Medicines for Malaria Venture

Genève, Switzerland

Medicines for Malaria Venture

Genève, Switzerland
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Novel compound is active across the entire parasite lifecycle and holds great promise as a single dose cure A new paper published today in the prestigious journal Science Translational Medicine describes the discovery and biological profiling of an exciting new anti-malarial clinical drug candidate, MMV390048, effective against resistant strains of the malaria parasite, and across the entire parasite lifecycle, with the potential to cure and protect in a single dose. The research was conducted by the University of Cape Town (UCT)'s Drug Discovery and Development Centre, H3D, and Medicines for Malaria Venture (MMV), in collaboration with a team of international researchers. The paper is the first full disclosure of data demonstrating the antimalarial promise of MMV390048 (also known as MMV048), a compound discovered by an international team led by Professor Kelly Chibale at UCT and MMV. "The ability of MMV048 to block all life cycle stages of the malaria parasite, offer protection against infection as well as potentially block transmission of the parasite from person to person suggests that this compound could contribute to the eradication of malaria, a disease that claims the lives of several hundred thousand people every year," said Professor Chibale, Founder and Director of H3D, founding Director of the South African Medical Research Council (SAMRC) Drug Discovery Research Unit at UCT, and senior author of the paper. In 2014, MMV048 became the first new antimalarial medicine to enter phase I human studies in Africa. Today, preparations are being made to begin phase IIa human trials on this promising compound as a single-dose cure. "This compound has enormous potential," said Dr David Reddy, MMV's CEO. "In addition to the exciting characteristics noted, it has the potential to be administered as a single dose, which could revolutionize the treatment of malaria. At MMV, we look forward to continuing our work in partnership with Professor Chibale and colleagues at UCT to pursue the development of this and future next-generation antimalarials." The project has benefited from sustained funding from MMV, the South African Technology Innovation Agency (TIA) and Strategic Health Innovation Partnerships (SHIP) unit of the SAMRC. MMV's support has also been critical in helping H3D build and reinforce their scientific networks of drug discoverers and understand the compound's role in blocking the transmission of the malaria parasite. Despite the positive impact of medication, indoor spraying with insecticides and the use of insecticide bed-nets, around 429,000 people died from malaria in 2015, mostly in Africa, according to the World Health Organisation's World Malaria Report. The paper said resistance to treatment regimens still posed a threat and highlighted the importance of developing treatments containing new chemical classes with different modes of action. Contacts: Professor Kelly Chibale, Drug Discovery and Development Centre (H3D), University of Cape Town via Saroja Naicker - saroja.naicker@uct.ac.za +27 21 6501433 (office) or Kim Cloete cloetek@yahoo.co.uk +27 82 4150736 (mobile) H3D is Africa's first integrated drug discovery and development centre. H3D was founded at the University of Cape Town in April 2011 and pioneers world-class drug discovery in Africa. The vision of H3D is to be the leading organisation for integrated drug discovery and development on the African continent. H3D strives to discover and develop innovative, life saving medicines through excellence in interdisciplinary, translational science. According to the World Health Organisation's World Malaria Report, there were 212 million new cases of malaria worldwide in 2015, with 90% of cases occurring in the WHO Africa region. In 2015, there were an estimated 429,000 malaria deaths worldwide, with 92% of these deaths occurring in Africa. Children under five are particularly susceptible to malaria illness, infection and death. In 2015, malaria killed an estimated 303,000 under-fives globally, including 292,000 children in the African region. Issued by Kim Cloete on behalf of H3D, University of Cape Town. +27 82 4150736; cloetek@yahoo.co.uk


