Randomized single oral dose phase 1 study of safety, tolerability, and pharmacokinetics of Iminosugar UV-4 Hydrochloride (UV-4B) in healthy subjects

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 At doses in humans up to 1000 mg there were no serious adverse events reported and no subjects were withdrawn from the study due to treatment-emergent adverse events.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 NCT02061358 https://clinicaltrials.gov/ct2/show/NCT02061358.

Dengue: Update on Clinically Relevant Therapeutic Strategies and Vaccines

“…Decrease in viremia, viral burden, and inflammatory cytokines, and improved survival in immunocompromised mouse model of DENV infection [ 53 •] Clinical trials for dengue prophylaxis in healthy individuals (NCT05201794) as well as for dengue therapy in patients with confirmed dengue fever (NCT04906980) are in progress Ivermectin Antiviral agent that inhibits host nuclear import receptors Reduced viral replication in vitro [ 56 , 57 ] Randomized double-blind placebo-controlled trial ( n = 203) showed faster NS1 antigenemia clearance but no improvement in virological or clinical efficacy (NCT02045069) [ 58 •] AT-752 Guanosine nucleotide analog inhibiting NS5 RdRp function, inhibits viral replication Reduced viremia on certain days and improved survival in immunocompromised mice models infected with DENV [ 63 ] Phase 1 (NCT05366439) and phase 2 (NCT05466240) clinical trials are in progress Doxycycline Tetracycline class antibiotic, inhibits viral entry and replication by inhibiting NS2B-NS3 Antiviral activity against all four DENV serotypes in vitro [ 64 ] One randomized clinical trial ( n = 231) showed reduction in inflammatory cytokines and another case control study ( n = 120) showed faster platelet recovery, leukocyte count, and reduced length of hospitalization. Clinical trials to test efficacy of doxycycline as a dengue therapeutic in pediatric (CTRI/2018/01/011548) and adult (CTRI/2021/09/036661) populations are on-going Eltrombopag Thrombopoietin receptor agonist Nil Randomized open-label placebo-controlled trial ( n = 101) showed improved platelet recovery, increased platelet count, and reduced bleeding manifestations in grade II DHF patients (SLCTR/2019/037) [ 39 •] UV-4B Endogenous alpha glucosidase inhibitor Antiviral activity in vitro [ 70 ] and in vivo [ 71 ] Phase 1a clinical trial (NCT02061358) with healthy subjects indicated that a single dose up to 1000 mg of UV-4B was safe and well tolerated [ 72 ] Zanamivir Neuraminidase inhibitor to block desialylation on platelet membrane Reduction in DENV2 NS1-induc...…”

“…In vivo studies using immunosuppressed mice showed decreased viremia and viral burden and improved survival in a lethal ADE model of dengue disease [ 71 ] . A Phase 1a clinical trial (NCT02061358) with healthy subjects, evaluating the safety, tolerability, and pharmacokinetics of the drug, indicated that a single dose of up to 1000 mg UV-4B was safe and well tolerated [ 72 ]. The efficacy of this drug in dengue patients has yet to be determined.…”

“…So far, clinical trials with repurposed drugs with antiviral activity in pre-clinical studies like balapiravir [49], chloroquine [50], lovastatin [51], and celgosivir [52] did not show any efficacy in reducing viremia nor beneficial clinical outcomes. In this section, we describe both direct-acting and host factors-targeting antivirals that show the UV-4B Endogenous alpha glucosidase inhibitor Antiviral activity in vitro [70] and in vivo [71] Phase 1a clinical trial (NCT02061358) with healthy subjects indicated that a single dose up to 1000 mg of UV-4B was safe and well tolerated [72] Zanamivir Neuraminidase inhibitor to block desialylation on platelet membrane Reduction in DENV2 NS1-induced endothelial hyperpermeability and vascular leakage in vitro [73] Clinical trial to test efficacy against vascular leakage (NCT04597437) is currently on-going Clinical trial in progress (NCT04377451) [104] Carica papaya leaf extract Anti-inflammatory agent, augments megakaryocyte development and platelet formation Reduced production of proinflammatory cytokines [118] and increased platelet count in vivo [119] Three randomized controlled trials showed an improvement in platelet counts [106][107][108] Vitamin E Unclear mechanism. Can act as an antioxidant Nil Randomized placebo-controlled trials showed faster platelet recovery (n = 66) [114] and reduced liver enzyme derangement (n = 127) (SLCTR/2015/012) [113] Vitamin D Unclear mechanism.…”

Identification of Active Compounds from Averrhoa bilimbi L. (Belimbing Wuluh) Flower using LC-MS and Antidiabetic Activity Test using in vitro and in silico Approaches

“…Inhibiting the activity of the α-glucosidase is 1 strategy that can be employed in the treatment of diabetes [24,25]. Miglitol consumption is currently the most popular treatment for diabetes mellitus and is considered to be one of the standard therapies for the disease [26]. In this study, computational predictions showed that 2 Averrhoa bilimbi flower compounds which have the highest RT value, specifically tautomycetin (−6.2 kcal/mol) and lithocholic acid (−10.0 kcal/mol), showed better binding affinity values than miglitol (−5.4 kcal /mol).…”

Exploring the Potential of Iminosugars as Antivirals for Crimean-Congo Haemorrhagic Fever Virus, Using the Surrogate Hazara Virus: Liquid-Chromatography-Based Mapping of Viral N-Glycosylation and In Vitro Antiviral Assays

“…Iminosugars are a diverse class of hydroxylated carbohydrate mimics, some of which competitively inhibit ER α-glucosidases [ 5 ]. These molecules can interfere with host N-linked glycosylation, conferring broad-spectrum antiviral activity in vitro and in vivo [ 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. In order to consider the potential applicability of iminosugar treatment for CCHF patients, at least two mechanistic angles should be considered.…”