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Aim: To assess the efficacy, safety and pharmacokinetic/pharmacodynamic properties of efpeglenatide, a long-acting glucagon-like peptide-1 receptor agonist, in patients with type 2 diabetes (T2D)., Research Design and Methods: Two randomized, double-blind, placebo-controlled phase 2 trials were conducted. The single-dose study (n = 48) was a first-in-patient, sequential dose-escalation study. Patients received a single subcutaneous injection of efpeglenatide (2-100 μg/kg) or placebo. The repeated-dose study (n = 71) was a multiple-ascending-dose trial. Patients received weekly (1, 2 or 4 mg once weekly; 8-week period) or monthly (8, 12 or 16 mg once monthly; 9-week period) subcutaneous injections of efpeglenatide or placebo (without titration)., Results: Both studies demonstrated dose-proportional increases in efpeglenatide serum concentrations. The median time to attain maximum serum concentration (t max ) for efpeglenatide ranged from 72 to 144 hours in the single-dose study and from 48 to 120 hours in the repeated-dose study (following final dose). Geometric mean t 1/2 ranged from 135 to 180 hours across studies. Peak-to-trough ratios in the repeated-dose study ranged from 1.3 to 1.4 with once-weekly dosing and from 5.9 to 12.9 with once-monthly dosing. Following a single dose of efpeglenatide 14-100 μg/kg, fasting plasma glucose and postprandial plasma glucose levels were decreased at week 1 and remained below baseline levels for ≥3 weeks post-dosing. Repeated doses of efpeglenatide led to significant reductions in glycated haemoglobin vs placebo. In both studies, efpeglenatide was generally well tolerated. Gastrointestinal disorders were the most frequently reported treatment-emergent adverse events in efpeglenatide-treated patients., Conclusions: The delayed t max, long half-life, and low peak-to-trough ratios observed demonstrate potential for improved efficacy and dosing flexibility, with good tolerability of efpeglenatide in patients with T2D., (© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To determine the optimal dose(s) of once-monthly administration of efpeglenatide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), in patients with type 2 diabetes (T2D) inadequately controlled on metformin., Materials and Methods: In this phase 2, randomized, placebo-controlled, double-blind trial (NCT02081118), patients were randomized 1:1:1:1 to subcutaneous efpeglenatide (8, 12 or 16 mg once monthly; n = 158) or placebo (n = 51). The 16-week treatment period included a 4-week titration phase with once-weekly efpeglenatide 4 mg, followed by one dose of efpeglenatide 8 mg once monthly and two doses of the assigned once-monthly dose. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to week 17., Results: All efpeglenatide doses significantly reduced HbA1c versus placebo (P < 0.0001 for all). Overall, the least squares mean difference in HbA1c reductions between efpeglenatide and placebo was -7.7 mmol/mol (-0.71%; baseline to week 17). At week 17, a significantly greater proportion of efpeglenatide patients had an HbA1c level <53 mmol/mol (<7%) versus placebo (48.7% vs. 30.6%; P = 0.0320). Significant body weight loss occurred across all efpeglenatide doses (placebo-corrected reduction -2.0 kg [efpeglenatide overall]; P = 0.0003). The safety profile was consistent with GLP-1RAs, with gastrointestinal (GI) disorders being the most common treatment-emergent adverse events. Fluctuations in effects on glucose levels and rates of GI events occurred between peak and trough efpeglenatide concentrations., Conclusions: Efpeglenatide once monthly (following once-weekly titration) has significant benefits with regard to HbA1c and weight reduction versus placebo in patients with T2D. Further studies are needed to evaluate the long-term efficacy and safety of efpeglenatide once monthly., (© 2020 John Wiley & Sons Ltd.)

Aim: To evaluate the safety of efpeglenatide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), and its effects on body weight management in adults without diabetes., Materials and Methods: In this phase II, randomized, placebo-controlled, double-blind trial, participants with a body mass index (BMI) ≥30 kg/m 2 or ≥27 kg/m 2 with comorbidity were randomized 1:1:1:1:1 to efpeglenatide (4 mg once weekly, 6 mg once weekly, 6 mg once every 2 wk, or 8 mg once every 2 wk; n = 237) or placebo (n = 60) in combination with a hypocaloric diet. The primary endpoint was body weight change from baseline after 20 wk of treatment, assessed using a mixed-effect model with repeated measures with an unstructured covariance matrix over all post-screening visits; treatment comparisons were based on least squares mean estimates., Results: Over 20 wk, all doses of efpeglenatide significantly reduced body weight from baseline versus placebo (P < 0.0001), with placebo-adjusted reductions ranging between -6.3 kg (6 mg once every 2 wk) and -7.2 kg (6 mg once weekly). Greater proportions of efpeglenatide-treated participants had body weight loss of ≥5% or ≥10% versus placebo (P < 0.01, all comparisons). Efpeglenatide led to significant improvements in glycaemic variables (fasting plasma glucose and glycated haemoglobin) and lipid profiles (cholesterol, triglycerides) versus placebo. Rates of study discontinuations as a result of adverse events ranged from 5% to 19% with efpeglenatide. Gastrointestinal effects were the most common treatment-emergent adverse events., Conclusions: Efpeglenatide once weekly and once every 2 wk led to significant body weight reduction and improved glycaemic and lipid variables versus placebo. It was also well tolerated for weight management in adults without diabetes., (© 2019 John Wiley & Sons Ltd.)