Madrid, Spain, May 16, 2017 (GLOBE NEWSWIRE) -- An ambitious effort has been launched to prevent malaria in pregnancy in communities in sub-Saharan Africa. This innovative initiative will complement existing antenatal care services and increase pregnant women’s opportunities to access care under a grant agreement signed today by Unitaid and Jhpiego, an international nonprofit health organization and affiliate of the Johns Hopkins University. Unitaid is investing US $50 million to ensure that pregnant women in malaria-affected countries in sub-Saharan Africa have access to a preventive therapy for malaria known as “intermittent preventive treatment in pregnancy” or IPTp. The five-year project, to be implemented by Jhpiego, will increase IPTp coverage and expand antenatal care attendance in four African countries—the Democratic Republic of Congo, Madagascar, Mozambique and Nigeria. The project–-also known as “Transforming IPT for Optimal Pregnancy” (TIPTOP) – will increase IPTp coverage through community-level distribution of quality-assured sulfadoxine-pyramithimine (the medicine used for IPT). Jhpiego has partnered with the Barcelona Institute for Global Health (ISGlobal), which will lead the research and evaluation components of the project. The two organizations will also collaborate with the World Health Organization (WHO) and Medicines for Malaria Venture to achieve the desired results. This community-based IPTp approach, which will augment and complement existing antenatal care services by reaching 400,000 pregnant women and their babies, will also produce the evidence needed to update WHO’s policy on IPTp. In areas with high malaria transmission, pregnant women and young children are especially vulnerable to malaria infection and death. Although malaria is preventable and treatable, an estimated 429,000 people died from the disease in 2015, according to WHO. Moreover, malaria during pregnancy can lead to a number of negative consequences, including low birth-weight for babies and even still births. In some cases, malaria can be fatal for the mother. In 2015, IPTp coverage rates remained at just 31 percent in 20 African countries. The Unitaid-funded TIPTOP project plans to engage community health workers to increase IPTp delivery and demand to ensure there are no missed opportunities for pregnant women to receive this life-saving medicine either in the community or through the antenatal services. “By accelerating access to this critical, life-saving preventive therapy, we are hoping to avert further unnecessary deaths from malaria,” said Lelio Marmora, Unitaid’s Executive Director. “Unitaid continues to advance on all fronts by developing innovative tools to fight malaria and insecticide resistance.” Dr. Leslie Mancuso, Jhpiego’s CEO and President, said the TIPTOP project offers an exciting opportunity to demonstrate an innovative approach to address pregnant women’s needs and stop malaria in pregnancy. “Preventing malaria in pregnancy and reducing malaria-related deaths is achievable—and this partnership will go a long way toward reaching those goals,” she said. Jhpiego, an international nonprofit health organization affiliated with the Johns Hopkins University, has worked for 45 years to empower frontline health workers by designing and implementing effective, low-cost, hands-on solutions to strengthen the delivery of health care services for women and their families. The Barcelona Institute for Global Health (ISGlobal), the result of an innovative alliance between the “la Caixa” Foundation, academic institutions and government bodies, was set up to contribute to the work undertaken by the international community to address the challenges of health in a globalized world. Unitaid is an international organization that invests in new ways to prevent, diagnose and treat HIV/AIDS, hepatitis C, tuberculosis and malaria more quickly, more cheaply and more effectively. It accelerates access to innovation so critical health products reach people who most need them. Unitaid’s work allows large-scale introduction of health products through funding by the Global Fund, the United States President’s Emergency Plan for AIDS Relief (PEPFAR) and governments. For more information go to www.jhpiego.org or contact Kristin Vibbert at 1-484-888-0277. A photo accompanying this announcement is available at http://www.globenewswire.com/NewsRoom/AttachmentNg/9ee55620-f33b-42bf-a8a6-4995043cd5e4 A photo accompanying this announcement is available at http://www.globenewswire.com/NewsRoom/AttachmentNg/14f4cb31-7953-4c07-a55c-fc9db067db74 A photo accompanying this announcement is available at http://www.globenewswire.com/NewsRoom/AttachmentNg/e0fe1c2c-a804-47fb-847e-e4cfed98181e


