An end to malaria?

Prof Kelly Chibale (centre front) and his team have brought the world closer than ever before towards finding a cure for malaria.
(Image: H3-D)

The female Anopheles mosquito picks up the disease when she drinks the blood of an infected person and transmits it when she moves to the next person..
(Image: Centres for Disease Control)

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• Elaine Rutherfoord-Jones
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Development Centre
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Lorraine Kearney

A malaria-free world: this is a tantalising possibility that may be now within our grasp. And it’s a proudly South African project, says Prof Kelly Chibale, the director and executive committee member of the Drug Discovery and Development Centre (H3-D) at the University of Cape Town (UCT).

Last week, flanked by the professor, Science and Technology Minister Naledi Pandor announced the discovery at the centre of a potential single oral dose cure for malaria, the holy grail in lightening the world’s disease burden.

Chibale, who is the lead researcher of the collaborative research project, explains: “This is a potential cure for malaria. It is now entering the clinical trial phase – clinical trials should begin at the end of 2013. If the trials are successful, then not only will we have a cure for malaria, but it will also have the potential to stop person-to-person transmission of the parasite.”

The breakthrough is huge: at stake is the possibility of eradicating malaria at some stage in the future, he stresses.

“With this molecule, we have a potential drug that works at all life cycle stages of the parasite, including at the blood stage, and at the stage where transmission back to the mosquito occurs.”

Essentially, this means that it would stop the parasite from infecting mosquitoes when they bite people who have malaria.

Work started on the discovery back in early 2008, in Geneva, Switzerland. Dr Tim Wells, the chief scientific officer at the Medicines for Malaria Venture (MMV) was about to start a campaign to test chemical samples to find new compounds that would act against the human malaria caused by the Plasmodium falciparum parasite. He was working with Prof Vicky Avery at the Eskitis Institute at Griffiths University in Brisbane, Australia.

The H3-D was set up in April 2010 through the joint efforts of MMV, UCT and other international stakeholders, as well as the South African government. They included Cape Biotech Trust, which is now part of the Technology Innovation Agency.

The project that led to the discovery of MMV390048 in September 2010 began on 1 April 2009, and became a purely South African venture in January 2012.

Professor Chibale explains that the discovery, which happened at UCT, was particularly significant because it was the first-ever clinical molecule discovered by Africans. It will be the first clinical candidate researched in Africa.

How malaria works

Once a person is bitten by a carrier mosquito and is infected, the parasite attacks the person’s liver. Malaria is transmitted by mosquitoes of the Anopheles genus, and in Africa the culprit is the A. gambiae complex of seven indistinguishable insects.

At this stage, there are no symptoms of the disease. It multiplies rapidly in the liver and invades the blood, causing red blood cells to explode. Debilitating sickness sets in, often leading to death, particularly among children. But the MMV390048 molecule could also potentially work as a prophylaxis, Chibale points out.

Taken before you entered a malaria area, it could prevent the parasite from multiplying if you were bitten. And for those people who lived in malaria areas, who can have several episodes of the disease a year, it could protect them from reinfection.

The potential cure can make other claims: it works on all strains of the disease, including that found in Africa, which is mostly from P. falciparum, the most deadly, and that found in Asia, mostly from P. vivax, which is responsible for relapse. And it works on drug-resistant strains of malaria. But perhaps most importantly, it is a potential cure.

“Our definition of a cure is that after 30 days there is not a single parasite in a sample from a live animal. Chloroquine, one of the drugs used now to treat malaria, does not cure in the same animal model; there are still some parasites in the blood of animals treated with chloroquine 30 days after treatment,” the professor explains.

“This is very exciting. It is a single dose, while other drugs need high multiple doses in the same animal model. This has huge cost and compliance [medicine adherence] implications. People often take a drug, feel better and stop taking the medication. But they still have the parasite in their systems. This leads to drug-resistance. This molecule could stop this.”

