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"There are essentially no patients with malaria on the planet that I can't treat and cure if they come to me the first day they have symptoms," says Stephen L. Hoffman, M.D., former director of the Malaria Program at the Naval Medical Research Center. "If they come to me after they have severe malaria, no matter what I do, at least 10% of them will die."
Hoffman, a past president of the American Society of Tropical Medicine & Hygiene, notes that "there is a drug out there for everybody." The issue is not one of availability but of identifying who needs the drugs, getting the drugs to them when they are needed, and making the drugs affordable. "And we're not quite sure how you do that," he adds. More than 40% of the world's population, much of it very poor, lives in areas where malaria is a risk. Looking now toward prevention rather than treatment, Hoffman created Sanaria, a start-up company working to develop a malaria vaccine (see page 85).
According to the World Health Organization (WHO), between 300 million and 500 million clinical cases of malaria occur every year. Recent empirical estimates have suggested the total could run as high as 660 million (Nature 2005, 434, 214). Malaria is estimated to kill more than 1 million people annually and possibly as many as 3 million, with most of the deaths among children under age six living in sub-Saharan Africa.
The health and economic toll is tremendous. Political, economic, and societal factors affecting health care and government involvement in malaria prevention and control are significant factors. Despite decades of fighting malaria, the disease is gaining ground as the parasite's resistance to drugs and the parasite-carrying mosquito's resistance to insecticides expand.
Malaria in humans is caused by one of four species of the Plasmodium parasite, which can be transmitted by about 60 species of Anopheles mosquito. P. vivax is the most widespread parasite, occurring largely in the tropics and throughout Asia, but it causes a less severe form of the disease than P. falciparum.
About 90% of malaria-related deaths occur in Africa and are caused by P. falciparum. If one survives multiple infections in childhood, such exposure leads to a natural immunity that limits the severity of the disease. This immunity will wane without continued exposure to infection. Pregnant women have reduced immunity.
Malarial parasites enter a human host when a female mosquito feeds. Infectious sporozoites quickly migrate to the liver, where they develop and multiply. This asymptomatic incubation phase can last from a week to months. Only when the parasites emerge from liver cells and invade red blood cells-where they multiply, burst from the cells, and infect new blood cells-does the infection result in the fever, flulike symptoms, and anemia associated with malaria.
A SMALL PERCENTAGE of infections become severe and lead to organ failure, seizures, coma, and death. Meanwhile, some parasites mature into reproductive gametocytes that are ingested by a feeding mosquito. In the insect gut, they develop into oocysts that grow and release sporozoites, which make their way to the mosquito's salivary glands, completing the cycle.
Local, regional, and international efforts have mobilized to support the development and implementation of preventive measures-such as environmental cleanup, insecticide spraying, treated bed nets, and immunizations-and treatments, including diagnostics and medicines. The effectiveness of such programs continues to be scrutinized and debated. The Global Fund to Fight AIDS, Tuberculosis & Malaria (GFATM) and Global Alliance for Vaccines & Immunization (GAVI) are among organizations stepping up to purchase the needed measures.
In 1997, the Multilateral Initiative on Malaria (MIM), an alliance of agencies, institutes, and governments, was formed to maximize the impact of scientific research through capacity building in Africa and global collaboration. The following year, WHO, the United Nations Children's Fund (UNICEF), the UN Development Program, and the World Bank launched Roll Back Malaria (RBM) Global Partnership to coordinate efforts in fighting malaria. RBM today involves 90 countries, companies, and other organizations. It recently published its “World Malaria Report 2005” on progress toward halving the burden of malaria by 2010.
For decades, malaria has been treated widely, but not always appropriately, with drugs that fall into three broad categories. Aryl aminoalcohol compounds include quinine, quinidine, chloroquine, amodiaquine, mefloquine, lumefantrine, and piperaquine. Other treatments are antifolates, often using a dihydrofolate reductase inhibitor-such as pyrimethamine, proguanil, and chlorproguanil-with a sulfa drug, such as dapsone or sulfadoxine. The last major category is artemisinin and its derivatives: artesunate, artemether, and dihydroartemisinin.
In some areas, a growing resistance among malaria parasites has seriously limited the drug therapies that can be used, as is the case for chloroquine. For a few drugs, such as halofantrine, side effects have been an issue. Since 2001, WHO has recommended specific combinations of at least two drugs-one preferably an artemisinin derivative-for treating falciparum malaria in all countries experiencing resistance to single-drug therapies.
