New malaria drug candidate could cure in a single dose

A brand new synthetic antimalarial drug candidate has shown spectacular activity in mice, and could lead to Phase 1 trials in humans next year. A dose of the "peroxide" molecule cut mouse malaria parasitaemias extremely rapidly, as quickly as artemisinin — the current record-holder. But whereas artemisinin and its derivatives let the malaria parasite grow back within a few days, requiring more doses of the drug or additional drugs in combination, the new peroxide kept the parasites down for more than 60 days with just a single dose.

"It's quite remarkable and doesn't quite fit with the pharmacokinetics [the way the drug moves through the animal] but we are working on that to put the pieces together to understand how it's working", John Vennerstrom of the University of Nebraska, leader of the international research team that created the drug, told the Bulletin.

In June the Medicines for Malaria Venture (MMV), a public–private partnership, picked this as the most promising research funded by MMV over the past year.

Simon Campbell, former Head of Worldwide Discovery at Pfizer, who chairs the MMV Expert Scientific Advisory Committee said "This group took the well-established antimalarial `warhead' found in artemisinin and developed it into a chemical series that is now very drug-like and amenable to modern drug optimization techniques and to industrial scale-up."

Vennerstrom would not describe the molecule precisely, because his US, Swiss and Australian research team are seeking a patent, but did tell the Bulletin "it's a different type of peroxide [an oxygen–oxygen chemical bond] than the trioxane you find in the peroxide of artemisinin. Its molecular weight is in the range of 300–500: artemisinin's is 280."

"The peroxide is the active bit of artemisinin. But that's where the similarity with our molecules ends. Artemisinin and its derivatives have a very elegant structure, but they can't be economically synthesized, and they also have some undesirable properties — they are very fast-acting but they have to be used in combinations with other drugs, because they are rapidly broken down in the body. That's where our molecule has major potential advantages."

"We're following up on it, and are looking at it as a prototype to make other derivatives" said Vennerstrom.

"Next we have to identify the exact candidate for drug development ... it could be this exact molecule, or another; the activity of this one is outstanding but we want to get some better pharmacokinetic properties ... we'd like to increase the stability in the plasma ... and we're thinking about the optimal compound — one that's as cheap as possible to produce. And then we also have to consider the toxicity/therapeutic index. We've not seen any toxicity in this compound, but we haven't done all the experiments yet."

This discovery was driven by a new synthetic reaction discovered by Karl Griesbaum of Karlsruhe University in Germany, said Vennerstrom. "We realized that his technology could enable us to synthesize some very interesting compounds, and this particular peroxide is stable enough that we can do some very interesting chemistry on it. In that way it's quite similar to artemisinin."

Also like artemisinin, the target of the drug is probably iron in the parasite, left over from the parasite's digestion of haemoglobin, Vennerstom believes.

The research began with a small grant from the UNDP/World Bank WHO Tropical Disease Research Programme (TDR), which collaborates closely with MMV. "A typical grant from TDR at that time was $50–70000, which gave us a technician and a PhD student." That got the discovery process going, "then MMV gave us US$ 1 million, so it was an order of magnitude boost at least". The Swiss pharmaceutical company Hoffmann-La Roche is also putting in a goodwill effort. "They used to have a small malaria drug development group. It was disbanded; but there are still some people who are interested, even though they have expressed no interest at this point in developing any potential candidate" said Vennerstrom.

Vennerstrom makes the compounds in Nebraska, the Swiss Tropical Insitute tests their activity against mouse malaria, and Monash University in Australia studies interactions with the body chemistry. According to Bill Charman, team leader at Monash, the global collaboration "works because people trust each other; a number of people have said that the way that we do this is better than 'big pharma'! There's no politics — none of that stuff happens. The slowest part in getting a readout on the metabolism and pharmacokinetics after John makes compounds in Nebraska is the Federal Express shipping time from there to here."

If the product goes beyond Phase 1, getting a developer and ensuring access to a registered drug as a "public good" will be MMV's job. Officially launched at the end of 1999 as a public– private partnership for the discovery and development of new antimalarial drugs, MMV is supported by the Bill and Melinda Gates Foundation, ExxonMobil Corporation, the Global Forum for Health Research, the International Pharmaceutical Manufacturers' Association, the Netherlands Ministry for Development Cooperation, the Rockefeller Foundation, the Swiss Agency for Development and Co-operation, the UK Department for International Development, the Wellcome Trust, the World Bank, WHO, Roll Back Malaria, and TDR.

MMV's structure should bring advantages. While bringing a new drug from discovery to market is usually estimated to cost more than US$ 500 million, MMV aims to do it for an outlay of just US$ 150 million — complemented by substantial in-kind support from the pharmaceutical industry. If its funding targets are reached, MMV's goal is to have its first commercial product available well before 2010. However there may be funding problems ahead: projections in MMV's annual report (2001) showed a potential cumulative shortfall from funding targets of nearly US$20 million by 2003.

"We are all working very hard at trying to raise the needed money, and hope the kind of results we and our collaborators have demonstrated with the synthetic peroxides will help. We would particularly like to see new government agencies from North America, Europe and the rest of the developed world join the ranks as donors" said an MMV spokeswoman. In 2001 MMV received US$6.1 million from philanthropic foundations, US$4.25 million from UN agencies, and US$2.8 million from government development agencies.

Robert Walgate, Bulletin

World Health Organization Genebra - Genebra - Switzerland