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- Title
Randomized single oral dose phase 1 study of safety, tolerability, and pharmacokinetics of Iminosugar UV-4 Hydrochloride (UV-4B) in healthy subjects.
- Authors
Callahan, Michael; Treston, Anthony M.; Lin, Grace; Smith, Marla; Kaufman, Brian; Khaliq, Mansoora; Evans DeWald, Lisa; Spurgers, Kevin; Warfield, Kelly L.; Lowe, Preeya; Duchars, Matthew; Sampath, Aruna; Ramstedt, Urban
- Abstract
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 and no subjects were withdrawn from the study due to treatment-emergent adverse events. These data suggest that therapeutically relevant drug levels of UV-4 can be safely administered to humans and support further clinical development of UV-4 hydrochloride or other candidate antivirals in the iminosugar class. Trial registration: ClinicalTrials.gov NCT02061358https://clinicaltrials.gov/ct2/show/NCT02061358. Author summary: Dengue Fever, a disease caused by infection with dengue virus, is a significant global health problem. Some estimates indicate that ~390 million dengue virus infections occur each year, resulting in ~ 500,000 cases of severe dengue disease which can be fatal. One Dengue virus vaccine (Sanofi Pasteur's Dengvaxia) has been approved in some countries for people aged 9 to 45 years but has limited effectiveness and the potential for increased risk of severe dengue in seronegative individuals. There are no other drugs or vaccines widely available to prevent or treat dengue virus disease given the European Medicines Agency announced delay in approval decision on Takeda's TAK-003 candidate. Therefore, development of a drug to treat dengue is a global public health priority. This would be an important tool to go along with vaccination, potentially saving lives and relieving human suffering caused by dengue virus infections around the world. UV-4 is an antiviral drug candidate for dengue virus and additional acute viral diseases. An important attribute of UV-4 is that it does not target the virus directly. This has potential advantages such as preventing the virus from developing resistance to the drug. In previous studies, UV-4 or the hydrochloride salt UV-4B were well tolerated and ameliorated dengue and influenza virus disease in animals. Here, we report the first evaluation of UV-4 hydrochloride administration to healthy human volunteers. UV-4 as the hydrochloride was safe at all doses tested up to 1000 mg. These results support the further development of UV-4 for antiviral activity against dengue or other acute viral diseases.
- Subjects
EUROPEAN Medicines Agency; VIRUS diseases; VETERINARY virology; DENGUE viruses; DENGUE; INFLUENZA viruses; NEUTRALIZATION tests; INTERFERON beta-1a; ORAL rehydration therapy; INSULIN aspart
- Publication
PLoS Neglected Tropical Diseases, 2022, Vol 16, Issue 8, p1
- ISSN
1935-2727
- Publication type
Article
- DOI
10.1371/journal.pntd.0010636