Safety, Tolerability and Pharmacokinetics of Single Dose Polyethylene Glycolated Exenatide Injection (PB-119) in Healthy Volunteers

Cui, Hong; Zhao, Caiyun; Lv, Yuan; Wei, Min-Ji; Zhu, Yan; Li, Yun; Xia, Yueyuan; Liu, Yan; Tian, Jihong; Zhang, Pu

doi:10.1007/s13318-020-00605-9

Cited by 4 publications

(4 citation statements)

References 17 publications

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“…Even after 6 weeks of administration, PB-119 had a long t½ in vivo with a strong correlation between dose and pharmacokinetic variables. After a single subcutaneous dose of 25-400 μg, the maximum serum concentrations achieved ranged from 7 ng/ml to 99 ng/ml with a time to maximum concentration ranging from 19 h to 34 h [23]. In the case of exenatide twice daily, the maximum concentration that was achieved after a dose of 2.5-5 μg was 0.056-0.085 ng/ml with a time to reach maximum serum concentration of 2 h [24].…”

Section: Discussionmentioning

confidence: 99%

“…It also reduces the immunogenicity, thereby preventing adverse immunological reactions. The study drug of this study, PEGylated exenatide injection (PB-119), has been previously evaluated for safety, tolerability, and PK effects in a Phase 1 study with 70 healthy volunteers, and the study recommended a once-weekly PB-119 injection of 2 to 200 μg, showing this dose to be safe and well tolerated [23]. In this study, we assessed the efficacy, tolerability and safety of different doses of PB-119 as a monotherapy, compared with placebo, in treatment-naive Chinese patients with type 2 diabetes.…”

Section: Introductionmentioning

confidence: 99%

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Efficacy and safety of PEGylated exenatide injection (PB-119) in treatment-naive type 2 diabetes mellitus patients: a Phase II randomised, double-blind, parallel, placebo-controlled study

et al. 2021

Diabetologia

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Aims/hypothesis Glucagon-like peptide 1 receptor agonists (GLP-1 RA) such as exenatide are used as monotherapy and add-on therapy for maintaining glycaemic control in patients with type 2 diabetes mellitus. The current study investigated the safety and efficacy of once-weekly PB-119, a PEGylated exenatide injection, in treatment-naive patients with type 2 diabetes. Methods In this Phase II, randomised, placebo-controlled, double-blind study, we randomly assigned treatment-naive Chinese patients with type 2 diabetes in a 1:1:1:1 ratio to receive subcutaneous placebo or one of three subcutaneous doses of PB-119 (75, 150, and 200 μg) for 12 weeks. The primary endpoint was the change in HbA1c from baseline to week 12, and other endpoints were fasting plasma glucose, 2 h postprandial glucose (PPG), and proportion of patients with HbA1c < 53 mmol/mol (<7.0%) and ≤48 mmol/mol (≤6.5%) at 2, 4, 8 and 12 weeks of treatment. Safety was assessed in all patients who received at least one dose of study drug. Results We randomly assigned 251 patients to one of the four treatment groups (n = 62 in placebo and 63 each in PB-119 75 μg, 150 μg and 200 μg groups). At the end of 12 weeks, mean differences in HbA1c in the treatment groups were −7.76 mmol/mol (95% CI −9.23, −4.63, p < 0.001) (−0.72%, 95% CI −1.01, −0.43), −12.89 mmol/mol (95% CI −16.05, −9.72, p < 0.001) (−1.18%, 95% CI −1.47, −0.89) and −11.14 mmol/mol (95% CI −14.19, −7.97, p <0 .001) (−1.02%, 95% CI −1.30, −0.73) in the 75 μg, 150 μg and 200 μg PB-119 groups, respectively, compared with that in the placebo group after adjusting for baseline HbA1c. Similar results were also observed for other efficacy endpoints across different time points. There was no incidence of treatment-emergent serious adverse event, severe hypoglycaemia or death. Conclusions/interpretation All tested PB-119 doses had superior efficacy compared with placebo and were safe and well tolerated over 12 weeks in treatment-naive Chinese patients with type 2 diabetes. Trial registration ClinicalTrials.gov NCT03520972 Funding The study was funded by National Major Scientific and Technological Special Project for Significant New Drugs Development and PegBio. Graphical abstract

