DSM265 at 400 Milligrams Clears Asexual Stage Parasites but Not Mature Gametocytes from the Blood of Healthy Subjects Experimentally Infected with Plasmodium falciparum

Katharine A Collins, Thomas Rückle, Suzanne Elliott, Louise Marquart, Emma Ballard, Stephan Chalon, Paul Griffin, Jörg J Möhrle, James S McCarthy, Katharine A Collins, Thomas Rückle, Suzanne Elliott, Louise Marquart, Emma Ballard, Stephan Chalon, Paul Griffin, Jörg J Möhrle, James S McCarthy

Abstract

DSM265 is a novel antimalarial drug in clinical development that acts as a selective inhibitor of Plasmodium dihydroorotate dehydrogenase. In a previous phase 1b study, a single 150-mg dose of DSM265 showed partial efficacy against experimentally induced blood-stage Plasmodium falciparum malaria (IBSM). Pharmacokinetic/pharmacodynamic modeling predicted a human efficacious dose of 340 mg. The primary objectives of the current study were to determine the safety and efficacy of a single oral 400-mg dose of DSM265 against P. falciparum in the IBSM model. Eight healthy participants were inoculated intravenously with 2,800 parasites and treated with DSM265 7 days later. Unexpectedly, one participant did not develop parasitemia during the study. All other participants developed parasitemia, with the complete clearance of asexual parasites occurring following DSM265 treatment. All seven subjects also became gametocytemic. The secondary objectives were to investigate the gametocytocidal and transmission-blocking activity of a second 400-mg dose of DSM265, which was administered 23 days after inoculation. Gametocytes were not cleared by the second dose of DSM265, and transmission-blocking activity could not be determined due to low gametocyte densities. Three DSM265-related adverse events occurred, including a cutaneous rash in one subject on the day of the second DSM265 dose. The results obtained in this study support the prediction of the efficacious dose of DSM265 and provide further evidence that DSM265 is generally safe and well tolerated. In addition, this study confirms preclinical data indicating that DSM265 permits the development and maturation of gametocytes and does not clear mature circulating gametocytes. (This study has been registered at ClinicalTrials.gov under identifier NCT02573857.).

Keywords: CHMI; DSM265; IBSM; antimalarial agents; blood stage; gametocytes; malaria; transmission; volunteer infection study.

Copyright © 2019 Collins et al.

Figures

FIG 1
FIG 1
DSM265 plasma concentration-time profiles. Participants received a single dose of DSM265 at 400 mg on day 7. The lines indicate the DSM256 concentration in plasma over time for each participant following DSM265 dosing (n = 8).
FIG 2
FIG 2
Time course of asexual parasitemia. Participants were inoculated with ∼2,800 viable parasites on day 0, and a single 400-mg dose of DSM265 was administered on day 7 (indicated by the vertical dashed line). Blood-stage parasitemia development and clearance were monitored by 18S rDNA qPCR. Thin lines represent each of the 7 participants who developed parasitemia, and the bold line represents the geometric mean.
FIG 3
FIG 3
Gametocytemia. (A, B) The gametocyte density was quantified using qRT-PCR assays specific for female gametocytes (pfs25) (A) and male gametocytes (PfMGET) (B). The first vertical dashed line indicates the day of the second dose of 400 mg DSM265 (day 23), and the second vertical dashed line indicates the end of study primaquine treatment (day 28). Thin lines represent curves for the individual participants, and the bold line is the geometric mean. (C) Comparison of peak gametocytemia (total number of gametocytes [gct] per milliliter measured by 18S rDNA qPCR) to asexual parasitemia at the time of treatment (18S rDNA qPCR). (D) The proportion of male (blue bars) and female (red bars) gametocytes was determined in the 12 samples where male and female gametocyte densities exceeded 100 gametocytes/ml. The samples were from participants R102, R103, and R107 and were taken at multiple time points between day 16 and day 26.

