Gates Foundation announces grant to MMV to accelerate new antimalarial drug R&D
Dr Pascoal Mocumbi, Prime Minister of Mozambique, welcomed Bill and Melinda Gates, co-founders of the Bill & Melinda Gates Foundation to Manhiça, Mozambique, on the occasion of one of the Foundation’s largest grant announcements ever – this time to help fight malaria.
The Gates Foundation committed a total of US$ 168 million to accelerate malaria research in the areas of drugs, vaccines and treatment strategies. MMV’s was one of three major grants announced as part of the call from Bill Gates for a renewed global fight against malaria. MMV will receive US$ 40 million over five years. The grant will provide resources for MMV to advance its unprecedented pipeline of 21 antimalarial drug R&D projects, including support to accelerate four of its most promising projects: synthetic peroxide (OZ), DB289 Phase II, protein farnesyltransferase inhibitors (Pf-PFT), and a paediatric combination drug. The two grants in addition to MMV’s went to a multinational consortium of research centres to study intermittent preventive treatment in infants (IPTi) and to the Malaria Vaccine Initiative (MVI) for development of an effective malaria vaccine and sup-porting activities. Both Dr Mocumbi and Deputy Health Minister Aida Libombo were on hand for the occasion. Mozambique is one of the African countries hardest hit by malaria, but it is also home to world-class malaria research, including the Manhiça research center, where the grant announcement took place. While acknowledging that the grants were an important step, Mr Gates emphasized that far greater resources are urgently needed to expand malaria research and access to existing malaria tools, stating, “World leaders must recognize that, like AIDS, malaria is a crisis that demands urgent and sustained action”. Medicines for Malaria Venture is extremely grateful to the Gates Foundation for this very significant new grant. The Gates Foun-dation is historically MMV’s largest donor, and its continued recog-nition and support have played a crucial role in MMV’s success to date.
Prime Minister of Mozambique joins MMV Board
The Prime Minister of Mozambique, Dr Pascoal Mocumbi, has joined the Board of the Medicines for Malaria Venture (MMV). In addition to his prominent government roles, Dr Mocumbi has extensive experience as a public health administrator in Mozambique and on the international scene. He knows first hand the toll malaria takes, particularly on children and pregnant women in disease-endemic countries, including his own home country. Dr Mocumbi has held senior positions in the Mozambican govern-ment including Provincial Director of Health and Chief Medical Officer, Sofala Province (1976-80); Minister of Health (1980-86); Minister of Foreign Affairs (1987-94); and Prime Minister, a pos-ition he has held since 1994, having been re-appointed in 2000. During his tenure as Minister of Health, he played a major role in restructuring the health sector in Mozambique. MMV is extremely grateful that Dr Mocumbi has agreed to lend his outstanding experience to MMV’s work to fight malaria. MMV currently has a nine-member board chaired by Dame Bridget Ogilvie, former head of the Wellcome Trust.
MMV and Novartis sign agreement
In an effort to combat malaria in infants and small children, MMV and Novartis announced an exciting collaboration to develop a paediatric formulation of Coartem ® . The partnership was signed at Novartis Head-quarters in Basel, Switzerland on 10 November by the Chairman and CEO of Novartis, Dr Daniel Vasella, and MMV CEO Dr Christopher Hentschel. “This new drug is primed to make an important public health impact,” said Dr Hentschel, “Malaria accounts for 20% of under-five-year mortality in Africa with more than 3,000 children dying every day from the disease.” Infants under 10 kilos are most at risk as their immune systems are not developed and they cannot swallow tablets. The new formulation will be in a granulated form that can be taken with water or milk. The paediatric Coartem ® (artemether and lumefantrine) will be the first fixed combination artemesinin-based paediatric formulation and could be used as a first line treatment for infants suffering from acute, uncom-plicated Plasmodium falciparum malaria. The combination of artemether and lumefantrine is already on the WHO list of essential medicines and registered in most malaria endemic countries. Therefore, MMV expects the implementation of the paediatric formulation in these countries to be rapid. Coartem ® has a short three-day treatment time and an unsurpassed safety profile. So far, no resistance has been observed.
MMV thanks founding ESAC Chair
MMV wishes to extend its sincere thanks to Dr Simon Campbell for his dedication and service to the organization as the founding chair of MMV’s ESAC from 1999 to 2003. Dr Campbell, a synthetic organic chemist, and co-author of over 110 publications and patents, retired from Pfizer in October 1998 as Senior VicePresident for Worldwide Discovery and Medicinal R&D Europe after more than 25
years with the company. He was a key member of the research teams that discovered doxazosin (Cardura™) and amlodipine (Norvasc™) and was senior author on the research proposal that led to sildenafil (Viagra™). He has received numerous honorary awards and serves on a number of professional, research and scientific bodies. He is currently President Elect of the Royal Society of Chemistry. Dr Campbell will continue to advise MMV on an ad hoc basis focusing on the optimal evolution of its growing R&D portfolio.