Any two drugs used in combination should have independent modes of action and different biochemical targets in the parasite, WHO says, and their ongoing effectiveness should be closely monitored. No reported clinical resistance has yet developed to the artemisinin derivatives, which are highly potent, fast acting, and well-tolerated. Many hope that artemisinin-based combination therapy (ACT) will improve efficacy and prolong the usable life of the combined drugs by delaying the onset of resistance.
ACTs now available cost up to $2.40 per course of treatment, which makes them at least 10 times more expensive than many older drugs, such as chloroquine. Prices at present are out of the reach of many who need the drugs, especially in Africa. Despite the higher cost of ACTs, more than 50 malaria-endemic countries have policies to adopt them; many nations will use them as a first-line treatment, and about half have begun implementing these policies.
All the required treatments are expected to cost at least $300 million to $500 million per year. The Institute of Medicine has recommended that international organizations and world leaders create a global annual subsidy of up to $500 million to help provide ACTs at about 10 cents per treatment course.
Meanwhile, international donors recently pledged $3.7 billion to GFATM for 2006 and 2007. The amount represents about half of the $7 billion it says it will need to fund all of its programs for the two-year period. GFATM spends nearly three-quarters of all money spent on malaria control, including drugs and bed nets, and has committed about $1 billion toward that end over the next two years. In 2004, it switched its support from general antimalarials to the purchase of ACTs by governments receiving its grants. Over the next two years, GFATM is expected to provide about 145 million ACT treatments.
According to WHO, since GFATM began disbursing funds in 2003, the demand for combination therapies based on artemisinin has increased rapidly and led to a drug shortage in late 2004. To ensure the quality of drugs, WHO and UNICEF established a mechanism to prequalify manufacturers; WHO is now calling on countries to use only WHO-approved ACTs. Although many companies produce artemisinin-based drugs worldwide, as of mid-2004, only Novartis' fixed-dose artemether-lumefantrine combination called Coartem and artesunate tablets from Sanofi-Aventis had been prequalified.
Both drugs depend on manufacturing support in China, the primary location for cultivating and harvesting the Artemisia annua, or sweet wormwood, plant, which has been used for centuries to treat fevers. In the 1970s, Chinese scientists isolated artemisinin and by the next decade had formulated and studied its derivatives. In 1991, Novartis (then Ciba-Geigy) began collaborating with Kunming Pharmaceutical on Coartem production and obtained marketing approval in 1998. Novartis partnered with WHO in 2001 to make Coartem available in malaria-endemic countries on a not-for-profit basis.
Since 2001, Novartis has supplied more than 10 million treatments. “The original 2001 agreement forecast demand for Coartem at just over 2 million treatments in 2005,” explains Hans Rietveld, global marketing manager for tropical medicine with Novartis. “Since then, nonbinding demand forecasts provided by WHO have continuously increased, including a sixfold jump between December 2003 and March 2004, when the 2005 forecast surged from 10 million to 60 million treatments.”
Producing Coartem requires a 14-month lead time for planting, harvesting, extracting, and completing drug manufacture. Together with its Chinese partners, Novartis is embarking on a scale-up program that, for its size and speed, is unprecedented in commercial drug production for a new chemical entity, Rietveld says. The effort will require the operation of two large-scale plants to produce more than 1.9 billion Coartem tablets-or more than 100 million treatments-in 2006.
Novartis also is investing in increasing and diversifying the supplier base for the raw material and in transitioning a largely wild crop to commercial plantation cultivation, Rietveld says. The company has established a close partnership with Kenya-based East African Botanicals (EAB) to significantly increase cultivation and extraction. EAB plans to extract artemisinin from A. annua in its Kenyan facility beginning in the fourth quarter of 2005.
"For the first time, significant volumes of artemisinin will be produced in Africa following the 2005 harvest," Rietveld says. EAB's production in Kenya, Tanzania, and Uganda, along with that taking place largely in China, brings agricultural production to about 10,000 hectares. This will yield tens of tons of extracted material and is sufficient to allow Novartis to increase production significantly in 2005 and 2006. Orders for Coartem are running at about 14 million treatments so far this year.
WHO convened a meeting in June that brought together growers and representatives from companies, government agencies, and nongovernmental organizations (NGOs). The attendees discussed the supply-and-demand situation as well as strategies to create a more stable and sustainable market that might help lower drug prices and encourage growers, drug producers, and donors to commit to production and purchases, as described in a draft report.
Elsewhere, biotechnology-based approaches are being explored to produce artemisinin. Through a $42.6 million, five-year Bill & Melinda Gates Foundation grant to the Institute for OneWorld Health, Amyris Biotechnologies is working to scale up a microbial process created by University of California, Berkeley, chemical engineering professor and company cofounder Jay D. Keasling (C&EN, Jan. 3, page 18). OneWorld Health will coordinate clinical testing and regulatory filing.
Microbial strains will be engineered to produce a precursor that will be converted chemically into artemisinin. "The Keasling lab is working to complete the pathway from amorphadiene to artemisinic acid, which is our target biosynthetic end point and the feedstock for the chemistry steps," says Kinkead Reiling, an Amyris founder and scientist. The company has been integrating the strains into its industrial systems and working on the downstream chemistry. A large-scale manufacturer will be chosen to produce the commercial batches.
The approach is expected to offer a stable, semisynthetic source of the drug. "If the project team achieves its milestones, we estimate that we will be able to reduce the cost of pure artemisinin by up to 75%," Reiling says. Although the final cost will depend on formulation with a combination drug, Amyris anticipates its product will enable ACT producers to bring the cost of these combination therapies down to less than a dollar per treatment.
Meanwhile, the effectiveness of different ACTs and other treatments is being studied in many countries, where they often show greater than 90% cure rates. The International Artemisinin Study Group, for example, analyzed 16 clinical trials that have taken place since 1992 and found that the addition of artesunate to existing drug therapies substantially reduced treatment failures, reemergence, and gametocyte transmission (Lancet 2004, 363, 9).
In a major clinical trial funded by the Wellcome Trust, another international group of researchers recently found that intravenous (IV) artesunate acted more rapidly than IV quinine to clear parasites and was safer and easier to administer in treating severe falciparum malaria in adults (Lancet 2005, 366, 717). Compared with the more regularly used quinine, artesunate was found to reduce by 35% the incidents of death among patients in Bangladesh, Myanmar, India, and Indonesia.
Taking this finding into account, WHO is expected to publish new guidelines for doctors. The problem, however, is supply. The injectable form of artesunate is produced in China, but there is no generally available version made to current Good Manufacturing Practices (cGMP) standards. The researchers, led by University of Oxford tropical medicine professor Nicholas White, who chairs the Wellcome Trust's South East Asian Tropical Medicine Research Programs and WHO's Antimalarial Treatment Guidelines Committee, expressed urgency that this situation needs to change.
The Medicines for Malaria Venture (MMV), which supports public-private partnerships, had been funding a project on IV artesunate with Walter Reed Army Institute of Research. WRAIR has been extremely active in malaria drug R&D, having partnered with drug firms to develop many existing drugs and to work on new projects. MMV's active support of the IV artesunate project was ended this year, however, because of slow progress in moving toward Phase I trials. MMV also notes that prospects for identifying a drug company partner in the near future are "slim."
Meanwhile, Coartem, the artemether-lumefantrine combination, offers positive results. In April, a study concluded that it was more effective than other combinations for treating children in Tanzania, where resistance to conventional drugs is high, although the cost was considered a major limitation (Lancet 2005, 365, 1474). Another research group reached a similar conclusion in a study in Uganda (Lancet 2005, 365, 1467).
In another instance, the South African province of KwaZulu-Natal was the first region in which an African Ministry of Health introduced an ACT policy, along with an intensified mosquito-control program using the insecticide DDT. Three years into the program, outpatient cases had fallen by 99% and malaria-related deaths, by 97% (PLoS Med. 2005, 2, e330). In the Gambia, ACTs have also been found to be effective at reducing transmission via gametocytes and thus lowering infectiousness after treatment (PLoS Med. 2005, 2, e92).
The KwaZulu-Natal results may have been influenced by a strong local economy, low transmission rates, and weak immunity that led to better insect control and higher levels of treatment, suggest Patrick E. Duffy of the Seattle Biomedical Research Institute and Theonest K. Mutabingwa of the London School of Hygiene & Tropical Medicine (LSHTM) in an accompanying perspective (PLoS Med. 2005, 2, e368). They warn that the long-term effectiveness of ACTs in highly endemic areas has not been proven.
