An overview of ACTs and their development, recently published on the Economist Intelligence Unit website ViewsWire
ACTs are improving and becoming cheaper, but fears of resistance remain
On January 27th, Novartis and the Medicines for Malaria Venture (MMV) launched a new medicine to treat malaria for children and infants. Coartem® Dispersible improves upon its WHO-endorsed predecessor, Coartem (artemether-lumefantrine), by masking the bitter taste of its artemisinin-based ingredients with a cherry flavor palatable to children. While the change may seem small, the drug’s makers hope that the medicine’s flavour and solubility will improve patient compliance, saving more children from a curable disease and preventing the development of resistance to effective treatments, namely artemisinin-based combination therapies (ACTs).
Like other poverty-related diseases, funding for malaria R&D is thin, amounting to approximately US$422m in 2007, less than one-half of the amount dedicated to HIV vaccine research that year (Roll Back Malaria Partnership and the HIV Vaccines and Microbicides Resource Tracking Working Group). Nonetheless, new ACTs have been rolling out at a fast pace in recent years, due in no small part to collaborative efforts between the public and private sectors and NGOs.
"From a public health perspective, it’s much better to have choice," MMV CSO Tim Wells told Healthcare Briefing. Some of the combinations are similar—a major concern in an under-funded field, where duplication of efforts can siphon resources from the development of novel new candidates—but a wider range may delay resistance from developing to a particular part of the drug combination, and provide more options for health providers in a variety of settings.
"At the moment we can say that these medicines are all good, but once we get out into the field there will be differences in how people respond," Wells said. "The major push is just to have alternative drugs, because we’re worried with something like Coartem, if we get resistance to lumefantrine, we’re in trouble."
Nudging out old treatments
ACTs have become silver bullets for curing the deadliest form of malaria parasite, Plasmodium falciparum, after the development of widespread resistance to chloroquine, a cheap generic still commonly used in Africa despite deteriorating effectiveness. The WHO recommended the use of ACTs in 2001, but governments in developing countries (notably in sub-Saharan Africa where roughly 90% of the world’s malaria deaths occur) were slow to take them up, largely due to the price tag.
However, initiatives from the past few years, especially by the Global Fund to Fight AIDS, Tuberculosis and Malaria, "blew the lid off production" of ACTs, making them much more affordable than in the past, according to George Jagoe, Executive Vice-President of Global Access at MMV. Now, "the funding is there for any willing government who is using the Global Fund properly to place the orders they need for the public systems they’re running, to supply the ACTs to their populations," he told Healthcare Briefing Jan. 21.
The cost of a course of Coartem—the first ACT to receive WHO prequalification—dropped from USD$2.50 in 2005 to USD$0.80 today. That’s still much more expensive than chloroquine, which sells at 10 to 15 cents per treatment, so organizations are working to drop the price further. This summer, the Affordable Medicines Facility- malaria (AMFm) Task Force—an international expert group borne from a 2004 Institute of Medicine report recommending a high-level ACTs subsidy—will launch a two-year pilot program with 11 countries in an effort to make ACTs more affordable. By negotiating co-payments with drug manufacturers, the project aims to make end-user ACT prices the same or lower than those of chloroquine and sulfadoxine-pyrimethamine (SP), another old first line malaria drug.
More medicines, new protections
The past two years have seen the launch of no less than three ACTs, including Coartem Dispersible. In October 2008, ASAQ, an artesunate-amodiaquine combination developed by DNDi and Sanofi-Aventis, received WHO prequalified status, which acts as a green light for public health officials to use the drug. So far, 21 countries have approved ASAQ, and three million treatments have been distributed. Another DNDi drug, ASMQ (artesunate and mefloquine) hit the Brazilian market last year through collaboration with Brazilian drugmaker Farmanguinhos. The drug will be distributed in Latin America and Asia, where no resistance is found to mefloquine.
In December 2008, MMV and South Korean pharmaceutical company Shin Poong finished most Phase III studies for another ACT, PYRAMAX, which uses a combination of pyronaridine and artesunate to treat uncomplicated P. falciparum malaria. A total of more than 3,500 patients in Asia and Africa participated in five clinical trials, the last of which will finish this year. PYRAMAX stands out as the first ACT to go through a pivotal trail in patients infected with Plasmodium vivax, a type of malaria parasite more common in Asia.
"That’s quite important in terms of the way we look at malaria in the future...the prediction is that vivax will become a bigger health problem," Wells said. MMV is also working on DHA-Piperaquine (dihydroartemisinin and piperaquine) with Italian company Sigma-Tau, which signed a license and supply agreement with Pfizer in December to market the new ACT via public and private channels in Africa following registration with the European Medicines Agency in 2009 and the U.S. Food and Drug Administration in 2010.
Saving lives with half-lives?
MMV researchers are excited about these candidates for several reasons: both PYRAMAX and DHA-Piperaquine are once-a-day therapies that do not have to be ground up —features that ought to improve patient compliance. Both have hit their endpoints and appear as efficacious or better than comparator drugs. Perhaps most intriguingly, both seem to provide protection from re-infection due to their long half-lives, raising the possibility that treating patients several times a year with lower doses of the drugs could act as a sort of malaria vaccine.
"If they get re-infected during the first 20-40 days....does that [long half-life] actually protect them from re-infection? The data says that it does," Wells said. "One of the questions in the future will be, ’Can we use the current generation, and the next, and the next generation of drugs to protect people?’"
Although ACTs are likely to provide effective malaria treatment for decades to come, researchers are turning their attentions to novel formulations in order to broaden the pre-clinical pipeline and reduce dependence on artemisinin supplies, which remain insufficient for the roughly 300m anti-malarial treatments needed each year. In addition, some evidence of resistance to artemisinin is emerging from the Thai-Cambodian border, where ACTs are taking up to three times as long to cure some malaria patients. MMV is planning to test ACTs and novel candidates, including OZ-439 made from synthetic artemesinin, in the region in order to gather more information about this alarming development.
"One of our priorities is not to have just a next generation of ACTs, but other compounds in our portfolio in case there’s resistance to ACTs," Wells said. Source: Industry Briefing
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