Diseases (TDR) is a global programme of scientific collaboration established in 1975. Its focus is research into neglected diseases of the poor, with the goal of improving existing approaches and developing new ways to prevent, diagnose, treat and control these diseases. TDR is sponsored by the following organizations:

World Bank