1. 1 © The Liverpool School of Tropical Medicine Accelerating Anti-infective Drug Discovery: Lessons from ten years working in PDPs STEVE WARD November 2013

2. 2 © The Liverpool School of Tropical Medicine The Product Development Landscape Medicines for Malaria Venture (MMV) Aeras Global TB Vaccine Foundation The CD4 Initiative Drugs for Neglected Diseases Initiative (DNDi) Foundation for Innovative New Diagnostics (FIND) International Aids Vaccine Initiative (AVI) Infectious Disease Research Initiative (IDRI) Institute for OneWorld Health International Partnership for Microbicides Innovative Vector Control Consortium (IVCC) Meningitis vaccine Project Malaria Control and Evaluation Partnership in Africa (MACEPA) at PATH Paediatric Dengue vaccine Initiative (PDVI) Sabin Vaccine Institute TB Alliance

3. 3 © The Liverpool School of Tropical Medicine The role of academia Basic and applied anti-infective research exists within – Academia – The Armed Services Screening and clinical experience exists within – Academia – Tropical Countries Public health awareness exists within – Academia – Tropical Countries Domain Specific expertise no longer strong within pharma? BUT Essential for development expertise and disciplined decision making

4. 4 © The Liverpool School of Tropical Medicine MMV as an exemplar Non-profit ‘product development partnership’ established 1999 in Geneva Mission: Discover, Develop and Deliver safe and effective antimalarials >90% of all projects have significant academic involvement Strong Industry role and mentorship Largest-ever pipeline of antimalarial drugs with over 50 projects from Discovery to Registration Two products launched, two products submitted Funded by Foundations, Governments, Companies, Individuals Nine pivotal phase III in three years: 11 000 patients

5. 5 © The Liverpool School of Tropical Medicine It has been a success Global Antimalarial Portfolio, 3Q 2013 Research Lead optimisation RegistrationPhase IIaPhase IIb/III In registration Development Patient exploratory Patient confirmatory Phase IV Approved* APM PreclinicalPhase I Translational Preclinical Human volunteers 1 Project Novartis Aminopyridines UCT 4 Projects GSK KAE609 Novartis OZ439/PQP (Monash/UNMC/ STI) ELQ-300 (USF/ OHSU-VAMC ) 21A092 (DrexelMed/UW) KAF156 Novartis DSM265 (UTSW/UW/ Monash) Whole cell leads AstraZeneca Tafenoquine GSK P218 DHFR ( Biotec/Monash/ LSHTM) 2 Projects Liverpool STM/Liverpool Uni Pyronaridine- Artesunate Paediatric Shin Poong Dihydroartemisinin- Piperaquine Paediatric Sigma-Tau Orthologue Leads Sanofi Heterocycles Dundee Sulfadoxine Pyrimethamine + Amodiaquine Guilin MMV390048 (UCT) dUTPase inhibitors Medivir Cell based lead Merck Serono Imidazolidinediones WRAIR RKA182 Liverpool STM NPC-1161-B University of Mississippi BCX4945 Biocryst/Albert Einstein College of Medicine SAR116242 Palumed SAR97276 Sanofi Ferroquine Sanofi Fosmidomycin Piperaquine Jomaa Pharma GmbH Methylene Blue AQ Uni. Heidelberg AQ13 Immtech Rectal Artesunate MMV/WHO-TDR Artemisone UHKST Antimalarial Actelion DF02 Dilafor CDRI 97-78 Ipca N-tert butyl isoquine Liverpool STM/GSK Co-trimoxazole Bactrim Inst. of Trop. Med. Artemisinin Naphthoquine KPC Arterolane/PQP Ranbaxy Artemether sub- lingual spray ProtoPharma Ltd Pyrazoles DrexelMed/UW DHODH UTSW/UW/Monash Oxaboroles Anacor SJ557733 St Jude/Rutgers Artesunate Mefloquine Cipla/DNDi Artesunate for injection Guilin Artemether- Lumefantrine Dispersible Novartis Pyronaridine- Artesunate Shin Poong Dihydroartemisinin- Piperaquine Sigma-Tau Artesunate Amodiaquine Sanofi /DNDi Artemether- Lumefantrine Novartis 1 2 6 7 3 4 5 * First approval by WHO Prequalification, or by regulatory bodies who are ICH members or observers 8 4 5 9 10 OZ439/FQ Sanofi Azithromycin chloroquine Pfizer Non MMV Included in MMV portfolio post registration

