Review TRENDS in Parasitology Vol.22 No.7 July 2006 Medicines for Malaria Venture: sustaining antimalarial drug development Ian Bathurst and Chris Hentschel Medicines for Malaria Venture (MMV), International Center Cointrin (ICC) Building, 20 rte de Pre´ -Bois, 1215 Geneva 15, Switzerland The Medicines for Malaria Venture (MMV) is committed Between 75% and 90% of malaria cases are currently to discovering, developing and delivering new drugs for found in sub-Saharan Africa but global warming and malaria. Founded in 1999 as a nonprofit organization demographic changes could change this. Both warming bringing private sector management methods to bear and increased flooding are conditions that favor the spread on a global public health problem, MMV is today of the mosquito species that transmits malaria, thus recognized as a leader among the public–private increasing the possibility that malaria will return to partnerships working on diseases for the developing parts of Europe and the USA [5,6]. world. Together with its many partners, MMV manages PPPs have rapidly evolved as the preferred way to the world’s largest malaria research and development ensure that progress can be made in addressing health- portfolio, covering the innovation spectrum from basic care issues that neither the public nor the private sector drug discovery to late-stage development. can solve on their own. MMV, incorporated as a Swiss foundation and officially launched on 3 November 1999, Introduction to MMV was among the first PPPs established to tackle the drug The Medicines for Malaria Venture (MMV; www.mmv.org) innovation gap of a major global neglected disease. The is a not-for-profit Swiss foundation that was created to synergistic combination of pharmaceutical industry discover, develop and deliver new affordable antimalarial knowledge and expertise in drug discovery and develop- drugs through effective public–private partnerships ment, and the public sector with its depth of expertise in (PPPs). After five years of operation, MMV, together basic biology, clinical medicine and malaria control with its many partners, manages the world’s largest experience, constituted the underlying rationale for its malaria research and development portfolio from basic chosen PPP formation. drug target discovery and validation projects through to The organizational structure of MMV (Figure 1) advanced formulations of existing drugs. All MMV enables flexibility in governance and management, development projects are executed to international Good making it possible for objectives to be met efficiently and Clinical Practices standards, as defined, for example, by rapidly. MMV is today governed by a board of up to 12 the US Food and Drug Administration or the European members chosen for their scientific, medical and public- Agency for the Evaluation of Medicinal Products. Equally, health expertise in malaria and related fields, their all drugs are manufactured to quality standards, as research and management competence, and their experi- promulgated under European Directive 2003/94/EC or ence in business, finance and fundraising. MMV uses an equivalent. Several drugs are currently in advanced Expert Scientific Advisory Committee (ESAC) to advise on development and MMV expects to launch several the selection and review of projects for funding by MMV important new antimalarial drugs before 2010. and to provide more general advice and information on appropriate technical strategies for the Foundation to achieve its goals. The members of the ESAC come from The extent of the challenge both industry and academia and cover the full range of Malaria kills between one and two million people annually, expertise required to assess projects in the extremely the majority of those affected being children under five complex process of drug research and development. years of age and pregnant women [1]. Each year, 300–500 Current and former members of the ESAC also participate million new clinical cases of malaria are reported in official in the MMV–ESAC Mentor Program. statistics. Although preventable through vector control or insecticide-treated bed nets, at present only drugs can be The need for continued drug innovation used to cure this life-threatening infection [2]. The true Although malaria control programs, malaria product number of clinical cases is not accurately known, and research and, indeed, the number of malariologists recent estimates suggest that actual numbers might be themselves decreased after the eradication era in the much larger than the official statistics suggest [3,4]. 