In MMV’s short 10 year history there have been numerous challenges that have shaped our development. These challenges – overcome in the true MMV spirit of tenacity and determination – are reflected by our achievements detailed in this book. In this brief period, MMV has blossomed into a successful and multi-skilled organization that has proved to be the leading PDP at the fore- front of the fight to defeat malaria.

Lynda, Baroness Chalker of Wallasey, Chairman of the Board

This year, we are proud to celebrate our 10 t h anniversary, and also the culmination of several years work with the launch of our first medicine – Coartem ® Dispersible – especially formulated for children. As we move forward, our sights are now firmly set on the ultimate goal of malaria eradication. Alongside our partners we will con- tinue to discover and develop the next generation of affordable and effective medicines, and ensure their availability to vulnerable people the world over. The next decade will surely be as amazing as the last !

Chris Hentschel, President and CEO

1999 1st call for proposals focuses on drug discovery to target Plasmodium falciparum. Gro Harlem Brundtland Results officially launches MMV 100 proposals: 6 approved on 3 November under the Portfolio status umbrella of the WHO Special 6 projects: 3 exploratory, 3 discovery Program for Research and 0 projects terminated Training in Tropical Diseases ( TDR ).

MMV adopts the mission to Discover and Develop new effective and affordable antimalarials.

MMV sets out with initial seed finance of USD 4 million from the Governments of Switzerland, the UK ( Department for International Development ) and the Netherlands ; The World Bank ; and Rockefeller Foundation.

2000 Call for proposals None Results N/A Portfolio status 6 projects: 3 exploratory, 3 discovery 1 project terminated

MMV recruits its first team of two, including Dr Chris Hentschel, Chief Executive Officer. Initially housed in the TDR offices, MMV rapidly becomes an independent foundation under Swiss law, and takes up permanent residence in the International Center Cointrin, Geneva.

MMV establishes its first Dame Bridget Ogilvie alliance with industry ( Glaxo chairs MMV’s first Board Wellcome ) and academia meeting and Dr Simon ( University of Bristol and Campbell chairs the first London School of Hygiene Expert Scientific Advisory and Tropical Medicine ) to Committee meeting, both work on the enzyme lactate held in Geneva. dehydrogenase. This new alliance is a huge turning MMV adopts its first business point for MMV – opening up plan, on the strength of a new world of possibilities which the Bill & Melinda through access to the Gates Foundation awards pharmaceutical industry’s its first major donation of chemical and natural product USD 25 million over 5 years. libraries. Moreover, it lays the foundation for fruitful ExxonMobil Foundation relationships with Pharma makes its first pledge. in the future.

2001 2nd call for proposals focuses on development and discovery. Results 84 proposals: 7 approved Portfolio status 6 projects: 3 exploratory, MMV holds its first 3 discovery 0 projects terminated Stakeholders’ meeting at the Olympic Museum MMV Project of the Year 2001 goes to synthetic in Lausanne. peroxides. Partners : University MMV discusses the idea of Nebraska/Monash of a novel concept – the University/Swiss Tropical Institute/Roche mini-portfolio – with legal counsel ( Stephen Whybrow, These compounds hold the potential to provide of Cameron McKenna ). a synthetic alternative to The mini-portfolio will allow the artemisinin derivatives, the efficient distribution and therefore a medicine of resources within a group free from the vagaries of of discovery projects held agricultural production. by MMV and an industrial partner.

By the end of 2001 the rapidly expanding team comprises the CEO, Human Resources and Administration Manager, Chief Scientific Officer, Chief Financial Officer, Personal Assistant to the Management Team and a Delhi-based Director of International Operations.

2002 3rd call for proposals focuses on discovery, development and natural products. Results 106 proposals: 7 approved Portfolio status 13 projects: 3 exploratory, 4 discovery, 5 preclinical, 1 clinical development 1 project terminated MMV Project of the Year 2002 goes to protein farnesyltransferase inhibitors. Partner : University of Washington TDR, MMV and Shin Poong The project has Pharmaceutical, Co. Ltd. progressed rapidly from sign an agreement to lead identification to develop pyronaridine- optimization. artesunate ( Pyramax ® ), just as the potential combination therapy embarks on preclinical development.

The Wellcome Trust donates £ 1.8 million over 5 years. MMV is honoured to be the first PDP to receive a Wellcome Trust grant.