6. 6 © The Liverpool School of Tropical Medicine Define What You Want Target Candidate Profiles (TCPs) define a stringent set of biological attributes to select and prioritize NCEs TCP1: Fast Parasite Clearance SERCaPSEC Artemisinin Gametocytocidal activity Hypnozoitocidal activity *Minimum Parasiticidal Concentration **Delivering a molecule that will remain in human blood for as long as mature gametocytes circulate is extremely challenging in the absence of a rapid gametocytocide; therefore, vector-stage parasite killing is seen as a desirable rather than critical activity TCP Desirable Attributes Current Gold Standard Critical Attributes TCP2: Long Duration TCP3: Transmission Blocking/ Relapse Prevention TCP4: Chemoprotection Minimum 99.9% parasite clearance over 48 hours >6 log total parasite reduction Time > MPC* critical >80% ACPR Day 28 monotherapy Delivers >95% ACPR combined with TCP1 Gametocytocidal activity Hypnozoitocidal activity Liver schizontocidal activity Slow killer (cannot be used as treatment) Supports 1x/month use (min.: 1x/week) High safety TCP3a: Hypnozoitocidal activity without G6PD liability TCP3b: Gametocytocidal activity Vector-stage activity** Vector-stage activity to deplete mosquito reservoir Orthogonal MoA to minimize resistance development to drugs used for treatment 4-aminoquinolinesPrimaquine Atovaquone/ Proguanil Mefloquine TPP

7. 7 © The Liverpool School of Tropical Medicine The drug discovery agenda: a catalyst for biological research Erythro cyte IndustryAcademia P. yoelii/berghei liver stage assay GNF Novartis/ UCSD, USA In vitro blood stage activity Swiss TPH, Switzerland & Eskitis, Australia Membrane feed assay Imperial College, UK P. cynomolgi hypnozoite assay BPRC, Netherlands Parasite Reduction Rate in vivo hu-SCID model GSK Tres Cantos, Spain Gametocycte and gamete formation assays Griffith University Australia and Imperial College UK Resistance risk assessment Columbia University, USA Gametocycte assay GSK Tres Cantos, Spain Delves M, et al., 2012 The activities of current antimalarial drugs on the life cycle stages of plasmodium PLoS Med. 9 :e1001169. Membrane feed assay TropIQ, Netherlands GSK, Tres Cantos

8. 8 © The Liverpool School of Tropical Medicine Phenotypic Screening High Throughput approaches to the whole parasite Screens of pharmaceutical collections (Novartis, GSK, Genzyme, sanofi aventis, Pfizer and AZ) completed Over 6M compounds screened with >25’000 actives <1 µM ~19,000 compounds inhibiting parasite growth published online! https://www.ebi.ac.uk/chemblntd

9. 9 © The Liverpool School of Tropical Medicine 9 MMV’s OPEN ACCESS MALARIA BOX Launched 19 th of December 2011 FREE resource to catalyse research and drug discovery in malaria and neglected tropical diseases In return, recipients agree to SHARE results with the malaria community

10. 10 © The Liverpool School of Tropical Medicine 10 Is there a role for Open Source Drug Discovery? M Todd U Sydney Australian Research Council/MMV funded Fund 1 postdoc. in M Todd lab U Sydney Everything posted on web - Anyone can contribute Open Project Meetings – Anyone can dial in + YouTube Understanding of OSDD Strengths and Issues

11. 11 © The Liverpool School of Tropical Medicine Challenges to translational infection research Lack of Centre/s of Excellence in Infection Translation (a variant on PDPs) Agenda setting/TCP/TPP Training/mentoring for translational Science To support the community not Just the Institution Insufficient volume of activity in single institutions Avoid replication of enabling technologies/platforms Rigorous transition timelines and milestones Need for Industry Mentors (RSC/efpia/IMI) Lack of peer recognition of translational Science REF exercise Funding Pre candidate selection Technology platforms

12. 12 © The Liverpool School of Tropical Medicine Opportunities in translational infection research Rapid advances in infection biology International focus and the possibility for coordination Funding Industry engagement Commitment to pre-competitive collaboration Access to library’s/ technology platforms / know how Regulatory pathway Commercial incentives Engagement with SME’s (spin ins and spin outs)