References

    1. World Health Organization. 2017. World malaria report 2017. World Health Organization, Geneva, Switzerland.
    1. World Health Organization. 2016. Artemisinin, and artemisinin-based combination therapy resistance. Status report. World Health Organization, Geneva, Switzerland.
    1. Phillips MA, Burrows JN, Manyando C, van Huijsduijnen RH, Van Voorhis WC, Wells TNC. 2017. Malaria. Nat Rev Dis Primers 3:17050. doi:10.1038/nrdp.2017.50.
    1. Burrows JN, Duparc S, Gutteridge WE, Hooft van Huijsduijnen R, Kaszubska W, Macintyre F, Mazzuri S, Möhrle JJ, Wells TNC. 2017. New developments in anti-malarial target candidate and product profiles. Malar J 16:26. doi:10.1186/s12936-016-1675-x.
    1. Alonso PL, Brown G, Arevalo-Herrera M, Binka F, Chitnis C, Collins F, Doumbo OK, Greenwood B, Hall BF, Levine MM, Mendis K, Newman RD, Plowe CV, Rodriguez MH, Sinden R, Slutsker L, Tanner M. 2011. A research agenda to underpin malaria eradication. PLoS Med 8:e1000406. doi:10.1371/journal.pmed.1000406.
    1. World Health Organization. 2015. Policy brief on single-dose primaquine as a gametocytocide in Plasmodium falciparum malaria. World Health Organization, Geneva, Switzerland.
    1. White NJ. 2013. Primaquine to prevent transmission of falciparum malaria. Lancet Infect Dis 13:175–181. doi:10.1016/S1473-3099(12)70198-6.
    1. Phillips MA, Rathod PK. 2010. Plasmodium dihydroorotate dehydrogenase: a promising target for novel anti-malarial chemotherapy. Infect Disord Drug Targets 10:226–239. doi:10.2174/187152610791163336.
    1. Flannery EL, Foquet L, Chuenchob V, Fishbaugher M, Billman Z, Navarro MJ, Betz W, Olsen TM, Lee J, Camargo N, Nguyen T, Schafer C, Sack BK, Wilson EM, Saunders J, Bial J, Campo B, Charman SA, Murphy SC, Phillips MA, Kappe SH, Mikolajczak SA. 2018. Assessing drug efficacy against Plasmodium falciparum liver stages in vivo. JCI Insight 3:92587. doi:10.1172/jci.insight.92587.
    1. Phillips MA, Lotharius J, Marsh K, White J, Dayan A, White KL, Njoroge JW, El Mazouni F, Lao Y, Kokkonda S, Tomchick DR, Deng X, Laird T, Bhatia SN, March S, Ng CL, Fidock DA, Wittlin S, Lafuente-Monasterio M, Benito FJ, Alonso LM, Martinez MS, Jimenez-Diaz MB, Bazaga SF, Angulo-Barturen I, Haselden JN, Louttit J, Cui Y, Sridhar A, Zeeman AM, Kocken C, Sauerwein R, Dechering K, Avery VM, Duffy S, Delves M, Sinden R, Ruecker A, Wickham KS, Rochford R, Gahagen J, Iyer L, Riccio E, Mirsalis J, Bathhurst I, Rueckle T, Ding X, Campo B, Leroy D, Rogers MJ, Rathod PK, Burrows JN, Charman SA. 2015. A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Sci Transl Med 7:296ra111. doi:10.1126/scitranslmed.aaa6645.
    1. McCarthy JS, Lotharius J, Ruckle T, Chalon S, Phillips MA, Elliott S, Sekuloski S, Griffin P, Ng CL, Fidock DA, Marquart L, Williams NS, Gobeau N, Bebrevska L, Rosario M, Marsh K, Mohrle JJ. 2017. 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 17:626–635. doi:10.1016/S1473-3099(17)30171-8.