Building on strengths while refreshing key MMV functions
Expertise in pharmaceutical drug discovery and development is rare outside of the mainstream pharmaceutical industry. When combined with knowledge of malariology and general organizational management skills, the talent pool becomes very small indeed. Not surprisingly, this can cause tension between MMV’s desire to retain/ access such talent and the need, embedded in its statutes, to refresh both the membership of its governing board and its Expert Scientific Advisory Committee (ESAC). Professor Win Gutteridge, a consultant in the area of neglected infectious disease and a visiting professor at the London School of Hygiene and Tropical Medicine, was the former Chief, Product R&D, UNDP/ World Bank/ WHO Special Programme for Research and Training in Tropical Diseases (TDR). He trained as a biochemist, taught at the University of Kent and then worked for 14 years in the pharmaceutical industry before moving to the World Health Organization (WHO). Professor Gutteridge was instrumental in fundraising for MMV early on, helping it to become an independent foundation. He served on the MMV board from its inception and has now agreed to act as chair of MMV’s Expert Scientific Advisory Committee (ESAC) for a term of three years. Professor Gutteridge will continue to serve on the MMV board as an observer. MMVnews recently spoke to both Dr Gutteridge and Dr Simon Campbell, founding Chair of MMV's ESAC. Many thanks to them both for their time. How/ when did you first become interested in malaria? WG: When I was a post-doc at the National Institute for Medical Research in London working on trypanosomes – a fellow post-doc, Peter Trigg, was struggling to culture malaria parasites in vitro and I offered to work with him in my spare time – I got hooked. We ended up doing a lot of collaborative work together and publishing a number of papers in the scientific literature (this was also the place where I first met Bridget [Ogilvie]; we did some work together on her favourite worm, Nippostrongylus brasiliensis). SC: I have been interested in malaria for a number of years mainly because of the devastating effect the disease has on children in the poorer parts of the world. In addition, as a medicinal chemist in the pharmaceutical industry, I was convinced that malaria could be controlled with novel drugs. What is your first MMV memory? WG: I was one of the instigators of the idea [of MMV] – others included Trevor Jones and Robert G. Ridley. Trevor and I worked for the Wellcome Foundation and Rob for Roche, the two large pharma companies that still had significant R&D activities in malaria at that time – early 1990s. It was clear by then that
even these companies could not go on in this area for much longer – the returns on the upfront investment in R&D for a New Chemical Entity (NCE) for malaria were getting too small, even when the travellers market was taken into account. We started to discuss what to do about this situation. Meanwhile, Glaxo took over Wellcome, I moved to WHO and Trevor to the Association of the British Pharmaceutical Industry (ABPI), and Roche closed their programme. I recruited Rob into WHO. The three of us then joined forces with Tore Godal, Director of TDR, Richard Feachem from the World Bank, Louis Currat from the Swiss Development Agency, Marcel Tanner from the Swiss Tropical Institute (STI), and Bob Howells from the Wellcome Trust, to brainstorm the problem. Many meetings later and after one false start, MMV emerged (we wanted to call it the New Medicines for Malaria Venture, but NMMV did not trip off the tongue, hence MMV). SC: I saw the original call for proposals in Nature I believe in late 1998 or early 1999 and wrote to MMV offering to help in any capacity. I then met Rob Ridley in London and that led to the invitation to act as chair of the Expert Scientific Advisory Committee. What in your opinion is the single most important thing MMV needs to do now to fulfill its mission? WG: An easy one - obtain regulatory approval for its first affordable product to treat malaria in disease-endemic countries and to foster the initiation of field trials to assess its value in the real world of malaria control. SC: MMV has shown that it can attract, select and fund relevant research projects, but the next step is to demonstrate that these exciting research projects can be transformed into new therapies for the treatment of malaria. What aspect of science are you most passionate about? WG: My scientific passion has always been selective chemotherapy – the ability to use small molecules to kill bugs but not patients. My favourite scientist thus has to be Ehrlich, who began it all. Until last week, my friends tell me that my favourite molecule – the one that brings the biggest twinkle to my eyes – is fosmidomycin. But then, last week, we found in another project that we had stumbled on something most unexpected and potentially quite exciting… SC: One of the most exciting times in my career was the late 60s and 70s when dramatic advances were made in our understanding of molecule structure and function