Madrid, Spain, May 16, 2017 (GLOBE NEWSWIRE) -- An ambitious effort has been launched to prevent malaria in pregnancy in communities in sub-Saharan Africa. This innovative initiative will complement existing antenatal care services and increase pregnant women’s opportunities to access care under a grant agreement signed today by Unitaid and Jhpiego, an international nonprofit health organization and affiliate of the Johns Hopkins University. Unitaid is investing US $50 million to ensure that pregnant women in malaria-affected countries in sub-Saharan Africa have access to a preventive therapy for malaria known as “intermittent preventive treatment in pregnancy” or IPTp. The five-year project, to be implemented by Jhpiego, will increase IPTp coverage and expand antenatal care attendance in four African countries—the Democratic Republic of Congo, Madagascar, Mozambique and Nigeria. The project–-also known as “Transforming IPT for Optimal Pregnancy” (TIPTOP) – will increase IPTp coverage through community-level distribution of quality-assured sulfadoxine-pyramithimine (the medicine used for IPT). Jhpiego has partnered with the Barcelona Institute for Global Health (ISGlobal), which will lead the research and evaluation components of the project. The two organizations will also collaborate with the World Health Organization (WHO) and Medicines for Malaria Venture to achieve the desired results. This community-based IPTp approach, which will augment and complement existing antenatal care services by reaching 400,000 pregnant women and their babies, will also produce the evidence needed to update WHO’s policy on IPTp. In areas with high malaria transmission, pregnant women and young children are especially vulnerable to malaria infection and death. Although malaria is preventable and treatable, an estimated 429,000 people died from the disease in 2015, according to WHO. Moreover, malaria during pregnancy can lead to a number of negative consequences, including low birth-weight for babies and even still births. In some cases, malaria can be fatal for the mother. In 2015, IPTp coverage rates remained at just 31 percent in 20 African countries. The Unitaid-funded TIPTOP project plans to engage community health workers to increase IPTp delivery and demand to ensure there are no missed opportunities for pregnant women to receive this life-saving medicine either in the community or through the antenatal services. “By accelerating access to this critical, life-saving preventive therapy, we are hoping to avert further unnecessary deaths from malaria,” said Lelio Marmora, Unitaid’s Executive Director. “Unitaid continues to advance on all fronts by developing innovative tools to fight malaria and insecticide resistance.” Dr. Leslie Mancuso, Jhpiego’s CEO and President, said the TIPTOP project offers an exciting opportunity to demonstrate an innovative approach to address pregnant women’s needs and stop malaria in pregnancy. “Preventing malaria in pregnancy and reducing malaria-related deaths is achievable—and this partnership will go a long way toward reaching those goals,” she said. Jhpiego, an international nonprofit health organization affiliated with the Johns Hopkins University, has worked for 45 years to empower frontline health workers by designing and implementing effective, low-cost, hands-on solutions to strengthen the delivery of health care services for women and their families. The Barcelona Institute for Global Health (ISGlobal), the result of an innovative alliance between the “la Caixa” Foundation, academic institutions and government bodies, was set up to contribute to the work undertaken by the international community to address the challenges of health in a globalized world. Unitaid is an international organization that invests in new ways to prevent, diagnose and treat HIV/AIDS, hepatitis C, tuberculosis and malaria more quickly, more cheaply and more effectively. It accelerates access to innovation so critical health products reach people who most need them. Unitaid’s work allows large-scale introduction of health products through funding by the Global Fund, the United States President’s Emergency Plan for AIDS Relief (PEPFAR) and governments. For more information go to www.jhpiego.org or contact Kristin Vibbert at 1-484-888-0277. A photo accompanying this announcement is available at http://www.globenewswire.com/NewsRoom/AttachmentNg/9ee55620-f33b-42bf-a8a6-4995043cd5e4 A photo accompanying this announcement is available at http://www.globenewswire.com/NewsRoom/AttachmentNg/14f4cb31-7953-4c07-a55c-fc9db067db74 A photo accompanying this announcement is available at http://www.globenewswire.com/NewsRoom/AttachmentNg/e0fe1c2c-a804-47fb-847e-e4cfed98181e