2003 Call for proposals None Results N/A Portfolio status MMV and Novartis sign 16 projects: 1 exploratory, an agreement to make 6 discovery, 4 preclinical, a paediatric formulation 5 development 3 projects terminated of Coartem ® ( artemether- lumefantrine ) – Coartem ® MMV Project of the Year 2003 goes to Dispersible. 4 ( 1H ) - pyridones. Partner : GlaxoSmithKline The project has moved rapidly – within 1 year – from discovery to development. The Gates Foundation pledges its continued support with USD 40 million over 5 years. This allows MMV to release the brakes previously applied to some projects and significantly accelerate others.

New 3D logo highlights the three components of MMV’s mission: Discover, Develop, Deliver.

MMV updates its business plan to incorporate the need to ensure access to products emerging from the project pipeline.

MMV and GSK sign the first mini-portfolio agreement, comprising four promising discovery projects.

2004 4th call for proposals focuses on populating the portfolio with promising projects. Results 81 proposals: 5 approved Portfolio status 21 projects: 3 exploratory, 8 discovery , 4 preclinical, 6 development 2 projects terminated MMV Project of the Year 2004 goes to the falcipain project focusing on cysteine proteases. Partner : University of California San Francisco The project team has made impressive progress. First children’s drawing contest takes place at the first ever Stakeholders’ meeting to be held in an African capital – , .

President Joacquim Chissano of Mozambique delivers a poignant keynote speech at the Stakeholders’ meeting in Maputo, stating : “ One day our children will be born free from malaria. With our determination and perseverance, that future is attainable ”.

USAID and BHP Billiton pledge their support to MMV. MMV joins hands with Sigma-Tau Industrie Farmaceutiche Reunite, Oxford University and Holley Pharmaceutical Co. Inc. to develop a high- quality medicine to treat uncomplicated malaria – dihdroartemisinin-piperaquine (Eurartesim ®).

2005 The R&D agenda continues Call for proposals to evolve, addressing None other aspects of malaria Results control, for example, N/A prophylaxis, Plasmodium Portfolio status vivax, severe malaria and 21 projects: 12 discovery , transmission blocking drugs. 2 preclinical, 7 clinical The pipeline shows signs 3 projects terminated of blossoming, with three MMV Project of Year projects in the final phase 2005 goes to pyronaridine artesunate ( Pyramax ® ). of clinical development. Partner : Shing Poong 2005 is MMV’s 5th Pharmaceutical Co. Ltd anniversary. Serendipitously, The project progressed in Roman numerals the year rapidly from Phase I into 2005 is written as MMV. Phase II of the clinical development trials. Significant new funding comes in from the Wellcome Trust ( £ 10 million over 5 years ), UK DIFID ( £ 10 million over 5 years ) and BMGF ( USD 100 million over 5 years ).

The Moran et al report, ‘ The New Landscape of A Burkina Faso clinical Neglected Disease Drug trial site is the first to enroll Development’, funded a patient for a clinical by the Wellcome Trust, development project and positions MMV as a first to receive MMV support leading public–private for capacity building. partnership.

An independent review of MMV by major donors and Stakeholders states, “ MMV has made tremendous progress, clearly ahead of its predicted milestones, towards achieving its goals. It has successfully mobilized academic institutions and pharma- ceutical companies in highly productive partnerships.”

2005 Call for proposals None Results N/A Portfolio status 21 projects: 12 discovery , 2 preclinical, 7 clinical 3 projects terminated MMV Project of Year 2005 goes to pyronaridine artesunate ( Pyramax ® ). Partner : Shing Poong Pharmaceutical Co. Ltd The project progressed rapidly from Phase I into Phase II of the clinical development trials.

