Antimalarial Activity of Artefenomel Against Asexual Parasites and Transmissible Gametocytes During Experimental Blood-Stage Plasmodium vivax Infection

Abstract

Background Interventions that effectively target Plasmodium vivax are critical for the future control and elimination of malaria. We conducted a P. vivax volunteer infection study to characterize the antimalarial activity of artefenomel, a new drug candidate. Methods Eight healthy, malaria-naive participants were intravenously inoculated with blood-stage P. vivax and subsequently received a single oral 200-mg dose of artefenomel. Blood samples were collected to monitor the development and clearance of parasitemia, and plasma artefenomel concentration. Mosquito feeding assays were conducted before artefenomel dosing to investigate parasite transmissibility. Results Initial parasite clearance occurred in all participants after artefenomel administration (log10 parasite reduction ratio over 48 hours, 1.67; parasite clearance half-life, 8.67 hours). Recrudescence occurred in 7 participants 11–14 days after dosing. A minimum inhibitory concentration of 0.62 ng/mL and minimum parasiticidal concentration that achieves 90% of maximum effect of 0.83 ng/mL were estimated, and a single 300-mg dose was predicted to clear 109 parasites per milliliter with 95% certainty. Gametocytemia developed in all participants and was cleared 4–8 days after dosing. At peak gametocytemia, 75% of participants were infectious to mosquitoes. Conclusions The in vivo antimalarial activity of artefenomel supports its further clinical development as a treatment for P. vivax malaria. Clinical Trials Registration NCT02573857.

Controlled human malaria infection with PvW1 – a new clone of Plasmodium vivax with high quality genome assembly

“…The AE profiles of both the mosquito-bite and blood-stage CHMI with PvW1 were highly comparable to previous reports of both models in malaria-naïve/non-immune adults using other isolates of P. vivax at the Colombian (8-10) or Australian sites (19)(20)(21)(22)(23). No SAEs occurred in either trial and all drug treatments were successful.…”

Liver Function Test Abnormalities in Experimental and Clinical Plasmodium vivax Infection

“…29 In the artefenomel study, eight subjects were treated with a single 200 mg dose of the drug 10 days post-inoculation. 30 Data from previous studies had indicated that a 200 mg dose would be subcurative, 31 and as expected, 7/8 subjects had recrudescent parasitemia; they subsequently received a standard course of artemether/ lumefantrine on day 21-28. In the chloroquine study, 24 subjects were treated with a standard 3-day course of chloroquine, totaling 25 mg/kg, beginning on day 8 (n = 8 subjects), day 9 (n = 1 subject), or day 10 (n = 15 subjects).…”

“…All eight subjects enrolled in the artefenomel study were male compared with a more even gender ratio in the chloroquine study where 13/24 (54%) of subjects were males. There was no difference in the age of subjects recruited in the artefenomel and chloroquine studies (median [IQR] 23.5 [22-25.8] years and 24.5 [20][21][22][23][24][25][26][27][28][29][30] years, respectively).…”

“…Data for the P. vivax IBSM analysis were obtained from 32 malaria-naive subjects who participated in two clinical trials at the Queensland Institute of Medical Research (QIMR) Berghofer between March 2016 and April 2017. The results of one of these studies, which used chloroquine 29 and artefenomel 30 as antimalarial treatment have been published. An article describing the results of the other study (NCT02573857), which used the experimental compound artefenomel as antimalarial treatment, is currently under review.…”

Targeting Gametocytes of the Malaria Parasite Plasmodium falciparum in a Functional Genomics Era: Next Steps

“…OZ439 is a strong contender for a gametocidal drug as it seems to inhibit exflagellation and reduce the number of oocysts formation in vitro [ 133 ]. Like other artemisinin derivatives, artefenomel is thought to act by alkylating heme and inducing protein damage [ 152 , 153 ]. In a recent trial, a single dose of artefenomel administered as a monotherapy in combination with another antimalarial drug showed significant reduction in parasitemia and gametocytemia, supporting its use for treatment of P .…”