Center for Global Health R&D Policy Assessment

Today, in 2011, we are a far cry from the empty malaria medicine pipeline of the 1990s. There are two WHO-prequalified artemisinin-based combination therapies (ACTs) available (artemether/lumefantrine and artesunate/amodiaquine) and two more due to be launched in 2012 (Eurartesim® [dihydroartemisinin/piperaquine] from sigma-tau Industrie Farmaceutiche Riunite and Medicines for Malaria Venture [MMV] and Pyramax® [pyronaridine/artesunate] from Shin-Poong Pharmaceuticals and MMV). Additionally, we now have a WHO-prequalified treatment for severe malaria at our disposal. But, the complex nature of the malaria parasite means further innovation in malaria treatment is a key aspect of progress toward elimination and eradication.

Drug resistance

This is not the first time the world is attempting to eradicate malaria; the emergence of resistance to chloroquine, the key therapy of the eradication campaign of the 1950s and 60s, was one of its main stumbling blocks. Fast forward to 2008, when we received the first reports of a delay in the parasite’s response to artemisinin in Southeast Asia, and we see signs of history repeating itself. It’s clear that we must do everything we can to prevent widespread artemisinin resistance, but we must also be prepared for it. Working to develop alternatives to artemisinin now, and even alternatives to the alternatives, is, therefore, a key R&D priority.

In MMV’s pipeline, there are seven new chemical entities already progressing through clinical development. OZ 439, a synthetic endoperoxide, is one of these. It is in Phase II and is the lead horse in a strong field of contenders to replace artemisinin. In addition, early discovery work is progressing to ensure we always have a strong set of alternatives in the future—so far, more than six million compounds have been screened for antimalarial activity, resulting in 25,000 new chemical starting points. The most advanced of these are in Phase I of clinical development.

Children and pregnant women

Treating children and pregnant women suffering from malaria is a lot more complex than treating the average adult patient, since these two groups are the most vulnerable. They require medicines tailored to their needs with robust safety profiles. One of the challenges is dosing, since the effect of medicines on the body may differ markedly in children and infants compared to adults. Also, antimalarial medicines are extremely bitter and often irritate the gastrointestinal tract, resulting in nausea and vomiting. MMV and Novartis developed a taste-masked formulation, Coartem® Dispersible–the first high-quality artemisinin-based combination therapy (ACT) for children. Since its launch in 2009, 92 million treatments have been delivered to 35 countries. We are now exploring whether Coartem Dispersible can also be used to accurately treat infants under 5kgs. The MMV team continues to address the needs of children by developing pediatric formulations of all our medicines at the earliest possible opportunity in the development process. The pediatric dossiers for both Eurartesim and Pyramax will be submitted for regulatory approval following those for the adult formulations.

For pregnant women, malaria poses a serious risk–it is the leading cause of death for them and their new-born babies in sub-Saharan Africa. One approach to tackle this is to provide protection known as Intermittent Preventive Treatment in pregnant women (IPTp), whereby women take a three-dose course of medicine, currently sulfadoxine–pyrimethamine (SP), during pregnancy (it’s akin to a pharmacological vaccination). It significantly increases the chances of a healthy baby being born and has been adopted by many African countries. However, the parasite has begun to develop resistance to SP thus creating an urgent need for an alternative. MMV is partnering with Pfizer to develop an alternative that will also treat any underlying sexually transmitted diseases, thereby improving overall pregnancy outcomes. The combination comprises azithromycin and chloroquine, both of which are well tolerated during pregnancy and work synergistically against chloroquine-resistant strains of the parasite, even in areas of high chloroquine resistance. The pivotal Phase III trial is underway and expected to be completed in 2013.

Relapsing malaria

Currently, there is no safe medicine to treat the relapse of Plasmodium vivax, a specific malaria parasite prevalent in Southeast Asia and South America. Because of its uncanny ability to remain dormant in the liver of its host in a form known as the hypnozoite, this parasite can reactivate any time between three weeks and several years–leaving its victims vulnerable to relapse, without warning, into the feverish symptoms of malaria. Compared to Plasmodium falciparum (the parasite responsible for the vast majority of malaria deaths), P. vivax has, until recently, been considered relatively benign. But current data showing that it is responsible for 80–300 million clinical cases a year is changing this perception.

The only approved anti-relapse drug is primaquine. However, it has two significant weak points. First, it must be taken daily for 14 days to be effective–such compliance is unachievable in reality. Second, in patients who are deficient in the enzyme glucose 6-phosphate dehydrogenase (G6PD) (a condition occurring in up to 10-20% of the population in some malaria-endemic countries) primaquine causes hemolytic anaemia. MMV and GlaxoSmithKline (GSK) are working to develop a next-generation anti-relapse drug, tafenoquine, which could provide a one-dose cure for the relapse. This would be a significant improvement on the current 14-day course of primaquine. However, because patients taking tafenoquine may also suffer from anaemia, MMV and partners have developed the technology to be able to screen molecules active against the hypnozoite with the aim of finding improved drug candidates. The first series of promising molecules have been identified and plans are in place to move a potential drug candidate into preclinical development in 2012.

Blocking transmission

Finally, blocking transmission from patient to patient will be critical for eradication. In a malaria patient the majority of the parasites are asexual, destroying red blood cells and causing the clinical symptoms of malaria. A small proportion of the parasites (1%), however, form gametocytes, the sexual form of the parasite. When taken into the gut of the mosquito where they reproduce, these gametocytes continue the cycle of infection. MMV and Imperial College London have developed several assays to screen all known and in-development antimalarials against the sexual forms of the parasite. So far, these assays have enabled us to identify and prioritise a new series of compounds with transmission-blocking activities in addition to blood-stage activity. We have also developed high-content screening assays with Eskitis Institute, Griffith University, Australia and GSK in Spain, which are being used to systematically screen large compound libraries.

Malaria is caused by multiple parasites with complicated lifecycles, and so in our response to treatment we must be multi-pronged. Though the timeline for eradication is uncertain, our current pipeline is strong – including many new options beyond ACTs to address the main treatment challenges today and in the future.