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of PEGylated exenatide injection (PB-119) in treatment-naive type 2 diabetes mellitus patients: a Phase II randomised, double-blind, parallel, placebo-controlled study

et al. 2021

Diabetologia

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“…Following these therapeutic needs, further modifications of the exenatide sequence led to slow-release compounds: an example is PB-119 , a polyethylene glycosylated exenatide developed by PegBio and obtained by modification of a single amino acid in exenatide, replacing Ser 39 with Cys ( Min Xu et al, 2019 ). Even if the mechanism of action is identical to that of Exenatide, the PEGylation on the analogue PB-119 reduces the excretion rate in the kidneys, and its increased molecular weight causes steric hindrance toward DPP-4, prolonging the half-life and allowing one weekly subcutaneous injection dose regimen ( Cui et al, 2020 ). The same concept of improved pharmacokinetic and resistance to DPP-4 was declined also by Jiangsu Hansoh Pharmaceutical through the development of the GLP-1R agonist Noiiglutide , a 40-mer exenatide analogue, currently in Phase 2 trials as subcutaneous injectable agent.…”

Section: Diabetes Obesity Short Bowel Syndrome and Hyperinsulinemia The Proglucagon Legacymentioning

confidence: 99%

Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives

Cabri

Cantelmi

Corbisiero

et al. 2021

Front. Mol. Biosci.

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Targeting protein-protein interactions (PPIs) has been recently recognized as an emerging therapeutic approach for several diseases. Up today, more than half a million PPI dysregulations have been found to be involved in pathological events. The dynamic nature of these processes and the involvement of large protein surfaces discouraged anyway the scientific community in considering them promising therapeutic targets. More recently peptide drugs received renewed attention since drug discovery has offered a broad range of structural diverse sequences, moving from traditionally endogenous peptides to sequences possessing improved pharmaceutical profiles. About 70 peptides are currently on the marked but several others are in clinical development. In this review we want to report the update on these novel APIs, focusing our attention on the molecules in clinical development, representing the direct consequence of the drug discovery process of the last 10 years. The comprehensive collection will be classified in function of the structural characteristics (native, analogous, heterologous) and on the basis of the therapeutic targets. The mechanism of interference on PPI will also be reported to offer useful information for novel peptide design.

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“… 9 The pharmacokinetics of visepegenatide showed slow absorption with a mean peak time of 20–40 h and a mean elimination half-life of 60–70 h with better safety and tolerable profile. 10 From the phase 2 clinical study, visepegenatide at a dose of 150 μg without titration, was recommended for the phase 3 study. Even though all three doses exhibited efficacy, optimal efficacy, and safety were observed at 150 μg with a significant reduction in HbA1c, fasting plasma glucose, and 2 h postprandial glucose, and a low incidence of adverse events, especially gastrointestinal events.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of visepegenatide, a long-acting weekly GLP-1 receptor agonist as monotherapy in type 2 diabetes mellitus: a randomised, double-blind, parallel, placebo-controlled phase 3 trial

Yan,

Ma,

Liu

et al. 2024

The Lancet Regional Health - Western Pacific

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Safety, Tolerability and Pharmacokinetics of Single Dose Polyethylene Glycolated Exenatide Injection (PB-119) in Healthy Volunteers

Cited by 4 publications

References 17 publications

Efficacy and safety of PEGylated exenatide injection (PB-119) in treatment-naive type 2 diabetes mellitus patients: a Phase II randomised, double-blind, parallel, placebo-controlled study

Efficacy and safety of PEGylated exenatide injection (PB-119) in treatment-naive type 2 diabetes mellitus patients: a Phase II randomised, double-blind, parallel, placebo-controlled study

Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives

Efficacy and safety of visepegenatide, a long-acting weekly GLP-1 receptor agonist as monotherapy in type 2 diabetes mellitus: a randomised, double-blind, parallel, placebo-controlled phase 3 trial

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