and in the synthesis of complex molecules. Chemists such as Barton, Woodward, Corey, Johnson and many others were in their prime and there was intense competition to be the first to read the latest journals and share most recent developments with laboratory colleagues. What has been your single most satisfying moment as a scientist, thus far? WG: Hearing that GlaxoWellcome (as they were called then) had obtained regulatory approval for the fixed combination of atovaquone and proguanil (i.e. Malarone™) for the treatment of uncomplicated malaria – the discovery of the potential of the fixed combination and the drive to get the development programme through quickly had all been done by a team of dedicated scientists, of which I was one, whilst Wellcome was an independent company. SC: I am not sure there is a single most satisfying moment, but being closely involved in the discovery of new drugs such as Cardura™, Norvasc™ and Viagra™ and hearing how patients have benefited takes some beating. What future scientific discovery do you consider crucial to furthering scientific progress? WG: Most of the candidate products in MMV's portfolio relate to existing antimalarial drugs or are old antimalarial drugs which have languished on the shelf for many years. That supply has pretty well now been used up. It is imperative therefore that scientists make best use of the information in the
public domain on the malaria genome to identify and validate new biological targets for chemotherapeutic attack and new chemical leads with which to attack them. SC: If we focus on drug discovery, then we need to dramatically improve our knowledge of protein structure and function as there are many important biological targets that are intractable to current approaches. For example, we have few clues on how to block protein-protein interactions.
Update: latest additions to MMV’s portfolio
The following projects have now been fully integrated into MMV’s portfolio and contract negotiations are moving ahead. Manzamine alkaloids Principal investigators/organizations: Mark Hamann, Larry A. Walker and Babu L. Tekwani, University of Mississippi, USA. Subagus Wahyuono, Gadjah Mada University, Indonesia. Russell T. Hill, University of Maryland Biotechnology Institute, USA Summary: a natural product discovery project. Manzamines are sponge-derived alkaloids with significant activity against Plasmodium sp. in vitro and in vivo. A number of chemical, biological and inherent clinical characteristics of this class of drugs make them ideal candidates for further development. Public health impact: could provide a new pharmacophore Contact at MMV: Solomon Nwaka, nwakas@mmv.org Novel tetracycline derivatives Principal investigators/organizations: Michael Draper, Mark Nelson, Elizabeth Cannon, Paratek Pharmaceuticals, Boston, USA Philip J. Rosenthal, University of California, San Francisco, USA Summary: a discovery project focused on new tetracyclines discovered by Paratek. Public health impact: will provide a safer and better tolerated tetracycline for malaria treatment Contact at MMV: Solomon Nwaka, nwakas@mmv.org 8-aminoquinolines Principal investigators/organizations: Larry A. Walker, Walter G. Chambliss, Dhammika Nanayakkara, Babu L. Tekwani, Mahmoud A. Elsohly, National Center for Natural Products Research, University of Mississippi, USA Frank B. Cogswell, Tulane University, USA Summary: 5-Phenoxy analogues of 8-aminoquinolines have improved radical curative and significant blood schizontocidal activity compared with other 8-aminoquinolines such as primaquine. However, the toxicity, particularly methaemo-globinaemia, associated with these compounds remains a major concern. The (-) enantiomer of one analogue (NPC 1161B), compared with the (+) enantiomer, was shown to have signifi-cantly more schizontocidal activity in animal models and was not associated with measurable methaemoglobinaemia toxicity. Public health impact: could provide the first new drug to treat P. vivax malaria in over 50 years Contact at MMV: Lise Riopel, riopell@mmv.org Dihydroartemisinin (DHA)-piperaquine Project leaders and partners: Professor Li Guo Qiao, Guangzhou University of Traditional
Chinese Medicine, Holleykin Pharmaceutical Company, Oxford University, Chonqing Holley Holding, WHO/TDR Summary: demonstrated in clinical trials to be an effective com-bination drug to treat malaria; additional work is needed to bring the registration file to international standards. Public health impact: will bring forward a potentially useful drug which could prove to be one of the least expensive artemisinin-based combinations. Added advantage of working with the Chinese private sector to bring their manufacturing and clinical development programmes up to International Conference on Harmonisation (ICH) standards. Contact at MMV: David Ubben, ubbend@mmv.org For additional information on these projects visit www.mmv.org at MMV Projects
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MMV in print