A recent multitrial study found that artemisinin-amodiaquine did not outperform less expensive combinations for recurrent infections in highly endemic areas of Africa (PLoS Med. 2005, 2, e190). The researchers, led by Grant Dorsey of the University of California, San Francisco, emphasized that “the ideal combination regimens remain uncertain,” and pointed to a recent review of antimalarial combinations (Lancet 2004, 364, 285).
Still, there seems to be general agreement that combination therapies offer the best option and warrant further study. “Cheap and effective treatment for malaria with one drug is no longer an option for most countries in Africa,” wrote the LSHTM researchers who conducted the Tanzanian study. On the plus side, that study and the one in Uganda found that adherence to the WHO-recommended six-dose ACT regimen was good and the treatment effective even when the drugs are taken at home or on an outpatient basis and not in a controlled trial setting.
Brian Greenwood, director of LSHTM's Malaria Centre, tells C&EN that frequent misdiagnosis complicates the appropriate use of antimalarial drugs. He believes the situation can be improved through diagnostic tools and changing doctors' attitudes toward prescribing. Greenwood directs the Gates Malaria Partnership, a collaboration created in mid-2000 among several universities under a five-year, $40 million Gates Foundation grant to develop approaches to control malaria through applied research and capacity development in endemic countries.
"There are going to have to be some behavioral changes taking place when more expensive drugs in relatively short supply are being used, and that's really difficult to do," Greenwood says. A new consortium is being created to look at the issues surrounding realistically making the switch to ACTs, he adds. "Nearly every country in Africa has now decided to change policy, but they have no idea how they are going to do it, where the drugs are coming from, and how they will pay for them."
Several leading pharmaceutical companies have been working alone or through partnerships to help make malaria drugs available. Sanofi-Aventis is among firms with a long history in antimalarial drug R&D; its portfolio includes quinine, chloroquine, amodiaquine, artemether, and artesunate products. The company sells Arsucam-copackaged artesunate and amodiaquine tablets-which is licensed in more than 15 African countries. In April, it began working with the Drugs for Neglected Diseases initiative (DNDi) on a single-tablet, fixed-dose artesunate-amodiaquine combination.
The combination is expected to improve patient compliance by reducing the three-day treatment from eight tablets per day to just three per day for adults. Fixed-dose formulations also avoid the risk of patients taking only one of the active drugs, which could contribute to resistance. With financial assistance to support the market, the partners have said, the combination should be less expensive than other ACTs-less than $1.00 for adults and 50 cents for children.
"The project is at the end of Phase III," says Gilles Roche, senior director for Sanofi-Aventis' Impact Malaria program. "The plan is to submit a dossier by the end of 2005 in Morocco, which will be the sourcing country." Submission for WHO prequalification will be the next step, he explains, with submission in the endemic countries soon after that. The product will be sold at cost in the public health markets and to international organizations and NGOs.
Sanofi-Aventis is exploring other antimalarial agents, including ferroquine, trioxaquine, thiazolium, and choline-uptake inhibitors. Separately, DNDi reported Phase III results for a fixed-dose artesunate-mefloquine combination last month. The combo was found to be as effective as the existing separate tablets, but better tolerated, with a greater than 92% cure rate. The combination is recommended in Southeast Asia and several Latin American countries. Far-Manguinhos in Brazil developed the formulation, and DNDi expects it to be available to patients in 2006.
The relationship between Sanofi-Aventis and DNDi is one example of what many see as a promising trend toward public-private partnerships (PPPs). And antimalarial drug discovery and development are among the areas starting to benefit from these types of collaborations and partnerships. Novartis, for example, is now working with MMV to develop a pediatric formulation of Coartem.
WHO, the World Bank, donor governments, industry, and philanthropic foundations started MMV in 1999. The venture has spent the past few years building its portfolio and today manages about 20 to 25 drug discovery and development projects. Now the independent nonprofit organization brings together more than 50 corporate, academic, and government partners and helps support their work with donor money. About 60–70% of its approximately $30 million annual budget comes from the Gates Foundation.
Total global spending on antimalarial drug R&D is estimated to be between $80 million and $120 million per year. The last comprehensive survey was done in the mid-1990s by the Wellcome Trust, says Anna Wang, MMV's communication and advocacy officer, and included little data on company investments. A new study is under way by the Malaria R&D Alliance, a group advocating for global commitment and appropriate and sustained investments for malaria R&D.