News Article | May 25, 2017
Site: www.sciencedaily.com

Researchers at LSTM, working in partnership with the University of Liverpool and other colleagues, have developed a molecule which has the potential to become the first fully synthetic, one-dose treatment for malaria. In a paper published today in the journal Nature Communications, the multinational team describe the molecule, known as E209, as meeting the key requirements of the Medicines for Malaria Venture drug candidate profiles. The molecule is effective against parasites expressing the key genetic marker for artemisinin resistance in in vitro studies The control and elimination of malaria requires effective treatment strategies. For several years, this has been in the form of artemisinin-based combination strategies (ACTs), which has seen artemisinin based drugs combined with a drug partner with a longer half-life. The semi-synthetic ACTs have had a significant impact on malaria treatment however, the search for a fully synthetic alternative has been on for over a decade. The growing problem of resistance to current ACTs can lead to complete treatment failure. This has led the group to look at alternatives to retain the effectiveness against parasites with the known genetic markers of resistance while at the same time being fast acting. LSTM's Deputy Director, Professor Steve Ward, is a senior author on the paper. He said: "Extensive molecular investigations have demonstrated that mutations in the K13 gene are makers for artemisinin susceptibility and are linked to drug resistance in some malaria parasites. These mutations allow the parasite to survive exposure to the drug during the early stages of infection in the red blood cell. E209 is a breakthrough molecule, it is fully synthetic, retains the killing efficiency of the artemisinins, works against K13 mutant parasites and is slowly eliminated raising the hope that it could be used as a single dose cure." The other lead author Professor Paul O'Neill of the University of Liverpool, said: "E209 is a second-generation peroxide based drug, designed at Liverpool, with significant improvements over the gold standard antimalarial treatment artesunate. E209 contains a unique core with two endoperoxide units; through medicinal chemistry optimization, the stability, potency and pharmacokinetics of this class has now been optimized. The development of E209 has been made possible by our close partnership with the Medicines for Malaria Venture (Geneva) with MMV's Expert Scientific Advisory Committee, providing invaluable input to the project. " The extensive data set obtained for E209 was obtained through a global collaborative network of scientists around the world allowing this drug discovery project to be rapidly advanced.


Researchers at LSTM, working in partnership with the University of Liverpool and other colleagues, have developed a molecule which has the potential to become the first fully synthetic, one-dose treatment for malaria. In a paper published today in the journal Nature Communications, the multinational team describe the molecule, known as E209, as meeting the key requirements of the Medicines for Malaria Venture drug candidate profiles. The molecule is effective against parasites expressing the key genetic marker for artemisinin resistance in in vitro studies The control and elimination of malaria requires effective treatment strategies. For several years, this has been in the form of artemisinin-based combination strategies (ACTs), which has seen artemisinin based drugs combined with a drug partner with a longer half-life. The semi-synthetic ACTs have had a significant impact on malaria treatment however, the search for a fully synthetic alternative has been on for over a decade. The growing problem of resistance to current ACTs can lead to complete treatment failure. This has led the group to look at alternatives to retain the effectiveness against parasites with the known genetic markers of resistance while at the same time being fast acting. LSTM's Deputy Director, Professor Steve Ward, is a senior author on the paper. He said: "Extensive molecular investigations have demonstrated that mutations in the K13 gene are makers for artemisinin susceptibility and are linked to drug resistance in some malaria parasites. These mutations allow the parasite to survive exposure to the drug during the early stages of infection in the red blood cell. E209 is a breakthrough molecule, it is fully synthetic, retains the killing efficiency of the artemisinins, works against K13 mutant parasites and is slowly eliminated raising the hope that it could be used as a single dose cure." The other lead author Professor Paul O'Neill of the University of Liverpool, said: "E209 is a second-generation peroxide based drug, designed at Liverpool, with significant improvements over the gold standard antimalarial treatment artesunate. E209 contains a unique core with two endoperoxide units; through medicinal chemistry optimization, the stability, potency and pharmacokinetics of this class has now been optimized. The development of E209 has been made possible by our close partnership with the Medicines for Malaria Venture (Geneva) with MMV's Expert Scientific Advisory Committee, providing invaluable input to the project. " The extensive data set obtained for E209 was obtained through a global collaborative network of scientists around the world allowing this drug discovery project to be rapidly advanced.