Discover, develop, deliver : it takes between 13 –15 years to discover

Preclinical development and candidate selection Time : 1.5 years Lead identification A drug candidate’s predicted Time : 1–2 years safety in man is determined The development of an Lead optimization via in vitro and in vivo pre- entirely new medicine Time : 2–4 years clinical tests, which assess begins with a broad array Lead compounds – once antimalarial activity and of compounds, each tested identified – are optimized until toxicology, as well as the for their potential antimalarial they have the ideal properties feasibility of manufacturing activity via a range of to be a drug candidate. at low cost. These data form screening methods, such Compounds must not only the basis of the decision as high-throughput screening. demonstrate antimalarial to start clinical trials in man. Compounds that demonstrate activity but must have antimalarial activity are pharmacological properties initially designated as ‘hits’. in line with our target product The antimalarial activity and profiles. Further chemical drug-like quality of these modifications are made to hits must be improved and improve the lead molecule’s confirmed through chemical drug-like properties, including manipulations and repeated its ability to be appropriately in vitro and in vivo studies, absorbed, distributed, in order to fit the required metabolized and excreted by profile. Only then can the the body – whilst maintaining compounds be upgraded or even improving it’s from ‘hit’ to ‘lead’ status. antimalarial activity.

Combining compound libraries Demonstrating the unique and drug discovery expertise power of public–private from both academic and partnerships in drug discovery, One of our preclinical projects, industrial partners, one of one of our partners, Novartis, from a collaboration originally MMV’s lead identification has completed an intense led by scientists at BIOTEC projects is led by scientists screening effort of both their Thailand, aims to develop at the University of South synthetic and natural product a curative antimalarial drug Florida. The team is under- compound libraries. As one active against the drug- taking a huge screening effort of the largest pharmaceutical resistant strains of malaria in search of the next elusive companies in the world, currently emerging in compounds to be designated Novartis has the capacity Southeast Asia and around with ‘hit’ status. The project required to power a project the world. The project team is utilizes the chemical diversity through the entire drug targeting the malaria parasite’s of natural product extracts discovery and development dihydrofolate reductase from Antarctica to Southeast process. From this latest (DHFR) enzyme in its naturally Asia as the primary source screening effort, around occurring and resistant forms. of compounds. This strategy 6,000 hits were identified Blocking the activity of this maximizes the potential of and confirmed. To date, enzyme compromises the discovering novel chemistry two of these compounds parasite’s ability to proliferate, – directly from nature. have progressed through thereby leading to its eventual lead identification and been demise. The lead DHFR- optimized. These two targeting compound from the successful compounds are project is now being prepared now undergoing evaluation for future clinical studies. as potential drug candidates. Clinical Phase II Time : 1–2 years Once the drug has been established to be safe in man at a potentially effective dose, it is ready to be tested for Clinical Phase I efficacy in addition to safety in malaria patients. The aim Registration and launch Time : 1 year of this stage is to attain ‘proof of concept’, which pro- This is the first opportunity Time : 1 year vides the first evidence that the treatment is efficacious Once a drug has been to examine the safety of in humans. Furthermore, it allows for the determination of proven to be safe and a potential new medicine in precisely what the optimum treatment and non-toxic dose efficacious in Phase III trials, man. A small group of healthy should be. Only then can the drug be tested in a larger the preclinical, clinical and human volunteers receive Phase III trial. manufacturing data are an initial dose of the drug, combined and submitted which has been deemed to for stringent regulatory be safe in preclinical studies. approval. All MMV-supported Provided no unexpected medicines are submitted for adverse events occur, the the most rigorous regulatory dose is then escalated, at approval in addition to WHO graded intervals, up to a prequalification. This ensures level at which efficacy can that all our medicines meet be expected. All the while, the highest national and patients are continuously international standards of monitored in order to detect quality. The new medicine can potential adverse events then be marketed and sold in at the earliest opportunity. the country or countries that have approved it.

