Saturday, October 24, 2015

Drugs in Clinical Pipeline: Artefenomel

Artefenomel  [4-(2-{4-[(1s,1''R,3''S,4s,5'r,5''S,7''S)-Dispiro[cyclohexane-1,3'-[1,2,4]trioxolane-5',2''-tricyclo[,7]decan]-4-yl]phenoxy}ethyl)morpholine] is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. The outstanding efficacy and prolonged blood concentrations of Artefenomel are the result of a design strategy that stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby reducing clearance yet maintaining the necessary Fe(II)-reactivity to elicit parasite death. In vitro, Artefenomel is fast-acting against all asexual erythrocytic Plasmodium falciparum stages with IC50 values comparable to those for the clinically used artemisinin derivatives. Unlike all other synthetic peroxides and semisynthetic artemisinin derivatives, Artefenomel completely cures Plasmodium berghei-infected mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity superior to that of the benchmark chemoprophylactic agent, Mefloquine. Compared with other peroxide-containing antimalarial agents, such as the artemisinin derivatives and the first-generation ozonide OZ277, Artefenomel exhibits a substantial increase in the pharmacokinetic half-life and blood concentration versus time profile in three preclinical species. These exceptional antimalarial and pharmacokinetic properties led to its selection as a clinical drug development candidate. Artefenomel has successfully completed Phase I clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase IIa trials in malaria patients [1].

1. Charma, S. A.; et. al. Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria. Proc Natl Acad Sci U S A 2011, 108(11), 4400-4405.