Randomized single oral dose phase 1 study of safety, tolerability, and pharmacokinetics of Iminosugar UV-4 Hydrochloride (UV-4B) in healthy subjects.
Background UV-4 (N-(9'-methoxynonyl)-1-deoxynojirimycin, also called MON-DNJ) is an iminosugar small-molecule oral drug candidate with in vitro antiviral activity against diverse viruses including dengue, influenza, and filoviruses and demonstrated in vivo efficacy against both dengue and influ...
Published in: | PLOS Neglected Tropical Diseases |
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Online Access: | https://doi.org/10.1371/journal.pntd.0010636 https://doaj.org/article/1b9a38644e1447e182ac97752d59a1a1 |
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ftdoajarticles:oai:doaj.org/article:1b9a38644e1447e182ac97752d59a1a1 2023-05-15T15:18:04+02:00 Randomized single oral dose phase 1 study of safety, tolerability, and pharmacokinetics of Iminosugar UV-4 Hydrochloride (UV-4B) in healthy subjects. Michael Callahan Anthony M Treston Grace Lin Marla Smith Brian Kaufman Mansoora Khaliq Lisa Evans DeWald Kevin Spurgers Kelly L Warfield Preeya Lowe Matthew Duchars Aruna Sampath Urban Ramstedt 2022-08-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0010636 https://doaj.org/article/1b9a38644e1447e182ac97752d59a1a1 EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0010636 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0010636 https://doaj.org/article/1b9a38644e1447e182ac97752d59a1a1 PLoS Neglected Tropical Diseases, Vol 16, Iss 8, p e0010636 (2022) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2022 ftdoajarticles https://doi.org/10.1371/journal.pntd.0010636 2022-12-30T22:14:49Z Background UV-4 (N-(9'-methoxynonyl)-1-deoxynojirimycin, also called MON-DNJ) is an iminosugar small-molecule oral drug candidate with in vitro antiviral activity against diverse viruses including dengue, influenza, and filoviruses and demonstrated in vivo efficacy against both dengue and influenza viruses. The antiviral mechanism of action of UV-4 is through inhibition of the host endoplasmic reticulum-resident α-glucosidase 1 and α-glucosidase 2 enzymes. This inhibition prevents proper glycan processing and folding of virus glycoproteins, thereby impacting virus assembly, secretion, and the fitness of nascent virions. Methodology/principal findings Here we report a first-in-human, single ascending dose Phase 1a study to evaluate the safety, tolerability, and pharmacokinetics of UV-4 hydrochloride (UV-4B) in healthy subjects (ClinicalTrials.gov Identifier NCT02061358). Sixty-four subjects received single oral doses of UV-4 as the hydrochloride salt equivalent to 3, 10, 30, 90, 180, 360, 720, or 1000 mg of UV-4 (6 subjects per cohort), or placebo (2 subjects per cohort). Single doses of UV-4 hydrochloride were well tolerated with no serious adverse events or dose-dependent increases in adverse events observed. Clinical laboratory results, vital signs, and physical examination data did not reveal any safety signals. Dose-limiting toxicity was not observed; the maximum tolerated dose of UV-4 hydrochloride in humans has not yet been determined (>1000 mg). UV-4 was rapidly absorbed and distributed after dosing with the oral solution formulation used in this study. Median time to reach maximum plasma concentration ranged from 0.5-1 hour and appeared to be independent of dose. Exposure increased approximately in proportion with dose over the 333-fold dose range. UV-4 was quantifiable in pooled urine over the entire collection interval for all doses. Conclusions/significance UV-4 is a host-targeted broad-spectrum antiviral drug candidate. At doses in humans up to 1000 mg there were no serious adverse events reported ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 16 8 e0010636 |