    1. Murphy SC, Duke ER, Shipman KJ, Jensen RL, Fong Y, Ferguson S, Janes HE, Gillespie K, Seilie AM, Hanron AE, Rinn L, Fishbaugher M, VonGoedert T, Fritzen E, Kappe SH, Chang M, Sousa JC, Marcsisin SR, Chalon S, Duparc S, Kerr N, Mohrle JJ, Andenmatten N, Rueckle T, Kublin JG. 2018. A randomized trial evaluating the prophylactic activity of DSM265 against preerythrocytic Plasmodium falciparum infection during controlled human malarial infection by mosquito bites and direct venous inoculation. J Infect Dis 217:693–702. doi:10.1093/infdis/jix613.
    1. Sulyok M, Ruckle T, Roth A, Murbeth RE, Chalon S, Kerr N, Samec SS, Gobeau N, Calle CL, Ibanez J, Sulyok Z, Held J, Gebru T, Granados P, Bruckner S, Nguetse C, Mengue J, Lalremruata A, Sim BKL, Hoffman SL, Mohrle JJ, Kremsner PG, Mordmuller B. 2017. DSM265 for Plasmodium falciparum chemoprophylaxis: a randomised, double blinded, phase 1 trial with controlled human malaria infection. Lancet Infect Dis 17:636–644. doi:10.1016/S1473-3099(17)30139-1.
    1. Llanos-Cuentas A, Casapia M, Chuquiyauri R, Hinojosa J-C, Kerr N, Rosario M, Toovey S, Arch RH, Phillips MA, Rozenberg FD, Bath J, Ng CL, Cowell AN, Winzeler EA, Fidock DA, Baker M, Möhrle JJ, Huijsduijnen RHV, Gobeau N, Araeipour N, Andenmatten N, Rückle T, Duparc S. 2018. Antimalarial activity of single-dose DSM265, a novel plasmodium dihydroorotate dehydrogenase inhibitor, in patients with uncomplicated Plasmodium falciparum or Plasmodium vivax malaria infection: a proof-of-concept, open-label, phase 2a study. Lancet Infect Dis 18:874–883. doi:10.1016/S1473-3099(18)30309-8.
    1. Joice R, Narasimhan V, Montgomery J, Sidhu AB, Oh K, Meyer E, Pierre-Louis W, Seydel K, Milner D, Williamson K, Wiegand R, Ndiaye D, Daily J, Wirth D, Taylor T, Huttenhower C, Marti M. 2013. Inferring developmental stage composition from gene expression in human malaria. PLoS Comput Biol 9:e1003392. doi:10.1371/journal.pcbi.1003392.
    1. Tadesse FG, Lanke K, Nebie I, Schildkraut JA, Goncalves BP, Tiono AB, Sauerwein R, Drakeley C, Bousema T, Rijpma SR. 2017. Molecular markers for sensitive detection of Plasmodium falciparum asexual stage parasites and their application in a malaria clinical trial. Am J Trop Med Hyg 97:188–198. doi:10.4269/ajtmh.16-0893.
    1. McCarthy JS, Ruckle T, Djeriou E, Cantalloube C, Ter-Minassian D, Baker M, O'Rourke P, Griffin P, Marquart L, Hooft van Huijsduijnen R, Mohrle JJ. 2016. 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 15:469. doi:10.1186/s12936-016-1511-3.
    1. Bousema T, Drakeley C. 2011. Epidemiology and infectivity of Plasmodium falciparum and Plasmodium vivax gametocytes in relation to malaria control and elimination. Clin Microbiol Rev 24:377–410. doi:10.1128/CMR.00051-10.
    1. Meibalan E, Marti M. 2017. Biology of malaria transmission. Cold Spring Harb Perspect Med 7:a025452. doi:10.1101/cshperspect.a025452.
    1. Collins KA, Wang CY, Adams M, Mitchell H, Rampton M, Elliott S, Reuling IJ, Bousema T, Sauerwein R, Chalon S, Mohrle JJ, McCarthy JS. 2018. A controlled human malaria infection model enabling evaluation of transmission-blocking interventions. J Clin Invest 128:1551–1562. doi:10.1172/JCI98012.