Chris Hentschel, MMV’s CEO and Megumi Itoh, a recent graduate of Princeton University and an intern at MMV in Summer 2002, co-authored an article entitled “The resurgence of malaria and the role of the Medicines for Malaria Venture” which appears in Sustainable Development International (Edition 9, Autumn 2003). See www.mmv.org for the full text. Solomon Nwaka, MMV Scientific Officer, co-authored “Virtual drug discovery and development for neglected diseases through public-private partnerships” with Robert G. Ridley of the UNDP/World Bank/ WHO Special Programme for Research and Training in Tropical Diseases (TDR). The article, which appears in Nature Reviews Drug Discovery (November 2003, vol. 2, no. 11, 919-928), discusses the challenges, recent developments and new thinking on drug R&D for neglected dis-ease through public-private partnerships (PPPs). The full text of the article in PDF format is available at www.mmv.org. Nature subscribers can view the interactive edition at www.nature.com/nrd
MMV Board
The ninth meeting of the MMV Board was held on 24-25 October 2003 at the Burroughs Wellcome Fund (www.bwfund.org) head-quarters in North Carolina. In addition to regular board business, a mini-symposium was held on “Challenges facing MMV and the Global Alliance for TB Drug Development (GATB)”. Many thanks to Maria Freire, CEO of GATB, and the experts from Research Triangle Park, NC, who joined Chris Hentschel on the panel. MMV Board Chair Dame Bridget Ogilvie was named a Kilby Laureate at the Kilby International Awards ceremony held on 7 November in London. The Kilby International Awards identify and celebrate extraordinary individuals who have made significant contributions to society through science, technology, innovation, invention, and edu-cation. In her acceptance speech, Dame Bridget evoked her childhood years on her father’s Australian sheep farm which led her to study the sciences underlying animal production; her 17 years at the National Institute for Medical Research (UK); the 19 years she spent at the Wellcome Trust, ultimately as Director, as well as her interaction with MMV and its success story to date. She reaffirmed her on-going com-mitment to support the communication of science, which will be further enhanced by her new role as a Kilby Laureate. For more about the Kilby International Awards Foundation visit www.kilby.org
The next MMV Board meeting will take place on 30 and 31 May 2004, followed by the Fourth Annual MMV Stakeholders’ Meeting, which will start on the evening of 31 May and continue through 1 June 2004. Both meetings will take place in Maputo, Mozambique.
MMV Expert Scientific Advisory Committee (ESAC)
Two new members have joined MMV’s ESAC: Dr David Floyd, former Vice-President, Discovery Chemistry, Bristol-Myers Squibb; currently Head, FOCUS Consulting, USA Professor Robert (Bob) William Snow, Head, Malaria Public Health Group, KEMRI/ Wellcome Trust Programme, Nairobi, Kenya Dr Floyd and Professor Snow come on board following the retirement of Dr Simon Efange and Dr Tanjore Balganesh from the ESAC earlier this year.
MMV Team
With extensive experience as a communications, political and business executive in the USA, Europe, Africa and Asia, Anna Wang has come on board MMV as Communication and Advocacy Officer. Anna will be responsible for public outreach and media relations. In addition, she will coordinate fundraising activities and help expand the current donor base. She can be reached at wanga@mmv.org
THE WIDER CONTEXT
Approaching clinical trials
Lise Riopel, MMV Scientific Officer, took part in a consultation for the UK Medical Research Council’s Clinical Trials for Tomorrow Review, which developed recommendations as to how the MRC might develop its policy and approach to randomized controlled trials to best meet the changing needs of participants, health professionals, researchers and the end users of research findings. The booklet resulting from the review can be found at http://www.mrc.ac.uk/pdf-clinical-trials-for-tomorrow.pdf Lise also took part in the forum discussion on 6 October in Brussels on The Role of the Sponsor in European Clinical Research: Toward the Responsible Funding and Organisation of European Clinical Trials, orga-nized by the European Forum for Good Clinical Practice (EFGCP) and Institut National de la Santé et de la Recherche Médicale (INSERM). It is imperative for MMV to be involved in such key discussions as a growing number of MMV’s projects reach the crucial clinical trials stage.
Initiative on Public-Private Partnerships for Health (IPPPH) launches
new website This autumn, the IPPPH launched its new website which now pro-vides a “News and Events” section focused on global health issues particularly relevant to PPPs, as well as a monthly news digest e-mailed to subscribers interested in the field of public-private collab-orations for health. The site also includes a searchable database for articles, reports and other documents about PPPs. For any questions, contact Armelle Armstrong at armelle.armstrong@ippph.org or visit www.ippph.org Latest news: As MMVnews went to press, Dr Jack C. Chow, Assistant Director-General, HIV/AIDS, TB & Malaria at the World Health Organization confirmed that he will join the MMV Board.