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

Katharine A Collins, Azrin N Abd-Rahman, Louise Marquart, Emma Ballard, Nathalie Gobeau, Paul Griffin, Stephan Chalon, Jörg J Möhrle, James S McCarthy, Katharine A Collins, Azrin N Abd-Rahman, Louise Marquart, Emma Ballard, Nathalie Gobeau, Paul Griffin, Stephan Chalon, Jörg J Möhrle, James S McCarthy

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.

Keywords: Plasmodium vivax; IBSM; Malaria; OZ439; Volunteer infection studies; artefenomel; transmission.

© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Artefenomel plasma concentration–time profiles for individual participants.
Figure 2.
Figure 2.
Individual participant parasitemia profiles. Participants (n = 8) were inoculated intravenously with Plasmodium vivax–infected erythrocytes on day 0 and were administered a single oral dose of 200 mg artefenomel on day 10 (vertical dashed line).
Figure 3.
Figure 3.
Individual participant gametocytemia profiles. Participants (n = 8) were inoculated intravenously with Plasmodium vivax–infected erythrocytes on day 0 and were administered a single oral dose of 200 mg artefenomel on day 10 (vertical dashed line).

References

    1. World Health Organization. World malaria report 2019. Geneva, Switzerland: World Health Organization, 2019.
    1. Howes RE, Battle KE, Mendis KN, et al. . Global epidemiology of Plasmodium vivax. Am J Trop Med Hyg 2016; 95:15–34.
    1. Price RN, Tjitra E, Guerra CA, Yeung S, White NJ, Anstey NM. Vivax malaria: neglected and not benign. Am J Trop Med Hyg 2007; 77:79–87.
    1. Bassat Q, Velarde M, Mueller I, et al. . Key knowledge gaps for Plasmodium vivax control and elimination. Am J Trop Med Hyg 2016; 95:62–71.
    1. Coatney GR. Pitfalls in a discovery: the chronicle of chloroquine. Am J Trop Med Hyg 1963; 12:121–8.
    1. Price RN, von Seidlein L, Valecha N, Nosten F, Baird JK, White NJ. Global extent of chloroquine-resistant Plasmodium vivax: a systematic review and meta-analysis. Lancet Infect Dis 2014; 14:982–91.
    1. Baird JK. Attacking Plasmodium vivax. Am J Trop Med Hyg 2016; 95:1–3.
    1. World Health Organization. Artemesinin and aretemisinin-based combination therapy resistance: status report 2016. Geneva, Switzerland: World Health Organization, 2016.
    1. Chen V, Daily JP. Tafenoquine: the new kid on the block. Curr Opin Infect Dis 2019; 32:407–12.
    1. Phillips MA, Burrows JN, Manyando C, van Huijsduijnen RH, Van Voorhis WC, Wells TNC. Malaria. Nat Rev Dis Primers 2017; 3:17050.
    1. McCarthy JS, Lotharius J, Rückle T, et al. . Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised study. Lancet Infect Dis 2017; 17:626–35.
    1. Griffin P, Pasay C, Elliott S, et al. . Safety and reproducibility of a clinical trial system using induced blood stage Plasmodium vivax infection and its potential as a model to evaluate malaria transmission. PLoS Negl Trop Dis 2016; 10:e0005139.
    1. McCarthy JS, Griffin PM, Sekuloski S, et al. . Experimentally induced blood-stage Plasmodium vivax infection in healthy volunteers. J Infect Dis 2013; 208:1688–94.
    1. Collins KA, Wang CY, Adams M, Mitchell H, Robinson GJ, Rampton M, et al. . A Plasmodium vivax experimental human infection model for evaluating efficacy of interventions. J Clin Invest 2020; 130:2920–2927.
    1. Meshnick SR, Taylor TE, Kamchonwongpaisan S. Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy. Microbiol Rev 1996; 60:301–15.
    1. Charman SA, Arbe-Barnes S, Bathurst IC, 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; 108:4400–5.
    1. Marfurt J, Chalfein F, Prayoga P, et al. . Comparative ex vivo activity of novel endoperoxides in multidrug-resistant Plasmodium falciparum and P. vivax. Antimicrob Agents Chemother 2012; 56:5258–63.
    1. McCarthy JS, Baker M, O’Rourke P, et al. . Efficacy of OZ439 (artefenomel) against early Plasmodium falciparum blood-stage malaria infection in healthy volunteers. J Antimicrob Chemother 2016; 71:2620–7.
    1. Moehrle JJ, Duparc S, Siethoff C, et al. . First-in-man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials. Br J Clin Pharmacol 2013; 75:524–37.
    1. Phyo AP, Jittamala P, Nosten FH, et al. . Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial. Lancet Infect Dis 2016; 16:61–9.
    1. Collins KA, Ruckle T, Elliott S, et al. . DSM265 at 400 milligrams clears asexual stage parasites but not mature gametocytes from the blood of healthy subjects experimentally infected with Plasmodium falciparum. Antimicrob Agents Chemother 2019; 63:e01837–18.
    1. Karl S, Laman M, Koleala T, et al. . Comparison of three methods for detection of gametocytes in Melanesian children treated for uncomplicated malaria. Malar J 2014; 13:319.
    1. Marquart L, Baker M, O’Rourke P, McCarthy JS. Evaluating the pharmacodynamic effect of antimalarial drugs in clinical trials by quantitative PCR. Antimicrob Agents Chemother 2015; 59:4249–59.
    1. World Health Organization. WHO handbook for reporting results of cancer treatment. Geneva, Switzerland: World Health Organization, 1979.
    1. Collins KA, Wang CY, Adams M, et al. . A controlled human malaria infection model enabling evaluation of transmission-blocking interventions. J Clin Invest 2018; 128:1551–62.
    1. Wang CYT, McCarthy JS, Stone WJ, Bousema T, Collins KA, Bialasiewicz S. Assessing Plasmodium falciparum transmission in mosquito-feeding assays using quantitative PCR. Malar J 2018; 17:249.
    1. Church LW, Le TP, Bryan JP, et al. . Clinical manifestations of Plasmodium falciparum malaria experimentally induced by mosquito challenge. J Infect Dis 1997; 175:915–20.
    1. McCarthy JS, Rückle T, Djeriou E, et al. . A phase II pilot trial to evaluate safety and efficacy of ferroquine against early Plasmodium falciparum in an induced blood-stage malaria infection study. Malar J 2016; 15:469.
    1. Woodford J, Shanks GD, Griffin P, Chalon S, McCarthy JS. The dynamics of liver function test abnormalities after malaria infection: a retrospective observational study. Am J Trop Med Hyg 2018; 98:1113–9.

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