New drugs are needed to treat malaria. Artefenomel (OZ439), a trioxolane that shares the peroxide pharmacophore of highly effective artemisinins, has been progressing through development, and results reported by Aung Pyae Phyo and colleagues in The Lancet Infectious Diseases THIS WEEK add to its promise.

As with every new potential antimalarial drug, artefenomel has advantages and disadvantages.
Before considering these issues, it is appropriate to ask fundamental questions, such as why do we need new drugs for malaria and what drug characteristics are most needed?

First, available drugs are limited by drug resistance. Artemisinin-based combination therapy is recommended for the treatment of falciparum malaria and is effective against other plasmodial species.

Artemisinin resistance, manifested as delayed parasite clearance after therapy, is established in southeast Asia. Less publicised is decreased activity of partner drugs, with decreased parasite sensitivity and changing sensitivity patterns over time documented for several drugs in different regions.
Recently in Cambodia, delayed parasite clearance as well as actual high failure rates have been seen after treatment of uncomplicated malaria with dihydroartemisinin plus piperaquine, presumably because of decreased responsiveness to both drugs.
New antimalarial drugs that are not affected by current resistance mechanisms are needed.

Second, available drugs require multiple doses. Artemisinin-based combination therapies are given once or twice daily for 3 days. An effective single-dose regimen, offering improved compliance and cost, would be a huge advance.
The identification of new agents effective after a single dose is a high priority.

Third, most available drugs are not highly active against non-erythrocytic and sexual stages. Treatment of malaria requires action against asexual erythrocytic parasites, which are responsible for all disease manifestations.
Added benefit would come from action against other stages to facilitate chemoprevention (by killing liver stages before they elicit clinical illness) and transmission blocking (by killing sexual stages before they infect mosquitoes).

Fourth, artemisinins are natural products, complicating maintenance of stable drug supplies and pricing. This challenge has been partly overcome with the development of bioengineered artemisinic acid in yeast. Bioengineered artemisinin has contributed to the worldwide supply of artemisinin-based combination therapies since 2014, but most available therapies include artemisinin derivatives from agricultural sources.
Compounds readily produced by simple and inexpensive synthetic methods are clearly preferred.

Finally, some antimalarial drugs have safety limitations.
Ideal antimalarial drugs must be safe in young children and pregnant women to enable treatment and also use of these drugs for malaria control and elimination, including intermittent preventive therapy, seasonal malaria chemoprevention, and mass drug administration.

TBC.

G MOHAN