News Article | April 26, 2017
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 - firstname.lastname@example.org +27 21 6501433 (office) or Kim Cloete email@example.com +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; firstname.lastname@example.org
University of Oregon, Medicines For Malaria Venture and University of South Florida | Date: 2013-10-16
Agency: European Commission | Branch: FP7 | Program: CSA-CA | Phase: HEALTH-2007-2.3.2-13 | Award Amount: 560.75K | Year: 2009
Antimalarial drug discovery and development initiatives globally are fragmented and uncoordinated. We have brought together key organisations including MMV, WHO and AntiMal, an EU-funded FP6 Integrated Project represented by its coordinating institution and a number of academic malaria researchers, to resolve this problem through a logical series of meetings, conferences, workshops and dissemination strategies. The Gates Foundation will be involved as an invited participant. The action will co-ordinate leading European malaria research initiatives in antimalarial drug discovery and development, co-ordinate the European effort with international initiatives, engage industry and provide guidance on standardisation of core requirements of regulatory drug development. This will contribute towards generating global priorities and prepare the European antimalarial research agenda for the next decade.
News Article | November 30, 2016
Sydney Grammar students, under the supervision of the University of Sydney and global members of the Open Source Malaria consortium, have reproduced an essential medicine in their high school laboratories. The drug, Daraprim, had been the subject of controversy when the price was hiked from US $13.50 to US$750 a dose last year. Daraprim - originally used as an antimalarial after its synthesis by Nobel Prize winner Gertrude Elion - is now more widely used as an anti-parasitic treatment for toxoplasmosis, which can be a dangerous disease for pregnant women and people with compromised immune systems, such as those living with HIV or AIDS. Daraprim is listed by the World Health Organisation as an essential medicine. In September 2015, Turing Pharmaceuticals acquired the market rights to Daraprim and raised the price of a dose more than 5000 percent overnight. CEO at the time, Martin Shkreli, stuck by the price, despite criticism including from US Secretary of State Hillary Clinton. To highlight the inequity of the monopoly, high school students in Sydney have been working with the Open Source Malaria consortium to make Daraprim in the laboratory using inexpensive starting materials, as part of the Breaking good - Open Source Malaria Schools and Undergraduate Program. Scientists anywhere in the world were able to view all the data generated and mentor the students to accelerate the science under the coordination from The University of Sydney's Dr Alice Williamson and Associate Professor Matthew Todd. Dr Williamson from the School of Chemistry said the scientific community could provide advice and guidance to the students online in real time. "The enthusiasm of the students and their teachers Malcolm Binns and Erin Sheridan was translated into a complete route in the public domain by the use of the Open Source Malaria platform," Dr Williamson said. "Anyone could take part and all data and ideas are shared in real time." Associate Professor Matthew Todd said the innovative open-source approach lowered the barrier to participation by researchers outside traditional institutions, such as universities and pharmaceutical companies, allowing students to work on real research problems of importance to human health. "Daraprim may be quickly and simply made, bringing into question the need for such a high price for this important medicine," Associate Professor Todd said. The findings were presented at the 2016 Royal Australian Chemical Institute Organic One Day Symposium today. Open Source Malaria is supported by the Medicines for Malaria Venture and the Australian Government, as well as by an international network of contributors.
The University Of Texas System, Monash University, Glaxosmithkline, University of Washington and Medicines For Malaria Venture | Date: 2010-09-28
Inhibitors of parasitic dihydroorotate dehydrogenase enzyme (DHOD) are candidate therapeutics for treating malaria. Illustrative of such therapeutic agents include the compound: and a triazolopyrimidine class of compounds that conform to Formula IX: and their solvates, stereoisomers, tautomers and pharmaceutically acceptable salts.
