"There will be statues of Bill Gates across the Third World. There’s a reasonable shot that – because of his money – we will cure malaria." So said author and journalist Malcolm Gladwell back in June 2012, as The Bill and Melinda Gates Foundation, replete with the Microsoft founder’s billions, made eradicating malaria its top priority.
In the years since the foundation has given out more than $2bn in grants to help combat the disease and has helped to drive some highly significant breakthroughs. In July the world’s first vaccine against the disease, Mosquirix – the development of which was backed by the foundation – was given the green light by the European Medicines Agency . It will now come under review of the World Health Organization (WHO).
While such victories are welcome, there is still a huge amount of work to be done. Mosquirix is by no means a silver bullet, demonstrating efficacy in only 27-46% of cases. Despite being completely curable, malaria claimed the lives of 584,000 people in 2013. A majority of these were children and pregnant women, mainly in Sub-Saharan Africa, as high costs and poor logistics stop vital medical supplies from getting to those most in need.
Around 319 million rapid diagnostic tests for malaria were bought worldwide in 2013, an increase of 85% on 2008 levels. Yet nearly 40% of people with suspected malaria in Africa during 2013 were not tested, according to the WHO, mainly due to lack of readily available equipment. While these problems can be helped by a combination of political will and the strategic reallocation of resources, there is another more foreboding challenge.
While on one side of the war zone malaria continues to adapt, on the other side research is intensifying.
In certain parts of the world, such as on the India-Burma border, malaria parasites have grown resistant to many available anti-malarial drugs, including Artemisinin, which in combination with other drugs is the first line of defence against the disease. To date, parasite resistance to Artemisinin has been documented in three of the five malaria species known to affect humans: falciparum, vivax and malariae.
Preventable, curable and noncommunicable
The race has been on to find new medicines that are effective but target the disease in a novel way that can sidestep the problem of growing resistance. A new discovery by scientists at Dundee University and Swiss non-profit organisation the Medicines for Malaria Venture (MMV) could be the biggest breakthrough yet. The team has developed a compound known as DDD107498, which in experiments with mice has proven to be as effective as, or more effective than, existing anti-malarials. It has also been shown to stop the transmission of the disease – an unprecedented step forward.
The compound stops transmission by disrupting the basic mechanics of the virus rather than by targeting it at a particular stage of its development, as existing drugs do. Typically after being bitten by an infected mosquito, infection spreads first to cells in the liver and then to the red blood cells (which is when the severe flu-like symptoms start). The infection then reproduces in the blood, so if a victim gets bitten again at this stage, the offending mosquito can become infected and go on to infect another human.
Most existing therapies target the disease in its red blood cell phase, ignoring the parasite as it reproduces in the blood. DDD107498 blocks the production of a protein vital to the virus’s development and survival, making it affective across all three phases. To boot, if current results are replicated, the drug will only require a single, $1 dose in the form of a tablet taken orally, which will help make it accessible to sufferers in the poorest and most remote regions.
Put them together and see what happens
According to Kevin Read, joint leader of the team that developed the compound, this discovery is the culmination of more than five years of work. In 2009, the University of Dundee ‘s Drug Discovery Unit started blind testing a collection of 4700 compounds, "screening them against the falciparum parasite just to see what happens." The team brought a handful of the most promising ones to MMV, which offered to fund the further development of three particularly strong examples.
It took some time to engineer the right molecular properties in the compound, but a process of chemical optimisation (outlined in the journal Nature ) reduced its molecular mass and lipophilicity and increased its potency by 100 times. By the end of 2013, DD107498 had become a candidate for full pre-clinical development. Specifically, the compound targets what is known as translation elongation factor 2, a protein that is essential to protein synthesis.
"Obviously we didn’t know anything about the drug target at the time because we were screening directly against the parasite," Read tells us. "During 2013, once we had a molecule that was of interest, we did some sequencing with the Sanger Institute [a genome research institute funded primarily by the Wellcome Trust] and that brought out what the target ended up being. Clearly this is a novel disease target for malaria so it was a double whammy for us – we’ve got a good drug that offers anti-malarial activity across the lifecycle stages but also a molecule that has identified a new potential drug target."
Rights to the compound have been acquired by Merck Serono, the biopharmaceutical arm of Merck. Final tests with rodents and dogs are being carried out now, with phase one clinical trials likely to start in the first half of next year. The big question is whether the compound works as well on humans as it has on mice. Its pharmacokinetic properties are encouraging – good oral bioavailability, which means a lot of it enters the bloodstream when taken in pill form, and long plasma half-life, giving hope that it will remain active in the blood stream for long enough to only require a single dose, even in more severe cases.
"We are very hopeful this will deliver what it says on the tin," Read says. "It’s certainly got a very long half-life as well so in predicted human pharmacokinetics things are looking very encouraging. Then we can have a huge splash with clinical proof of concept in two and a half years’ time."