Artemisone, a potent artemisinin derivative, identified by Coartem ® Dispersible the Hong Kong University of Science and Technology, is one (artemether-lumefantrine) was example from the MMV portfolio of a project in Phase II trials. developed in partnership with It is hoped that artemisone will prove to be a vital tool Novartis specifically for children to treat patients who have exhibited malaria resistant to – the most vulnerable victims current drug therapy, such as those recorded in Cambodia. of malaria. The new medicine was approved by Swissmedic in December 2008 and launched in February 2009. Clinical Phase III Coartem Dispersible is the Time : 3 years culmination of over 4 years The definitive test of a drug’s safety and efficacy occurs in of dedicated work and is the form of a randomized, controlled Phase III trial in a large a huge MMV success story. patient group. The new medicine is compared head-to-head Fully synthetic peroxides provide with the best currently available treatment. an exciting prospect as future antimalarials, since ; by definition, Two new medicines that have recently completed successful they are not reliant on the Phase III trials include: Eurartesim ® (dihydroartemisinin- vagaries of agriculture for their piperaquine) developed in partnership with Sigma-Tau Pharma- production. In concert with the ceuticals and Pyramax ® (pyronaridine-artesunate) developed University of Nebraska, Monash with Shing Poong Pharmaceutical Co. Ltd. Eurartesim has now University, and the Swiss Tropical been submitted for regulatory approval. It provides a once- Institute, MMV has supported a-day therapy and is the best ACT currently in development this project since its inception. to provide protection against new infections. Pyramax is also Although, this chemical class exciting, as it has been proven to be highly effective against holds the potential to provide both P. falciparum and the blood stages of P. vivax malaria. a fast-acting and effective antimalarial, selected candidates also have a relatively long half life and thus could provide a reduced treatment regimen. and develop a new antimalarial ready to be delivered to those in need

2006 5th Call for proposals focuses on discovery and natural products. Results Former Irish President 105 proposals: 7 approved Mary Robinson announces Portfolio status a donation of o 9 million 39 projects: 29 discovery, over 3 years from 3 preclinical, 7 clinical development the Irish government at 7 projects terminated the Stakeholders’ meeting MMV Project of the Year in Zambia. The newly created Access 2006 goes to next generation and Delivery department OZ ( synthetic peroxide). transforms MMV Partners : University into a 3D organization – of Nebraska; Monash University; Swiss Tropical Discover, Develop, Deliver. Institute and Roche The Access and Delivery The synthetic peroxides hold Advisory Committee the promise of generating ( ADAC ) is established. a fast-acting antimalarial of the future. Lynda, Baroness Chalker of Wallasey succeeds Dame Bridget Ogilvie as Board Chairperson.

Dutch Government funds enable the refurbishment of an old research facility in Gabon into a state-of-the- art clinical trial unit ( Albert Schweitzer Clinic ) to conduct safety and efficacy studies for antimalarial drugs, particularly in paediatric patients.

MMV establishes two new mini-portfolios, one with Novartis Institute for Tropical Disease, and the other with Broad Institute of MIT/Harvard & Genzyme Corporation.

2007 Call for proposals None Results N/A Portfolio status 39 projects: 29 discovery, 3 preclinical, 7 clinical development 5 projects terminated MMV Project of the Year 2007 goes to Queensland natural products. Partner : The Nature Bank at Eskitis Institute, Griffith University This project combines The Pivotal Phase III study of the chemical diversity of natural products with the dihydroartemisinin-piperaquine technological power of ® ( Eurartesim ), with the high-throughput screening contracted service of MDS in the search for the next Pharma Services, wins the generation of antimalarials. Good Clinical Practice Journal ( GCPj ) Award, honouring excellence in clinical research.

Access Symposium in Uganda sparks keen interest Regulatory dossier for in the critical need for Coartem ® Dispersible is improved access to effective submitted to Swissmedic. antimalarial treatment in Africa. MMV completes two major Phase III studies – The Gates Foundation Eurartesim ® and Pyramax ®. donates an additional USD 37 million over 2 years and the NIH awards its first donation of USD 5.6 million over 5 years.

President Museveni of Uganda The World Bank Independent inaugurates the Stakeholders’ Global Program Review meeting in Kampala, Uganda. considers MMV ‘ a success- ful product development MMV takes to the road in Africa public–private partnership.’ ( Kenya, Mozambique, , Uganda, Togo and Benin ) for 5 weeks, drawing attention to the new products soon to emerge from the portfolio.

2008 6th Call for proposals focuses on products for uncomplicated malaria and prophylaxis. Results 166 proposals: 9 approved Portfolio status 50 projects: 37 discovery, Coartem® Dispersible is 6 preclinical, 6 development approved by Swissmedic ( 2 in late-stage clinical ) – a stringent regulatory development, 1 registered 4 projects terminated authority. MMV Project of the Year 2008 and first-ever Our fourth artemisinin MMV Drug Innovation combination therapy ( ACT ), Award goes to Coartem® Dacart™ ( GSK ) completes Dispersible. its Phase III studies, but Partner : Novartis is discontinued due to Coartem Dispersible is side effects of haemolysis the first MMV-supported in patients with G6PD - medicine to be approved deficiency. Nonetheless, by a stringent regulatory the studies were useful authority. in terms of the lessons they provided.