In a paper published today in the journal Nature Communications, the multinational team describe the molecule, known as E209, as meeting the key requirements of the Medicines for Malaria Venture drug candidate profiles. The molecule is effective against parasites expressing the key genetic marker for artemisinin resistance in in vitro studies The control and elimination of malaria requires effective treatment strategies. For several years, this has been in the form of artemisinin-based combination strategies (ACTs), which has seen artemisinin based drugs combined with a drug partner with a longer half-life. The semi-synthetic ACTs have had a significant impact on malaria treatment however, the search for a fully synthetic alternative has been on for over a decade. The growing problem of resistance to current ACTs can lead to complete treatment failure. This has led the group to look at alternatives to retain the effectiveness against parasites with the known genetic markers of resistance while at the same time being fast acting. LSTM's Deputy Director, Professor Steve Ward, is a senior author on the paper. He said: "Extensive molecular investigations have demonstrated that mutations in the K13 gene are makers for artemisinin susceptibility and are linked to drug resistance in some malaria parasites. These mutations allow the parasite to survive exposure to the drug during the early stages of infection in the red blood cell. E209 is a breakthrough molecule, it is fully synthetic, retains the killing efficiency of the artemisinins, works against K13 mutant parasites and is slowly eliminated raising the hope that it could be used as a single dose cure." The other lead author Professor Paul O'Neill of the University of Liverpool, said: "E209 is a second-generation peroxide based drug, designed at Liverpool, with significant improvements over the gold standard antimalarial treatment artesunate. E209 contains a unique core with two endoperoxide units; through medicinal chemistry optimization, the stability, potency and pharmacokinetics of this class has now been optimized. The development of E209 has been made possible by our close partnership with the Medicines for Malaria Venture (Geneva) with MMV's Expert Scientific Advisory Committee, providing invaluable input to the project. " The extensive data set obtained for E209 was obtained through a global collaborative network of scientists around the world allowing this drug discovery project to be rapidly advanced. Explore further: Genetic surveillance and why it's critical in the fight against antimalarial drug resistance More information: Paul M. O'Neill et al, A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance, Nature Communications (2017). DOI: 10.1038/ncomms15159


Patent
University of Oregon, Medicines For Malaria Venture and University of South Florida | Date: 2013-10-16

Compounds of formula I: or formula II:


Wells T.N.,Medicines for Malaria Venture
Discovery medicine | Year: 2010

Malaria kills an estimated one million people a year--mostly children under 5. State-of-the-art medicines known as artemisinin combination therapies (ACTs) are available, and successfully cure up to 99% of patients. Additionally, insecticide-treated bed nets and insecticide spraying are helping to prevent the disease, while a vaccine is in clinical development. With all these tools at hand, you might ask why we need more new medicines. Why not just concentrate on improving the distribution of existing ones? Whilst access to medicines is clearly a major challenge, there are several reasons why new antimalarials are urgently needed--and will continue to be needed until we have finally defeated the parasite. First, the emergence of drug resistance to any infectious disease treatment is inevitable. A range of medicines with varying mechanisms of action are needed to stem the tide of drug resistance as well as fill the gap when it takes hold. Second, malaria is a disease predominantly affecting children and expectant mothers. These vulnerable patient groups require medicines tailored to their needs with robust safety profiles. Third, of the five species of malarial parasites that infect humans, two can relapse, and there is currently no safe medicine to combat the relapse for all patients. Finally, in order to ultimately eradicate malaria, medicines are needed that go a step beyond simple treatment and break the transmission of the parasite from patient to patient.