In a recent report financed by the Wellcome Trust, a team from the London School of Economics notes that PPPs have been a critical driver behind new drugs for neglected diseases. Although only 13 new drugs were developed for neglected tropical diseases between 1975 and 1999, including a handful of antimalarials, activity has increased in recent years (PLoS Med. 2005, 2, e302). PPPs today account for about three-quarters of all such R&D projects and are expected to yield six or seven new drugs within the next five years.
"In the diseases of the developing world, the problems are so big that collaboration-putting together all the different capabilities of industry, government, academia, and PPPs-is necessary," says Federico Gomez de las Heras, director of GlaxoSmithKline's Diseases of the Developing World (DDW) Drug Discovery unit. GSK's antimalarial work dates back at least 50 years to Dar-aprim (pyrimethamine). Today its products include halofantrine, atovaquone, an atovaquone-proguanil combination, and a chlorproguanil (Lapudrine) and dapsone combination called Lapdap.
GSK was among the first to partner with MMV. J Carl Craft, MMV's chief scientific officer, says he's been pleased with the response from academic and industrial researchers to MMV's calls for proposals. "We do it about every other year and get about 100 proposals," he says. "From that we can usually get 10 to 15 that are really quite good and then narrow it down to the number we can support, which this year was five."
MMV's independent scientific advisory committee uses rigorous criteria for choosing and reviewing what projects to support or abandon, Craft explains. These criteria take into account not only scientific and clinical aspects but production, cost, and commercialization considerations as well. This year, MMV stopped supporting several discovery- and two developmental-stage projects. One was artemifone, a semisynthetic derivative of artemisinin being worked on by Bayer and Hong Kong University of Science & Technology. Bayer took over the project, which had moved into Phase II trials in 2004, and tells C&EN only that it is reviewing the data.
Besides pediatric Coartem, MMV's most advanced project is a fixed-dose combination-Lapdap (chlorproguanil-dapsone) and artesunate (CDA)-that is moving into Phase III studies. GSK commercialized Lapdap, an inexpensive treatment at about 30 cents for adults, in 2004. Along with GSK, the CDA project has involved researchers at WHO's Special Program for Research & Training in Tropical Diseases, the University of Liverpool, and LSHTM. If targets are met, they hope to apply for regulatory approval for CDA in 2006.
MMV has also moved a fixed-dose dihydroartemisinin-piperaquine combination called Euartekin into all phases of clinical trials at once, Craft says. The combination has been used for many years in China, and production now meets cGMP standards. In March 2004, the University of Oxford; Chongqing Holley, a major Chinese artemisinin producer; and Sigma-Tau, an Italian pharmaceutical company, joined the project. The partners hope for approval in late 2007. Meanwhile, MMV and Shin Poong Pharm in South Korea started Phase II trials this summer of a fixed-dose pyronaridine-artesunate combination nicknamed PANDA.
Although it has artemisinin-related programs, MMV believes its main contribution will be in developing new combination therapies that do not rely on drugs extracted from plants, Craft says. Within the MMV portfolio is a "mini-portfolio" of discovery programs managed jointly with GSK. It includes projects on Fab i, an enoyl-acyl carrier protein reductase target involved in fatty acid biosynthesis; inhibitors of falcipains, a cysteine-class of proteases; and 4(1H)-pyridone derivatives.
"With the mini-portfolio, there is a continuity that allows us to recruit and maintain high-quality people, to follow the projects, and to have a long-term focus," GSK's Gomez de las Heras says. The approach also streamlines the process for evaluating projects under way and incorporating potential new ones and makes work much more efficient overall, he adds.
In addition, resources can be applied effectively to yield the best results. The mini-portfolio projects are housed at GSK's DDW research center in Tres Cantos, Spain, while other GSK sites also contribute to the DDW projects. At Tres Cantos, MMV supports 25 researchers and GSK covers all other expenses and provides a matching number of scientists.
Another MMV project that has progressed with partners is OZ277, also known as RBx11160. Keeping the peroxide-based activity of the artemisinins, this endoperoxide-containing ozonide was discovered by a group that included researchers from the University of Nebraska Medical Center in Omaha, Monash University in Australia, Swiss Tropical Institute, and Roche. The team has recently described the structure-activity relationship in detail (J. Med. Chem. 2005, 48, 4953).