Prime Minister of Uganda, Rt. Honorable Apolo Nsibambi launches the MMV – MOH pilot to study the effects of provid- ing a heavily subsidised ACT through private channels in four rural districts of Uganda. This work aims to inform the Affordable Medicines Facility – malaria ( AMFm ).

MMV launches revised 5-year business plan with a new vision to target eradication.

Spanish government becomes MMV’s 6th public sector donor with a grant of o 3 million for 2008.

2009 MMV receives its fifth and 7th Call for proposals largest grant from the Gates focuses on powering the Foundation of USD 115 million malaria eradication agenda; in addition to new funding projects targeting the liver stage and gametocytes are from DFID of USD 30 million requested. – both to support MMV over Results 5 years. This renewed support 70 proposals; 6 selected demonstrates both the for full application Gates Foundation and DFID’s Portfolio status continued belief in MMV’s 52 projects by the 2nd ability to succeed. quarter : 40 discovery, 4 preclinical, 8 clinical development

Coartem ® Dispersible is launched in three African countries as well as Switzerland. The regulatory dossier for Eurartesim ® is submitted to EMEA, the European stringent regulatory authority. The dossier for Pyramax ® is being prepared for submission in 2010. MMV continues to work ’s Minister of Health, towards eradication by sup- Mme Therese Coumba Diop, porting the first cellular assay offers her country’s continued to screen compounds for support to MMV’s mission activity against the hypnozoite at the Stakeholders’ meeting of P. vivax. in . In MMV’s 10th year, the dedicated, multi-skilled team of two has blossomed to 40. Medicines for Malaria Venture ( MMV ) is a not-for-profit organization dedicated to reducing the burden of malaria in disease-endemic countries by discovering, developing and delivering new affordable antimalarial drugs through effective public–private partnerships. Our vision is a world in which these innovative medicines will cure and protect the vulnerable populations at risk from malaria, and help to ultimately eradicate this terrible disease. International Centre Cointrin Route de Pré-Bois 20 Post Box 1826 CH - 1215 Geneva 15 Switzerland T + 41 22 799 40 60 F + 41 22 799 40 61 [email protected] www.mmv.org Medicines for Malaria Venture Editors Elizabeth Poll and Jaya Banerji, MMV, Switzerland Designer phg-Pascale Henriod, Switzerland Lithograph and Printer Imprimerie Genoud SA, Switzerland Images BIOTEC, Thailand; MMV, Switzerland; Monash University, Australia; Anna Wang, Switzerland Special thanks go to Pascale Henriod, our graphic designer, and Imprimerie Genoud SA, our printer, for their invaluable contribution to the production of this anniversary book.

© 2009 Medicines for Malaria Venture All rights are reserved by Medicines for Malaria Venture. The document may be freely reviewed and abstracted, with the usual acknowledgment of source, but is not for sale or for use in conjunction with commercial purposes. Requests for permission to reproduce or translate the document, in part or in full, should be addressed to the administration of Medicines for Malaria Venture, where information on any translation or reprints is centralized.

