Experimental drug candidate shows promise as next generation treatment for drug-resistant malaria

Resistance to existing antimalarial drugs, including artemisinin derivatives, is on the increase and new drugs are urgently needed to combat the problem. Yet despite advances in our understanding of the parasite's genome, identifying and validating new drug targets has proven challenging.

The new candidate, NITD609, belongs to the spiroindolene family of drugs and was identified by a team at the Novartis Institute for Tropical Diseases (NITD) working in collaboration with researchers from the Genomics Institute of the Novartis Research Foundation (GNF), the Swiss Tropical and Public Health Institute and The Scripps Research Institute.

Major support for the project was provided by the Wellcome Trust, Medicines for Malaria Venture (MMV) and the Agency for Science, Technology and Research (A*STAR), as well as the US and Singapore governments.

The study, published in the journal 'Science', shows that NITD609 is active against the two most common parasites responsible for malaria - Plasmodium falciparum and P. vivax - and is also effective against a range of drug-resistant strains.

In a mouse model of malaria infection, a single dose of NITD609 was sufficient to clear the disease and the experimental drug shows chemical properties that are compatible with a once-daily dosing regimen.

Bryan Yeung from Novartis Institute of Tropical Diseases, who led the project, explains how they identified NITD609: "Using a novel Plasmodium whole-cell assay we were able to tap into the Novartis archive of 12 000 pure natural products and synthetic compounds to identify 275 compounds highly active against P. falciparum, the most prevalent and deadly form of malaria.

"From this set all but 17 compounds were discarded for failing to meet pharmacological and efficacy standards. Of the remaining compound classes - the spirotetrahydro-beta-carbolines or spiroindolones - displayed the desired physicochemical properties for drug development as well as a mechanism of action distinct from the currently used therapies based on aminoquinolines and artemisinin derivatives."

Unlike existing antimalarial drugs, NITD609 works by rapidly suppressing protein synthesis in the parasite. The team discovered its target by screening the drug candidate against a panel of parasite strains with defined genetic mutations. Strains with mutations in a protein called PfATP4 were resistant to its effects, indicating that this protein is important for NITD609 to work. This new mechanism of action suggests that the compound will remain effective against parasites that have evolved resistance to current antimalarial therapies.

According to the World Health Organization (WHO), each year there are approximately 243 million cases of malaria, causing an estimated 863 000 deaths, mostly among young children in Africa. Although malaria is preventable and curable, it is estimated that in Africa, a child dies every 45 seconds from the disease.

"Malaria remains a scourge," said Mark Fishman, president, Novartis Institutes for BioMedical Research. "The parasite has demonstrated a frustrating ability to outwit new medicines, from quinine to today's unsettling increased tolerance to artemisinin derivatives. We are delighted that our scientists could provide this potential new malaria therapy, based on an unprecedented chemical structure and directed to a novel target."

Rick Davis, Business Development Manager at the Wellcome Trust, added: "This study illustrates how philanthropic organisations can support pharmaceutical partners undertaking innovative drug discovery for neglected diseases. A single dose cure would go a long way to addressing the unmet medical need in malaria, and we look forward to seeing how this compound performs in clinical trials."

Further safety evaluation is currently ongoing and, provided the outcome of these studies is favourable, a phase I clinical trial in humans could begin at the end of the year.