1950–1960s, resistance to antimalarial drugs and to Corresponding author: Bathurst, I. ([email protected]). insecticides has increased [7]. The world’s poorest people Available online 6 June 2006 in endemic regions do not benefit from drugs developed for www.sciencedirect.com 1471-4922/$ - see front matter Q 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2006.05.011 302 Review TRENDS in Parasitology Vol.22 No.7 July 2006 Key committees Stakeholders Outsourced support Remuneration Legal Audit Board of directors Fundraising President and I.T. Nominations Chief Executive Officer C.R.O. Expert Scientific Advisory Direction Reporting Committee (ESAC) Consultants: science MMV Communications Geographic spread management team MMV Geneva MMV Europe Project teams & New Delhi support staff support office TRENDS in Parasitology Figure 1. The organizational structure of MMV. The reporting system and key committees that are involved in the operation of MMV are shown. Abbreviations: C.R.O., contract research organization; I.T., information technology. the specialized travelers’ market in wealthy countries times that used to treat malaria [10,11].Theyare because these drugs are expensive and largely designed specifically contraindicated in early pregnancy [12,13]. for prophylaxis rather than therapy. Although the Moreover, because these agents are extracted from travelers’ market in industrialized countries totals, plants, their production time is lengthy and costly. perhaps, some US$300 million per year, this is still well Although usually purchased through global donations below the amount required to generate commercial for the public sector in developing countries, the research and development from the research-based underlying cost is still 10–30 times more than the pharmaceutical industry. Furthermore, the potential market for innovative new antimalarial drugs is ham- pered by competing counterfeit and substandard drugs, Table 1. The effectiveness of antimalarial drugs can be limited owing to a poor regulatory and enforcement infrastructure by resistance and safetya,b in many disease-endemic countries (http://www.cdc.gov/ Antimalarial drug Year Year resist- Other malaria/travel/counterfeit_drugs.htm). The net result has introduced ance found limitations been a lack of innovation and diversity that has led to Quinine 19th century 1910 Compliance, increasing drug resistance. The old, affordable first-line safety drug treatments such as chloroquine and sulfadoxine– Chloroquine 1945 1957 None pyrimethamine are today virtually useless in many parts Proguanil 1948 1949 None Primaquine 1950 No resistance Safety of Africa and Asia [8,9] (Table 1). Sulfadoxine– 1967 1967 None pyrimethamine Amodiaquine 1975 No resistance Safety, Artemisinin combination therapies possibly The Chinese initiated the development of the fast-acting resistance artemisinin drugs during the Vietnam War (1966–1971) Mefloquine 1977 1982 Cost, safety and have continued working on them as combinations Artemisinins 1970s No resistance Compliance, with slower-acting partner drugs. Artemisinin com- cost, possibly bination therapies (ACTs) are by far the best class of safety antimalarial drugs available today, both in terms of Halofantrine 1988 1992 Cost, safety efficacy and prospective longevity. However, ACT drugs Atovaquone 1996 1996 Cost are still not ideal in terms of safety, with potential Lapdap 2003 No resistance Resistance neurotoxicity and neuronal degeneration observed in potential aSource: MMV, World Health Organization. animals, and cell culture conditions that use artemisinin bTable reproduced, with permission, from Ref. [27]. q (2005) American Chemical or artemisinin derivatives at concentrations several Society. www.sciencedirect.com Review TRENDS in Parasitology Vol.22 No.7 July 2006 303 traditional first-line drug treatments. Scale-up requires a uncomplicated malaria. Artekine has been widely used considerable quantity of agricultural land and dedicated in Southeast Asia but has not yet been developed to extraction plants that can pose environmental risks. international registration or quality standards. The active Because of the time lag between needs forecasts, pharmaceutical ingredients in Eurartekine (the new fully procurement and delivery times, which are also affected international standard drug) were initially manufactured by lengthy planting and growing seasons, shortages at by Sigma-Tau in Italy for the clinical trials, and this the point of use of this plant-based drug are common. expertise is being transferred back to our Chinese Furthermore, use of artemisinin-based monotherapy, partners, Holley Pharmaceuticals. Because of extensive which threatens much of the rationale of the combination human experience, the nonclinical development plan drugs by risking the generation of resistance, continues (toxicology and pharmacokinetics) is being performed virtually unabated. concurrently with the clinical development plan, which Ideally,