Strategic planning group Current Board members ( and their affiliations in 1999 ) Dr Pedro Alonso Mr Harvey Bale Jr. ( International Federation Lynda, Baroness Chalker of Wallasey ) of Pharmaceutical Manufacturers Association MMV has received funding from the following Mr James Cochrane ( ) entities ( in addition to numerous individuals ) Ms Amy Batson World Bank Dr Christopher Elias ( Mr Louis Currat Swiss Agency Dr Winston Gutteridge for Development Cooperation ) BHP Billiton Dr Christopher Hentschel Dr Jürgen Drews ( Roche ) Bill and Melinda Gates Foundation Prof. Eyitayo Lambo Dr Timothy Evans ( Rockefeller Foundation ) Exxon Mobil Corporation Dr Pascoal Mocumbi Sir Richard Feachem ( The World Bank ) Irish Aid Dr Carlos Morel Dr Tore Godal ( WHO / TDR ) National Institutes of Health Dr Hiroki Nakatani Dr Winston Gutteridge ( WHO / TDR ) Netherlands Minister for Development Cooperation Dr Regina Rabinovich Dr Robert Howells ( Wellcome Trust ) Rockefeller Foundation Dr Dennis Schmatz Prof. Trevor Jones ( Association of the British Pharmaceutical Industry ) Roll Back Malaria Partnership Prof. Peter G. Smith Dr Carlos Morel ( WHO / TDR ) Spanish Agency for International Cooperation Mr Per Wold-Olsen for Development Dr David Nabarro ( WHO / RBM ) Swiss Agency for Development and Dr Robert Ridley ( WHO / TDR and Roche ) Former Board members Cooperation Dr Simon Sargent ( Glaxo Wellcome ) United Kingdom Department for International Mr David Alnwick Sir Richard Sykes ( Glaxo Wellcome ) Development Dr Anarfi Asamoa-Baah Prof. Marcel Tanner ( Swiss Tropical Institute ) United States Agency for International Dr Enriqueta Bond Development Dr Jack Chow Wellcome Trust Mr Louis Currat World Bank Dr Tore Godal Prof. Trevor Jones Dr R. A. Mashelkar Dr Graham Mitchell Dr David Nabarro Prof. Francis Nkrumah Dame Bridget Ogilvie Prof. Leon Rosenberg Current ESAC members Current MMV team members

Dr Salim Abdulla Nada Araeipour Dr Pedro Alonso Jaya Banerji Dr Simon Campbell Andrew Balyeku Prof. William Charman Ian Bathurst Prof. Kelly Chibale Isabelle Borghini Prof. Christine Clayton Jeremy Burrows Prof. Simon Croft Renia Coghlan Prof. Ogobara Doumbo Current ADAC members Diana Cotran

Prof. Brian Greenwood Maud Couturier Mr Joseph Amoussou Dr R. Kiplin Guy Christine Crettenand Mr Girindre Beeharry Dr Alan Hudson Matthew Doherty Prof. Awa Marie Coll-Seck Dr Chantal Laburte Stephan Duparc Dr Issa Diop Dr Trevor Laird Julia Engelking Prof. Winston Gutteridge Dr Michael Makanga Alejandro Estrada Mr Paul Lalvani Dr Maurizio Mariani Pascal Fantauzzi Mr P. A. Narayan Dr David Matthews Sylvie Fonteilles-Drabek Dr Naawa Sipilanyambe Dr David McGibney Penny Grewal Dr Francisco Songane Prof. Wilbur Milhous Roberto Hanania Prof. Marcel Tanner Prof. François Nosten Joan Herbert Prof. Geoff Targett Dr Bernhards Ogutu Christopher Hentschel Prof. Prashant Yadav Prof. Margaret Philips Andrew Humberstone Dr Hashim Yusufu Dr Dennis Schmatz George Jagoe Prof. Carol Hopkins Sibley Elizabeth Kernen Former ADAC members Dr Terrie Taylor Erin Kimaoui Dr Tran Tinh Hien Dr Dora Akunyili Didier Leroy Dr Neena Valecha Dr Daniel Ngamije Julie Lotharius Prof. Stephen Ward Prof. Robert Snow Maud Lugand Dr Michael Witty Dr Ambrose Talisuna Jörg Möhrle Prof. Christopher Whitty Patrick Nef Former ESAC members Claude Oeuvray Sophie Pereira Dr Richard Auty Carla Pinoargote-Meister Dr George Aynilian Elizabeth Poll Dr Tanjore Balganesh Peter Potter-Lesage Dr Simon Efange Rana Rossignol Dr David Floyd Samuel Sierro Prof. Winston Gutteridge Yuko Takase Prof. Gilbert Kokwaro Ambrose Talisuna Prof. Sornchai Looareesuwan David Ubben Dr David Matthews Timothy Wells Dr Maria Paris Prof. Zulfiqarali Gulamhussien Premji Former MMV team members Dr Yves Ribeill Prof. David Roos J. Carl Craft Dr Ronnatrai Ruangweerayut Marion Hutt Dr John Salmon Anthony Kalm Dr Jürg Seiler Mugo Mumbi Wa Prof. Robert Snow Solomon Nwaka Dr Henrietta Ukwu Robert Ridley Dr Thomas Wellems Lise Riopel Dr David Wesche V. P. Venugopal Dr Kitima Yuthavong Anna Wang Thank you