The compound is reported to be more potent, long lasting, and structurally simple than the artemisinins, and its synthesis is amenable to industrial scale-up, Craft explains. India's Ranbaxy Laboratories is leading development and making the drug on a multikilogram scale (C&EN, Aug. 23, 2004, page 4). Phase II studies of the compound began in December 2004. The company has evaluated partner drugs, according to MMV, and clinical testing of a combination with piperaquine is expected to begin soon. A final product could reach the market by 2009.
Also moving toward later stage clinical trials is DB289, the orally active prodrug of the active diamidine DB75. It has broad antiparasitic and antifungal activities, Craft points out, including against Plasmodium, Trypanosoma, and Leishmania. Academic collaborators include the University of North Carolina, Chapel Hill. In a recent study supported by MMV and Immtech International, researchers saw a 96% cure rate against P. falciparum (J. Infect. Dis. 2005, 192, 319.)
Although in original tests, the drug was administered twice daily for five days, clinical researchers have found that a once-a-day, three-dose regimen may be adequate for treating uncomplicated malaria. Immtech has started a Phase IIb trial in Thailand comparing DB289 alone and in combination with artesunate. MMV reports that a new manufacturing process is being scaled up to 75 kg. Dicationic molecules like DB289 are slated to move into development, such as those from collaborators at Georgia State University and Swiss Tropical Institute (J. Med. Chem. 2005, 48, 5480).
THIS YEAR, MMV added four new discovery projects-on plasmodial surface anion channel inhibitors, cyclofarnesyl sequiterpenes, novel macrolides, and novel imidazolidinediones-and a development project on AQ13, a new aminoquinoline. "Although it's a chloroquine-like drug, it's active in resistant species," Craft says. "It also may be considered for use during pregnancy. The artemisinins have the potential for early spontaneous abortion, at least in animal models, whereas DB289 and AQ13 don't appear to have these kinds of problems."
Developed by Tulane University scientists, AQ13 has already completed Phase I trials. MMV says it is needed as a partner drug for possible combination with one or more existing drugs in its portfolio and has just merged it with the DB289 program. Similarly, with GSK and University of Liverpool researchers, MMV has a project exploring isoquine, a structurally modified aminoquinoline with lower hepatotoxicity than the related drug amodiaquine.
Most of MMV's exploratory- and discovery-phase projects represent novel compounds against new targets. Among the compounds are protein farnesyltransferase (PFT) inhibitors identified-along with PFT as a promising new target-during the sequencing of the human and P. falciparum genomes. Collaborators in the project include researchers at Yale University; Bristol-Myers Squibb; the University of Washington, Seattle; and others in Florida, who have recently published on their discoveries (J. Med. Chem. 2005, 48, 3704; Angew. Chem. 2005, 117, 481).
Many small and large companies, as well as government organizations, have other candidates in development. Pfizer, for example, has a combination of its azythromycin antibiotic Zithromax and chloroquine in Phase III trials in Asia, South America, and Africa. Hollis Eden Pharmaceuticals has tested its Immunitin product in Phase II trials in Thailand, while LICA Pharmaceuticals in Denmark is working with WRAIR to develop a chalcone drug candidate.
MMV's goal has always been to register at least one new effective and affordable drug before 2010, but it may actually be more successful. "We will probably have one to two new combination drugs available by 2007 and could have as many as three or four by 2010, " Craft says. "What we are trying to do is get enough out there to give people a continuous supply of new drugs to meet any change in the resistance patterns."
The organization believes it may also be able to expand its focus to tackle other challenges in treating malaria, Craft says. A major one is the treatment of malaria during pregnancy; pregnant women are the main adult risk group for malaria, and infection can result in spontaneous abortion, neonatal death, and low birth weight. Antimalarial drugs must be safe for use in pregnancy, and one approach has been intermittent preventive treatment, in which at least two preventive treatment doses are given during routine antenatal clinic visits.
Other challenging goals include further study of intermittent preventive treatment for infants, treatments for emergency situations, and treatments for severe malaria. But to address an overriding concern related to all its efforts, MMV continuously consults and collaborates with organizations including WHO, RBM, World Bank, and GFATM to make sure that any drugs that are developed are not just effective and affordable but become accessible as well to those who need them.
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