To assess the safety and pharmacokinetics of a new synthetic ozonide antimalarial, OZ439, in a first-in-man, double-blind study in healthy volunteers. OZ439 was administered as single oral daily doses of a capsule formulation (50-1200 mg) or an oral dispersion (400-1600 mg, fed and fasted states) and for up to 3 days as an oral dispersion (200-800 mg day(-1)). Plasma concentrations of OZ439 and its metabolites were measured by LC-MS. The pharmacokinetic (PK) profile of OZ439 was characterized by a t(max) of around 3 h, followed by a multiphasic profile with a terminal half-life of 25-30 h. The PK parameters were approximately dose proportional for each group and profiles of the metabolites followed a similar pattern to that of the parent compound. Following dosing for 3 days, accumulation was less than two-fold but steady-state was not achieved. In the presence of food, no effect was observed on the t(1/2) of OZ439 while the exposure was increased by 3 to 4.5-fold. Exposure was higher and inter-subject variability was reduced when OZ439 was administered as an oral dispersion compared with a capsule. The urinary clearance of OZ439 and its metabolites was found to be negligible and OZ439 did not induce CYP3A4. The antimalarial activity profiles of a subset of serum samples suggested that the major antimalarial activity originated from OZ439 rather than from any of the metabolites. The safety and pharmacokinetic profile of OZ439 merits progression to phase 2a proof of concept studies in the target population of acute uncomplicated malaria. © 2012 Medicines for Malaria Venture (MMV). British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.


Wells T.N.C.,Medicines for Malaria Venture
Malaria Journal | Year: 2011

Background: The discovery and development of new anti-malarials are at a crossroads. Fixed dose artemisinin combination therapy is now being used to treat a hundred million children each year, with a cost as low as 30 cents per child, with cure rates of over 95%. However, as with all anti-infective strategies, this triumph brings with it the seeds of its own downfall, the emergence of resistance. It takes ten years to develop a new medicine. New classes of medicines to combat malaria, as a result of infection by Plasmodium falciparum and Plasmodium vivax are urgently needed. Results: Natural product scaffolds have been the basis of the majority of current anti-malarial medicines. Molecules such as quinine, lapachol and artemisinin were originally isolated from herbal medicinal products. After improvement with medicinal chemistry and formulation technologies, and combination with other active ingredients, they now make up the current armamentarium of medicines. In recent years advances in screening technologies have allowed testing of millions of compounds from pharmaceutical diversity for anti-malarial activity in cellular assays. These initiatives have resulted in thousands of new sub-micromolar active compounds - starting points for new drug discovery programmes. Against this backdrop, the paucity of potent natural products identified has been disappointing. Now is a good time to reflect on the current approach to screening herbal medicinal products and suggest revisions. Nearly sixty years ago, the Chinese doctor Chen Guofu, suggested natural products should be approached by dao-xing-ni-shi or acting in the reversed order, starting with observational clinical studies. Natural products based on herbal remedies are in use in the community, and have the potential unique advantage that clinical observational data exist, or can be generated. The first step should be the confirmation and definition of the clinical activity of herbal medicinal products already used by the community. This first step forms a solid basis of observations, before moving to in vivo pharmacological characterization and ultimately identifying the active ingredient. A large part of the population uses herbal medicinal products despite limited numbers of well-controlled clinical studies. Increased awareness by the regulators and public health bodies of the need for safety information on herbal medicinal products also lends support to obtaining more clinical data on such products. Conclusions: The relative paucity of new herbal medicinal product scaffolds active against malaria results discovered in recent years suggest it is time to re-evaluate the smash and grab approach of randomly testing purified natural products and replace it with a patient-data led approach. This will require a change of perspective form many in the field. It will require an investment in standardisation in several areas, including: the ethnopharmacology and design and reporting of clinical observation studies, systems for characterizing anti-malarial activity of patient plasma samples ex vivo followed by chemical and pharmacological characterisation of extracts from promising sources. Such work falls outside of the core mandate of the product development partnerships, such as MMV, and so will require additional support. This call is timely, given the strong interest from researchers in disease endemic countries to support the research arm of a malaria eradication agenda. Para-national institutions such as the African Network for Drugs and Diagnostics Innovation (ANDi) will play a major role in facilitating the development of their natural products patrimony and possibly clinical best practice to bring forward new therapeutics. As in the past, with quinine, lapinone and artemisinin, once the activity of herbal medicinal products in humans is characterised, it can be used to identify new molecular scaffolds which will form the basis of the next generation of anti-malarial therapies. © 2011 Wells; licensee BioMed Central Ltd.

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