Table 1 Rationale for the clinical development of Triple Artemisinin-based Combination Therapies

Clinical failure of ACT in the Greater Mekong Region

Artemisinin resistance—or delayed treatment response to artemisinins—is a concern in the Greater Mekong Region. If drug resistance against the partner drug emerges at the same time, ACT treatment is associated with unacceptably high rates of treatment failure.

Adding a second partner drug to a failing ACT restores cure rates to high levels. This is facilitated by independent modes of action and in the case of mefloquine and piperaquine thought to be mediated by counter-selection of drug resistance markers.

Adding a single drug to a failing drug combination is thought to accelerate the selection of drug resistant mutants. TACT should therefore ideally be evaluated and implemented before drug resistance against ACT emerge on a large scale in an endemic region.

Prevention of emergence and spread of drug resistance by Triple Artemisinin Combination Therapies

The short but rapidly acting artemisinin derivative quickly reduces the total number of parasites circulating in a patient and thus reducing the stochiastic chances for selection of resistant mutants in the remaining low number of parasites.

This benefit of artemisinins is reduced in regions of delayed parasite clearance by artemisinins thus increasing the risk for selection of drug resistance. TACT should therefore ideally be implemented before the rapid activity of artemisinins is compromised.

Adding a pharmacokinetically matched long acting partner drug to ACT leads to mutual protection of partner drugs against selection of drug resistance over the prolonged elimination period.

Combining three drugs with different modes of action reduces the likelihood for the selection of drug resistant mutants

Priority patient population for TACT

According to the global epidemiology of falciparum malaria and its impact on mortality, African children are undoubtedly the most important patient population for new antimalarial treatments. Historically, it was also demonstrated in sub-Saharan Africa that drug resistance against previous first line antimalarials translated to a substantial increase in excess mortality.

Efficacy, tolerability, safety of TACT need to be evaluated in African children early on in the development plan.

Efficacy, tolerability, and safety are not necessarily similar in adults as in children as well as in semi-immune and non-immune patients.