This post-hoc analysis of the DURATION-3 study aimed to identify factors associated with sustained glycaemic response with exenatide once weekly (QW) or insulin glargine (IG) among patients with type 2 diabetes. Response was defined as achieving treatment target of HbA1c <7.0% (<53 mmol/mol) at Week 26; sustained responders maintained the treatment target for ≥80% of remaining visits, including one during the final 6 months. Of 467 patients, 287 (61.5%) completed 156 weeks of treatment. At Week 26, 175 patients (61.0%) (exenatide QW, n = 95; IG, n = 80) achieved an HbA1c response. At Week 156, 84 of 175 responders (48.0%) had sustained response, with more sustained responders with exenatide QW (22.7% vs 13.9% with IG; P < 0.03). Logistic regression identified three predictors of sustained response: (a) exenatide QW vs IG treatment (odds ratio, 2.584 [95% confidence interval, 1.288-5.187]; P = 0.0075), (b) lower HbA1c at Week 26 (0.139 [0.053-0.366]; P < 0.0001), and (c) lower fasting serum glucose at Week 26 (0.693 [0.541-0.888]; P = 0.0037). A regression model was used to estimate the likelihood of sustained response with either treatment. This analysis provides a helpful tool for predicting sustained response with exenatide QW or IG., (© 2018 John Wiley & Sons Ltd.)

Aims: Antibody formation to therapeutic peptides is common. This analysis characterizes the time-course and cross-reactivity of anti-exenatide antibodies and potential effects on efficacy and safety., Methods: Data from intent-to-treat patients in 12 controlled (n = 2225,12-52 weeks) and 5 uncontrolled (n = 1538, up to 3 years) exenatide twice-daily (BID) trials and 4 controlled (n = 653,24-30 weeks) exenatide once weekly (QW) trials with 1 uncontrolled period (n = 128,52 weeks) were analysed., Results: Mean titres peaked early (6-22 weeks) and subsequently declined. At 30 weeks, 36.7% of exenatide BID patients were antibody-positive; 31.7% exhibited low titres (≤125) and 5.0% had higher titres (≥625). Antibody incidence declined to 16.9% (1.4% higher titre) at 3 years. Similarly, 56.8% of exenatide QW patients were antibody-positive (45.0% low/11.8% higher titre) at 24-30 weeks, declining to 45.4% positive (9.2% higher titre) at 52 weeks. Treatment-emergent anti-exenatide antibodies from a subset of patients tested did not cross-react with human GLP-1 or glucagon. Other than injection-site reactions, adverse event rates in antibody-positive and antibody-negative patients were similar. Efficacy was robust in both antibody-negative and antibody-positive patients (mean HbA1c change: -1.0 and -0.9%, respectively, exenatide BID; -1.6% and -1.3% exenatide QW). No correlation between change in HbA1c and titre was observed for exenatide BID, although mean reductions were attenuated in the small subset of patients (5%) with higher titres. A significant correlation was observed for exenatide QW with no difference between antibody-negative and low-titre patients, but an attenuated mean reduction in the subset of patients (12%) with higher titres., Conclusions: Low-titre anti-exenatide antibodies were common with exenatide treatment (32% exenatide BID, 45% exenatide QW patients), but had no apparent effect on efficacy. Higher-titre antibodies were less common (5% exenatide BID, 12% exenatide QW) and within that titre group, increasing antibody titre was associated with reduced average efficacy that was statistically significant for exenatide QW. Other than injection-site reactions, anti-exenatide antibodies did not impact the safety of exenatide., (© 2012 Blackwell Publishing Ltd.)

Aim: Exenatide, an incretin mimetic for the adjunct treatment of type 2 diabetes (DM2), reduced A1C and weight in 30-week placebo-controlled trials. This analysis examined the effects of exenatide on glycaemic control and weight over an 82-week period in patients with DM2 unable to achieve adequate glycaemic control with sulphonylurea (SU) and/or metformin (MET)., Methods: This interim analysis is of 314 patients who received exenatide in the 30-week placebo-controlled trials and subsequently in 52 weeks of open-label uncontrolled extension studies for 82 weeks of exenatide in total. Patients continued their SU and/or MET regimens throughout., Results: Patients completed 82 weeks of exenatide treatment [n = 314, 63% M, age 56 +/- 10 years, weight 99 +/- 21 kg, body mass index 34 +/- 6 kg/m2, A1C 8.3 +/- 1.0% (mean +/- SD)]. Reduction in A1C from baseline to week 30 [-0.9 +/- 0.1% (mean +/- SE)] was sustained to week 82 (-1.1 +/- 0.1%), with 48% of patients achieving A1C < or = 7% at week 82. At week 30, exenatide reduced body weight (a secondary endpoint) from baseline (-2.1 +/- 0.2 kg), with progressive reduction at week 82 (-4.4 +/- 0.3 kg). Similar results were observed for the intent-to-treat population (n = 551), with reductions in A1C and weight at week 82 of -0.8 +/- 0.1% and -3.5 +/- 0.2 kg respectively. The 82-week completer cohort showed statistically significant improvement in some cardiovascular risk factors. The most frequent adverse events were generally mild-to-moderate nausea and hypoglycaemia., Conclusion: In summary, 82 weeks of adjunctive exenatide treatment in patients with DM2 treated with SU and/or MET resulted in sustained reduction in A1C and progressive reduction in weight, as well as improvement in some cardiovascular risk factors.