title: Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised study.
abstract: DSM265 is a novel antimalarial that inhibits plasmodial dihydroorotate dehydrogenase, an enzyme essential for pyrimidine biosynthesis. We investigated the safety, tolerability, and pharmacokinetics of DSM265, and tested its antimalarial activity.
  
  
  
  Healthy participants aged 18-55 years were enrolled in a two-part study: part 1, a single ascending dose (25-1200 mg), double-blind, randomised, placebo-controlled study, and part 2, an open-label, randomised, active-comparator controlled study, in which participants were inoculated with Plasmodium falciparum induced blood-stage malaria (IBSM) and treated with DSM265 (150 mg) or mefloquine (10 mg/kg). Primary endpoints were DSM265 safety, tolerability, and pharmacokinetics. Randomisation lists were created using a validated, automated system. Both parts were registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12613000522718 (part 1) and number ACTRN12613000527763 (part 2).
  
  
  
  In part 1, 73 participants were enrolled between April 12, 2013, and July 14, 2015 (DSM265, n=55; placebo, n=18). In part 2, nine participants were enrolled between Sept 30 and Nov 25, 2013 (150 mg DSM265, n=7; 10 mg/kg mefloquine, n=2). In part 1, 117 adverse events were reported; no drug-related serious or severe events were reported. The most common drug-related adverse event was headache. The mean DSM265 peak plasma concentration (Cmax) ranged between 1310 ng/mL and 34 800 ng/mL and was reached in a median time (tmax) between 1·5 h and 4 h, with a mean elimination half-life between 86 h and 118 h. In part 2, the log10parasite reduction ratio at 48 h in the DSM265 (150 mg) group was 1·55 (95% CI 1·42-1·67) and in the mefloquine (10 mg/kg) group was 2·34 (2·17-2·52), corresponding to a parasite clearance half-life of 9·4 h (8·7-10·2) and 6·2 h (5·7-6·7), respectively. The median minimum inhibitory concentration of DSM265 in blood was estimated as 1040 ng/mL (range 552-1500), resulting in a predicted single efficacious dose of 340 mg. Parasite clearance was significantly faster in participants who received mefloquine than in participants who received DSM265 (p<0·0001).
  
  
  
  The good safety profile, long elimination half-life, and antimalarial effect of DSM265 supports its development as a partner drug in a single-dose antimalarial combination treatment.
  
  
  
  Wellcome Trust, UK Department for International Development, Global Health Innovative Technology Fund, Bill & Melinda Gates Foundation.
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Q-Pharm Pty Ltd, Herston, QLD, Australia. Electronic address: james.mccarthy@qimrberghofer.edu.au.
authors.forename: James S
authors.initials: JS
authors.lastname: McCarthy
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Julie
authors.initials: J
authors.lastname: Lotharius
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rückle
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Chalon
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Phillips
authors.affiliation: Q-Pharm Pty Ltd, Herston, QLD, Australia.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Elliott
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Silvana
authors.initials: S
authors.lastname: Sekuloski
authors.affiliation: Q-Pharm Pty Ltd, Herston, QLD, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Griffin
authors.affiliation: Columbia University, New York, NY, USA.
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Ng
authors.affiliation: Columbia University, New York, NY, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Louise
authors.initials: L
authors.lastname: Marquart
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Noelle S
authors.initials: NS
authors.lastname: Williams
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gobeau
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Lidiya
authors.initials: L
authors.lastname: Bebrevska
authors.affiliation: Takeda Development Center Americas, Inc, Cambridge, MA, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Rosario
authors.affiliation: AbbVie, North Chicago, IL, USA.
authors.forename: Kennan
authors.initials: K
authors.lastname: Marsh
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland. Electronic address: moehrlej@mmv.org.
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Möhrle
mesh_terms: D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001315:Australia; D000090722:Dihydroorotate Dehydrogenase; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D015767:Mefloquine / Q000627:therapeutic use*; D008875:Middle Aged; D009520:New Zealand; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010963:Plasmodium falciparum; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014230:Triazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000962:Antimalarials; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D014230:Triazoles; C000606979:DSM265; D044925:Oxidoreductases Acting on CH-CH Group Donors; D015767:Mefloquine