Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised study

James S. McCarthy, Julie Lotharius, Thomas Rückle, Stephan Chalon, Margaret A. Phillips, Suzanne Elliott, Silvana Sekuloski, Paul Griffin, Caroline L. Ng, David A. Fidock, Louise Marquart, Noelle S. Williams, Nathalie Gobeau, Lidiya Bebrevska, Maria Rosario, Kennan Marsh, Jörg J. Möhrle

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Background 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. Methods 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). Findings 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 log10 parasite 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). Interpretation 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. Funding Wellcome Trust, UK Department for International Development, Global Health Innovative Technology Fund, Bill & Melinda Gates Foundation.

Original languageEnglish (US)
Pages (from-to)626-635
Number of pages10
JournalThe Lancet Infectious Diseases
Volume17
Issue number6
DOIs
StatePublished - Jun 2017

Fingerprint

Antimalarials
Pharmacokinetics
Safety
Mefloquine
Half-Life
Parasites
DSM265
Placebos
Biomedical Technology
Microbial Sensitivity Tests
Plasmodium falciparum
Random Allocation
Drug-Related Side Effects and Adverse Reactions
New Zealand
Pharmaceutical Preparations
Malaria
Headache
Registries
Healthy Volunteers
Clinical Trials

ASJC Scopus subject areas

  • Infectious Diseases

Cite this

Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265 : a two-part first-in-human phase 1a/1b randomised study. / McCarthy, James S.; Lotharius, Julie; Rückle, Thomas; Chalon, Stephan; Phillips, Margaret A.; Elliott, Suzanne; Sekuloski, Silvana; Griffin, Paul; Ng, Caroline L.; Fidock, David A.; Marquart, Louise; Williams, Noelle S.; Gobeau, Nathalie; Bebrevska, Lidiya; Rosario, Maria; Marsh, Kennan; Möhrle, Jörg J.

In: The Lancet Infectious Diseases, Vol. 17, No. 6, 06.2017, p. 626-635.

Research output: Contribution to journalArticle

McCarthy, JS, Lotharius, J, Rückle, 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 & Möhrle, 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', The Lancet Infectious Diseases, vol. 17, no. 6, pp. 626-635. https://doi.org/10.1016/S1473-3099(17)30171-8
McCarthy, James S. ; Lotharius, Julie ; Rückle, Thomas ; Chalon, Stephan ; Phillips, Margaret A. ; Elliott, Suzanne ; Sekuloski, Silvana ; Griffin, Paul ; Ng, Caroline L. ; Fidock, David A. ; Marquart, Louise ; Williams, Noelle S. ; Gobeau, Nathalie ; Bebrevska, Lidiya ; Rosario, Maria ; Marsh, Kennan ; Möhrle, Jörg J. / Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265 : a two-part first-in-human phase 1a/1b randomised study. In: The Lancet Infectious Diseases. 2017 ; Vol. 17, No. 6. pp. 626-635.
@article{78694b169f354d58bd90884bef3ca1db,
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 = "Background 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. Methods 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). Findings 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 log10 parasite 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). Interpretation 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. Funding Wellcome Trust, UK Department for International Development, Global Health Innovative Technology Fund, Bill & Melinda Gates Foundation.",
author = "McCarthy, {James S.} and Julie Lotharius and Thomas R{\"u}ckle and Stephan Chalon and Phillips, {Margaret A.} and Suzanne Elliott and Silvana Sekuloski and Paul Griffin and Ng, {Caroline L.} and Fidock, {David A.} and Louise Marquart and Williams, {Noelle S.} and Nathalie Gobeau and Lidiya Bebrevska and Maria Rosario and Kennan Marsh and M{\"o}hrle, {J{\"o}rg J.}",
year = "2017",
month = "6",
doi = "10.1016/S1473-3099(17)30171-8",
language = "English (US)",
volume = "17",
pages = "626--635",
journal = "The Lancet Infectious Diseases",
issn = "1473-3099",
publisher = "Lancet Publishing Group",
number = "6",

}

TY - JOUR

T1 - Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265

T2 - a two-part first-in-human phase 1a/1b randomised study

AU - McCarthy, James S.

AU - Lotharius, Julie

AU - Rückle, Thomas

AU - Chalon, Stephan

AU - Phillips, Margaret A.

AU - Elliott, Suzanne

AU - Sekuloski, Silvana

AU - Griffin, Paul

AU - Ng, Caroline L.

AU - Fidock, David A.

AU - Marquart, Louise

AU - Williams, Noelle S.

AU - Gobeau, Nathalie

AU - Bebrevska, Lidiya

AU - Rosario, Maria

AU - Marsh, Kennan

AU - Möhrle, Jörg J.

PY - 2017/6

Y1 - 2017/6

N2 - Background 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. Methods 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). Findings 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 log10 parasite 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). Interpretation 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. Funding Wellcome Trust, UK Department for International Development, Global Health Innovative Technology Fund, Bill & Melinda Gates Foundation.

AB - Background 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. Methods 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). Findings 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 log10 parasite 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). Interpretation 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. Funding Wellcome Trust, UK Department for International Development, Global Health Innovative Technology Fund, Bill & Melinda Gates Foundation.

UR - http://www.scopus.com/inward/record.url?scp=85016636532&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85016636532&partnerID=8YFLogxK

U2 - 10.1016/S1473-3099(17)30171-8

DO - 10.1016/S1473-3099(17)30171-8

M3 - Article

C2 - 28363636

AN - SCOPUS:85016636532

VL - 17

SP - 626

EP - 635

JO - The Lancet Infectious Diseases

JF - The Lancet Infectious Diseases

SN - 1473-3099

IS - 6

ER -