Cost is a big issue. “We want it to be a single oral dose costing less than a dollar per treatment. This was one of the issues we identified in the lead optimisation phase of development.”

The molecule is synthetic, from the aminopyridine class, helping to keep costs down. It is made in the laboratory from readily available resources. Supply issues are very important in drug manufacture, and this molecule can be made in a few steps, which makes it cheaper, Chibale stresses.

“During the crucial lead optimisation phase, we tested for cardiotoxicity and drug-drug interaction risks. Then, the penultimate phase was the candidate profiling stage, when we gathered data, mostly on safety – because the safety of future patients is the most important thing. Once we had a dossier, we presented it to Medicines for Malaria Venture’s expert scientific advisory committee in July. They approved the molecule for clinical development.”

MMV’s funders include BHP Billiton and Exxon Mobile.

Clinical trials next

The next step, now being taken, is preparing for clinical trials: patients and volunteers need to be recruited and permission needs to be granted by the authorities. A commercial venture also needs to be found to manufacture the drug at scale.

“This is being discussed now. The idea is to do as much as possible in South Africa.”

Developing the molecule has been a steep but worthwhile learning curve for the scientists at UCT.

“We have no guarantee on the clinical trials,” Chibale says. “But we have so many positive spin-offs so far. We’ve been able to develop skills and expertise. Lessons have been learned. And the skills are now being used for other illnesses. Now we know how to discover drugs – it is not only a gift to Africa, but a gift to the world.

“It also provides employment, such as in manufacturing. And we now have back-ups. We have a healthy pipeline to keep discovering and making useful drugs. Because it is a continuous war against the organisms. They want to live, and they are very clever, so we need to keep finding new ways to beat them, because we want to live too.”

Funding for the project came from the Department of Science and Technology, which invested R25-million (US$3-million). Chibale also has a research chair from the department. MMV invested about R15-million ($1.8-million), and UCT provided the infrastructure and some funding. A partnership has also been set up between MMV and the department’s Technology Innovation Agency, and the project is now being funded by the two entities on a one for one basis. It has been scaled up with this new funding, and the team has been able to expand from four to 10 scientists.

If MMV390048 indeed proves to be a cure, the implications will be far-reaching. Malaria plays a big role in the cycle of poverty, Chibale points out. It debilitates its victims; they cannot work and take weeks to recover. Without proper nutrition and the ever-present possibility of reinfection, the disease’s toll is massive in human terms and on productivity.

A child dies every 46 seconds from malaria in sub-Saharan Africa, and 90% of malaria deaths take place in sub-Saharan Africa, Dr Tom Ellman, head of Medecins Sans Frontieres South African Medical Unit, was quoted as saying in the Daily Maverick. It was estimated that African economies lost up to R100.5-billion ($12-billion) a year directly related to malaria and its impact on productivity.

Malaria fact sheet

The World Malaria Report 2011 issued by the World Health Organisation in December 2011 reported:

• There were 216 million cases of malaria in 2010; 81% of these were in the WHO African Region.
• An estimated 3.3 billion people were at risk of malaria in 2010.
• An estimated 655 000 people died of malaria in 2010; 86% of the victims were children under 5 and 91% of malaria deaths occurred in the WHO African Region.
• In 2010, there were 46 malaria-endemic countries in sub-Saharan Africa; 43 of these belong to the WHO African Region, and three (Sudan, Somalia and Djibouti) were in the WHO Eastern Mediterranean Region.
• 45 countries around the world have identified resistance to at least one of the four classes of insecticides used for malaria vector control; 27 of these are in sub-Saharan Africa.

Estimated malaria cases and deaths by WHO Region, 2010

Region                                           Estimated cases        Estimated deaths

African Region                                 174-million                   596 000

Americas Region                              1-million                       1 000

Eastern Mediterranean Region           10-million                     15 000

European Region                              20                              0

South-East Asia Region                     28-million                     38 000

Western Pacific Region                      2-million                       5 000