News Article | September 15, 2016
Malaria remains one of the world’s leading causes of mortality in developing countries. Last year alone, it killed more than 400,000 people, mostly young children. This week in ACS Central Science, an international consortium of researchers unveils the mechanics and findings of a unique “open science” project for malaria drug discovery that has been five years in the making. The current gold standard antimalarial treatments are based on artemisinin, a compound developed in the 1970s in China, combined with a partner drug. Yet, resistance to artemisinin and its partners has already emerged in some parts of the world. If the resistance spreads, there are no viable replacement treatments. Given the lack of commercial incentive for industry to develop drugs for neglected diseases such as malaria, and because academic researchers often lack resources to move compounds forward, there is a clear need for new approaches. In response, Matthew Todd from the University of Sydney together with the not-for-profit research and development organization Medicines for Malaria Venture proposed an “open source” solution akin to the open source concept used in software development. More than 50 researchers from 21 organizations in eight countries added their research to the project, which started with a large set of potential drug molecules made public by the company GlaxoSmithKline. Anyone willing to contribute — anywhere in the world — was welcome to share data and collaborate by adding comments to an electronic notebook as part of the Open Source Malaria Consortium. Some scientists designed and synthesized new generations of the antimalarial compounds; others ran assays and interpreted results. Several rounds of research were conducted, addressing water solubility and structural issues, with all the data being made public in real time. A wide array of scientists, from professors to undergraduates, participated by choice, agreeing that no one would individually seek patents to protect their contributions. The authors note that the current results, while promising, are merely the beginning of the story. They continue to welcome additional contributions, also researched openly and collaboratively.
News Article | September 7, 2016
Researchers have discovered a family of antimalarial agents that use a new mode of action to battle the malaria parasite. Malaria, transmitted by mosquitos, is endemic in developing countries, especially in Africa. The World Health Organization estimates there were 214 million malaria cases and 438,000 deaths from the disease last year. Plasmodium falciparum is the parasite responsible for most deaths worldwide. A number of treatments are available, but the microorganism has developed resistance to many of them. When the parasite infects animals, it attacks in three stages: It goes into liver cells first, then enters blood cells, and finally forms gametes that can be transmitted to mosquitos. Most treatments primarily target parasites in the blood stage, which causes malaria’s symptoms—fever, vomiting, and coma. Stuart L. Schreiber of the Broad Institute and Harvard University and coworkers have now discovered agents that kill the parasite in all three stages in infected mice, curing the mice for up to 30 days with a single oral dose (Nature 2016, DOI: 10.1038/nature19804). The team identified the compounds by screening 100,000 molecules in the Broad’s diversity-oriented synthesis (DOS) library. DOS, a strategy Schreiber’s group introduced in 1990, is a way to synthesize compounds that mimic the structural complexity and diversity of natural products. “The study is a tour-de-force combination of innovative synthetic chemistry and elegant functional screening applied to a major human health problem,” comments Benjamin Cravatt, an expert in enzymes and human disease at Scripps Research Institute California. After initial screening of the 100,000 compounds for antimalarials, additional screening focused on compounds effective against all three parasite stages and likely to hit previously unknown targets. The result was a series of bicyclic azetidines, including a promising compound called BRD7929. The agents’ new mechanism of antimalarial action is inhibition of the enzyme phenylalanyl tRNA synthetase, which helps the microorganism synthesize proteins. By hitting all three parasite stages, a drug not only could eliminate malaria symptoms but also stop disease transmission and perhaps deter resistance. Eisai Inc. is developing the antimalarials with support from the Global Health Innovative Technology Fund. Schreiber’s group also made all structures and screening data available online at a new Malaria Therapeutics Response Portal. “We invite the scientific community to use this database as a jumping-off point” for antimalarials development, Schreiber says. Jeremy Burrows and James Duffy of the drug discovery unit at the Medicines for Malaria Venture, an organization that coordinates international efforts to develop antimalarials, comment that if a candidate from the series is ultimately shown to have long-duration efficacy in patients, then “it could be a significant contribution to MMV’s goal to deliver single-dose treatments and chemoprotectants.” Single-dose oral treatments are especially important in the resource-limited areas where malaria is prevalent because they can be cheap and easy to administer. However, Burrows and Duffy note, extensive optimization and further development will be necessary for this discovery to have impact in the field.
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.
Moehrle J.J.,Medicines for Malaria Venture
British journal of clinical pharmacology | Year: 2013
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.