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Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Michael Callahan Anthony M Treston Grace Lin Marla Smith Brian Kaufman Mansoora Khaliq Lisa Evans DeWald Kevin Spurgers Kelly L Warfield Preeya Lowe Matthew Duchars Aruna Sampath Urban Ramstedt Randomized single oral dose phase 1 study of safety, tolerability, and pharmacokinetics of Iminosugar UV-4 Hydrochloride (UV-4B) in healthy subjects. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Background UV-4 (N-(9'-methoxynonyl)-1-deoxynojirimycin, also called MON-DNJ) is an iminosugar small-molecule oral drug candidate with in vitro antiviral activity against diverse viruses including dengue, influenza, and filoviruses and demonstrated in vivo efficacy against both dengue and influenza viruses. The antiviral mechanism of action of UV-4 is through inhibition of the host endoplasmic reticulum-resident α-glucosidase 1 and α-glucosidase 2 enzymes. This inhibition prevents proper glycan processing and folding of virus glycoproteins, thereby impacting virus assembly, secretion, and the fitness of nascent virions. Methodology/principal findings Here we report a first-in-human, single ascending dose Phase 1a study to evaluate the safety, tolerability, and pharmacokinetics of UV-4 hydrochloride (UV-4B) in healthy subjects (ClinicalTrials.gov Identifier NCT02061358). Sixty-four subjects received single oral doses of UV-4 as the hydrochloride salt equivalent to 3, 10, 30, 90, 180, 360, 720, or 1000 mg of UV-4 (6 subjects per cohort), or placebo (2 subjects per cohort). Single doses of UV-4 hydrochloride were well tolerated with no serious adverse events or dose-dependent increases in adverse events observed. Clinical laboratory results, vital signs, and physical examination data did not reveal any safety signals. Dose-limiting toxicity was not observed; the maximum tolerated dose of UV-4 hydrochloride in humans has not yet been determined (>1000 mg). UV-4 was rapidly absorbed and distributed after dosing with the oral solution formulation used in this study. Median time to reach maximum plasma concentration ranged from 0.5-1 hour and appeared to be independent of dose. Exposure increased approximately in proportion with dose over the 333-fold dose range. UV-4 was quantifiable in pooled urine over the entire collection interval for all doses. Conclusions/significance UV-4 is a host-targeted broad-spectrum antiviral drug candidate. At doses in humans up to 1000 mg there were no serious adverse events reported ... |
format |
Article in Journal/Newspaper |
author |
Michael Callahan Anthony M Treston Grace Lin Marla Smith Brian Kaufman Mansoora Khaliq Lisa Evans DeWald Kevin Spurgers Kelly L Warfield Preeya Lowe Matthew Duchars Aruna Sampath Urban Ramstedt |
author_facet |
Michael Callahan Anthony M Treston Grace Lin Marla Smith Brian Kaufman Mansoora Khaliq Lisa Evans DeWald Kevin Spurgers Kelly L Warfield Preeya Lowe Matthew Duchars Aruna Sampath Urban Ramstedt |
author_sort |
Michael Callahan |
title |
Randomized single oral dose phase 1 study of safety, tolerability, and pharmacokinetics of Iminosugar UV-4 Hydrochloride (UV-4B) in healthy subjects. |
title_short |
Randomized single oral dose phase 1 study of safety, tolerability, and pharmacokinetics of Iminosugar UV-4 Hydrochloride (UV-4B) in healthy subjects. |
title_full |
Randomized single oral dose phase 1 study of safety, tolerability, and pharmacokinetics of Iminosugar UV-4 Hydrochloride (UV-4B) in healthy subjects. |
title_fullStr |
Randomized single oral dose phase 1 study of safety, tolerability, and pharmacokinetics of Iminosugar UV-4 Hydrochloride (UV-4B) in healthy subjects. |
title_full_unstemmed |
Randomized single oral dose phase 1 study of safety, tolerability, and pharmacokinetics of Iminosugar UV-4 Hydrochloride (UV-4B) in healthy subjects. |
title_sort |
randomized single oral dose phase 1 study of safety, tolerability, and pharmacokinetics of iminosugar uv-4 hydrochloride (uv-4b) in healthy subjects. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2022 |
url |
https://doi.org/10.1371/journal.pntd.0010636 https://doaj.org/article/1b9a38644e1447e182ac97752d59a1a1 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 16, Iss 8, p e0010636 (2022) |
op_relation |
https://doi.org/10.1371/journal.pntd.0010636 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0010636 https://doaj.org/article/1b9a38644e1447e182ac97752d59a1a1 |
op_doi |
https://doi.org/10.1371/journal.pntd.0010636 |
container_title |
PLOS Neglected Tropical Diseases |
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16 |
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8 |
container_start_page |
e0010636 |
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