    1. Baker DA. 2010. Malaria gametocytogenesis. Mol Biochem Parasitol 172:57–65. doi:10.1016/j.molbiopara.2010.03.019.
    1. Bousema T, Dinglasan RR, Morlais I, Gouagna LC, van Warmerdam T, Awono-Ambene PH, Bonnet S, Diallo M, Coulibaly M, Tchuinkam T, Mulder B, Targett G, Drakeley C, Sutherland C, Robert V, Doumbo O, Toure Y, Graves PM, Roeffen W, Sauerwein R, Birkett A, Locke E, Morin M, Wu Y, Churcher TS. 2012. Mosquito feeding assays to determine the infectiousness of naturally infected Plasmodium falciparum gametocyte carriers. PLoS One 7:e42821. doi:10.1371/journal.pone.0042821.
    1. Churcher TS, Bousema T, Walker M, Drakeley C, Schneider P, Ouedraogo AL, Basanez MG. 2013. Predicting mosquito infection from Plasmodium falciparum gametocyte density and estimating the reservoir of infection. Elife 2:e00626. doi:10.7554/eLife.00626.
    1. Da DF, Churcher TS, Yerbanga RS, Yameogo B, Sangare I, Ouedraogo JB, Sinden RE, Blagborough AM, Cohuet A. 2015. Experimental study of the relationship between Plasmodium gametocyte density and infection success in mosquitoes; implications for the evaluation of malaria transmission-reducing interventions. Exp Parasitol 149:74–83. doi:10.1016/j.exppara.2014.12.010.
    1. Edstein MD, Kotecka BM, Anderson KL, Pombo DJ, Kyle DE, Rieckmann KH, Good MF. 2005. Lengthy antimalarial activity of atovaquone in human plasma following atovaquone-proguanil administration. Antimicrob Agents Chemother 49:4421–4422. doi:10.1128/AAC.49.10.4421-4422.2005.
    1. Hodgson SH, Llewellyn D, Silk SE, Milne KH, Elias SC, Miura K, Kamuyu G, Juma EA, Magiri C, Muia A, Jin J, Spencer AJ, Longley RJ, Mercier T, Decosterd L, Long CA, Osier FH, Hoffman SL, Ogutu B, Hill AV, Marsh K, Draper SJ. 2016. Changes in serological immunology measures in UK and Kenyan adults post-controlled human malaria infection. Front Microbiol 7:1604. doi:10.3389/fmicb.2016.01604.
    1. Rockett RJ, Tozer SJ, Peatey C, Bialasiewicz S, Whiley DM, Nissen MD, Trenholme K, McCarthy JS, Sloots TP. 2011. A real-time, quantitative PCR method using hydrolysis probes for the monitoring of Plasmodium falciparum load in experimentally infected human volunteers. Malar J 10:1–6. doi:10.1186/1475-2875-10-48.
    1. Stone W, Sawa P, Lanke K, Rijpma S, Oriango R, Nyaurah M, Osodo P, Osoti V, Mahamar A, Diawara H, Woestenenk R, Graumans W, van de Vegte-Bolmer M, Bradley J, Chen I, Brown J, Siciliano G, Alano P, Gosling R, Dicko A, Drakeley C, Bousema T. 2017. A molecular assay to quantify male and female Plasmodium falciparum gametocytes: results from 2 randomized controlled trials using primaquine for gametocyte clearance. J Infect Dis 216:457–467. doi:10.1093/infdis/jix237.
    1. Marquart L, Baker M, O'Rourke P, McCarthy JS. 2015. Evaluating the pharmacodynamic effect of antimalarial drugs in clinical trials by quantitative PCR. Antimicrob Agents Chemother 59:4249–4259. doi:10.1128/AAC.04942-14.

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