Dataset Information

Single and multiple dose evaluation of a novel MetAP2 inhibitor: Results of a randomized, double-blind, placebo-controlled clinical trial.

ABSTRACT: Methionine aminopeptidase 2 (MetAP2) inhibition has been shown to result in significant weight loss and improved glucose control. This Phase 1 clinical trial assessed the safety and tolerability, pharmacokinetics and preliminary efficacy of a novel MetAP2 inhibitor, ZGN-1061.This clinical trial included a single ascending dose (SAD) phase in healthy subjects (BMI, 23 to <30?kg/m2 ) and a multiple ascending dose (MAD) phase in otherwise healthy subjects (BMI, 27 to 40?kg/m2 ). SAD phase doses, administered subcutaneously (SC), were 0.2, 0.6, 1.2, 2.4, 3.6 and 4.8?mg and the MAD phase evaluated doses of 0.2, 0.6 and 1.8?mg twice weekly SC for 4?weeks.The SAD phase included 39 subjects (ZGN-1061, N?=?28; placebo, N?=?11); 90% were male and BMI was 26.4?kg/m2 . ZGN-1061 was well tolerated across all doses, with the most frequent adverse events being mild headache and procedural-related irritation. There were no severe or serious adverse events. All doses of ZGN-1061 were rapidly absorbed and cleared, resulting in short duration of exposure that is anticipated to minimize potential off-drug target risks. The MAD phase included 29 subjects (ZGN-1061, N?=?22; placebo, N?=?7); 76% were male and BMI was 33.5?kg/m2 . Safety observations were consistent with SAD findings. Efficacy measures in the MAD phase indicated trends for weight change (-1.5?kg total ZGN-1061 vs -0.2?kg placebo) and other biomarker changes.ZGN-1061 was well tolerated with no safety signals in all doses tested. In addition, the desired pharmacokinetic profile and preliminary efficacy observations with ZGN-1061 support evaluation in larger and longer clinical trials.

SUBMITTER: Malloy J

PROVIDER: S-EPMC6055687 | biostudies-other | 2018 Aug

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Single and multiple dose evaluation of a novel MetAP2 inhibitor: Results of a randomized, double-blind, placebo-controlled clinical trial.

Malloy Jaret J Zhuang Dongliang D Kim Terri T Inskeep Phil P Kim Dennis D Taylor Kristin K

Diabetes, obesity & metabolism 20180423 8

<h4>Aims</h4>Methionine aminopeptidase 2 (MetAP2) inhibition has been shown to result in significant weight loss and improved glucose control. This Phase 1 clinical trial assessed the safety and tolerability, pharmacokinetics and preliminary efficacy of a novel MetAP2 inhibitor, ZGN-1061.<h4>Methods</h4>This clinical trial included a single ascending dose (SAD) phase in healthy subjects (BMI, 23 to <30 kg/m<sup>2</sup> ) and a multiple ascending dose (MAD) phase in otherwise healthy subjects (BM ...[more]

PMID: 29577550

Similar Datasets

Project description:Dietary recommendations for selenium differ between countries, mainly because of uncertainties over the definition of optimal selenium status.The objective was to examine the dose-response relations for different forms of selenium.A randomized, double-blind, placebo-controlled dietary intervention was carried out in 119 healthy men and women aged 50-64 y living in the United Kingdom. Daily placebo or selenium-enriched yeast tablets containing 50, 100, or 200 microg Se ( approximately 60% selenomethionine), selenium-enriched onion meals ( approximately 66% gamma-glutamyl-methylselenocysteine, providing the equivalent of 50 microg Se/d), or unenriched onion meals were consumed for 12 wk. Changes in platelet glutathione peroxidase activity and in plasma selenium and selenoprotein P concentrations were measured.The mean baseline plasma selenium concentration for all subjects was 95.7 +/- 11.5 ng/mL, which increased significantly by 10 wk to steady state concentrations of 118.3 +/- 13.1, 152.0 +/- 24.3, and 177.4 +/- 26.3 ng/mL in those who consumed 50, 100, or 200 microg Se-yeast/d, respectively. Platelet glutathione peroxidase activity did not change significantly in response to either dose or form of selenium. Selenoprotein P increased significantly in all selenium intervention groups from an overall baseline mean of 4.99 +/- 0.80 microg/mL to 6.17 +/- 0.85, 6.73 +/- 1.01, 6.59 +/- 0.64, and 5.72 +/- 0.75 microg/mL in those who consumed 50, 100, or 200 microg Se-yeast/d and 50 microg Se-enriched onions/d, respectively.Plasma selenoprotein P is a useful biomarker of status in populations with relatively low selenium intakes because it responds to different dietary forms of selenium. To optimize the plasma selenoprotein P concentration in this study, 50 microg Se/d was required in addition to the habitual intake of approximately 55 microg/d. In the context of established relations between plasma selenium and risk of cancer and mortality, and recognizing the important functions of selenoprotein P, these results provide important evidence for deriving estimated average requirements for selenium in adults. This trial was registered at clinicaltrials.gov as NCT00279812.

Project description:AimTo examine the efficacy and safety of otilonium bromide (OB) in treatment-sensitive functional irritable bowel syndrome (IBS) clinical parameters.MethodsNinety-three patients (44.8 ± 12.6 years, 69% female) with IBS symptoms complying with Rome II criteria participated in this double-blind, placebo-controlled, randomised, dose-ranging phase I/II study. Patients were administered OB 20 mg (n = 24), 40 mg (n = 23) and 80 mg (n = 23) tid or placebo (n = 23) in 4 parallel groups for 4 wk. Primary efficacy variables included abdominal discomfort, intestinal habits, number of daily evacuations and stool consistency. Secondary efficacy measures included return to regular intestinal habits and global discomfort. Safety was also assessed.ResultsBaseline clinical characteristics were similar among the 4 groups. Although individual parameters such as intensity and frequency of abdominal discomfort, bloating or pain were reduced by OB over the 4 wk, no significant differences were observed between groups. Similarly, no difference was observed between OB treatment or placebo for mucus in stool and incomplete or difficulty of evacuation. However, evacuation frequency was significantly reduced after 4 wk by 80 mg OB compared to placebo (-8.36% for placebo vs -41.9% for 80 mg OB, P < 0.01). While 21.7% of patients in the placebo group experienced regular intestinal habits after 4 wk, this improvement was greater for patients treated with 40 mg OB (P < 0.01 vs placebo). Furthermore, a dose-dependent reduction in frequency of diarrhoea (χ(2)-test for trend = 11.5, P < 0.001) and an increase in normal stool frequency was observed. Combining individual variables into a global discomfort index revealed significant improvement among increasing OB doses, favouring 40 mg (P = 0.013) and 80 mg OB (P = 0.001) over placebo. No difference was observed between frequency of adverse events for placebo vs OB.ConclusionThis dose-ranging study demonstrates that OB at 40 and 80 mg can improve individual and global clinical symptoms of IBS compared to placebo over a 4-wk period.

Dataset Information

Single and multiple dose evaluation of a novel MetAP2 inhibitor: Results of a randomized, double-blind, placebo-controlled clinical trial.

Publications

Single and multiple dose evaluation of a novel MetAP2 inhibitor: Results of a randomized, double-blind, placebo-controlled clinical trial.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets