A drug that is currently under testing at UT Southwestern Medical Center and in Australia has shown the ability to cure malaria in a single dose. Also tests reveal that the drug offers promise as a preventive treatment as well.
The new drug - DSM265 - kills drug-resistant malaria parasites in the blood and liver by targeting their ability to replicate. The enzyme dihydroorotate dehydrogenase (DHODH), enables the parasite to replicate and spread during infection of humans. DSM265 is the first DHODH inhibitor to reach clinical development for treatment of malaria.
Malaria is a highly infectious, mosquito-transmitted disease that kills nearly 600,000 people worldwide each year, mostly children under 5 years old living in sub-Saharan Africa. Nearly 200 million cases of malaria are reported annually, and about 3 billion people are at risk of malaria in 97 countries.
"DSM265 could be among the first single-dose cures for malaria, and would be used in partnership with another drug. The drug also could potentially be developed as a once-weekly preventive," said lead author Dr. Margaret Phillips, Professor of Pharmacology at UT Southwestern.
Researchers determined that the compound DSM265 kills the malaria parasite Plasmodium
in both liver and blood stages of infection. Further, the compound was shown to be well-tolerated and effective in pre-clinical models.
Currently, the frontline anti-malarial treatments are artemisinin-based combination therapies, or ACTs, which are credited with helping to reduce the malaria burden. However, malaria strains resistant to ACTs have recently been reported in Thailand, Cambodia, Vietnam, Myanmar, and Laos.
"The problem is we're starting to see more drug resistance, and this is what's taken out every anti-malarial drug we've had," said Dr. Phillips, who holds the Beatrice and Miguel Elias Distinguished Chair in Biomedical Science. "The parasite is very good at adapting and becoming resistant to drugs - this is inevitable. What we can do is deliver new medicines with new modes of action and safeguard the longevity of the anti-malarial through use in combination as long as possible."
In order to combat drug resistance, DSM265 likely would be partnered with another new drug and used as a one-dose combination therapy. Another option is to develop DSM265 as a once-weekly preventive for individuals traveling to malaria-endemic regions or for people living in areas where malaria infections are primarily seasonal and human immunity is low. Either scenario is still several years away, pending the outcome of current and future trials, said Dr. Phillips.
DSM265 targets the ability of the parasite to synthesize the nucleotide precursors required for synthesis of DNA and RNA, said Dr. Phillips.
The study concluded that DSM265 appeared to be safely tolerated in non-human tests and established optimal dosing levels and length of drug effectiveness in preclinical models to estimate dosing for humans, paving the way for clinical trials. Additional human studies are planned, including one to test the drug as a preventive medicine.