A non-randomized, open-label, single-arm, Phase 2 study of emibetuzumab in Asian patients with MET diagnostic positive, advanced gastric cancer.

PURPOSE: Mesenchymal-epithelial transition factor (MET) is expressed in gastric cancer and associated with poor clinical outcomes. We assessed activity, safety, and pharmacokinetics of emibetuzumab, a bivalent monoclonal anti-MET antibody that blocks ligand-dependent and ligand-independent MET signaling. METHODS: This non-randomized, single-arm, Phase 2 study enrolled Asian patients with MET diagnostic positive advanced gastric adenocarcinoma. Emibetuzumab (2000 mg, intravenous) was given on days 1 and 15 (28-day cycle). The primary endpoint was 8-week progression-free survival rate. Secondary objectives included safety, pharmacokinetics, overall survival, and change in tumor size. RESULTS: Tumors from 65 patients were immunohistochemically screened to enroll 15 MET diagnostic positive patients (23% positivity; 8 Japanese, 7 Korean; 10 male). Eight-week progression-free survival rate was 0.47 (70% CI, 0.33-0.59). Disease control rate was 40% (target lesion decreases, three patients; no complete/partial responses according to RECIST). Median overall survival was 17.1 weeks (95% CI, 6.3-not achievable). No serious emibetuzumab-related adverse events or new safety signals emerged. Grade ≥ 3 possibly drug-related adverse events were hyperkalemia, hyponatremia, and hyperuricemia (one each). Emibetuzumab's pharmacokinetics profile was similar to that observed previously. MET expression and clinical outcomes were not obviously associated. CONCLUSION: Emibetuzumab was well tolerated with limited single-agent activity in advanced gastric adenocarcinoma.

Improved glycemic control and reduced bodyweight with exenatide: A double-blind, randomized, phase 3 study in Japanese patients with suboptimally controlled type 2 diabetes over 24 weeks.

UNLABELLED: Aims/Introduction: To evaluate the efficacy and safety of the glucagon-like peptide-1 receptor agonist, exenatide, in Japanese patients with type 2 diabetes mellitus suboptimally controlled despite therapeutic doses of a sulfonylurea alone or combined with a biguanide or thiazolidinedione. MATERIALS AND METHODS: Patients were randomized to a placebo or exenatide, either 5 or 10 µg, given subcutaneously b.i.d. in addition to oral therapy. Patients randomized to 10 µg exenatide received 5 µg b.i.d. for the first 4 weeks, followed by 10 µg b.i.d. for the last 20 weeks. RESULTS: A total of 179 patients received the study drug and composed the full analysis set (n = 35, placebo; n = 72, exenatide 5 µg; n = 72, exenatide 10 µg; 68% male; 58 ± 10 years; body mass index 25.5 ± 4.1 kg/m(2); HbA1c 8.2 ± 0.9%; means ± standard deviations). Baseline to end-point (least-squares means ± standard errors) HbA1c changes (%) were -0.28 ± 0.15 (placebo), -1.34 ± 0.11 (exenatide 5 µg) and -1.62 ± 0.11 (exenatide 10 µg) (both P < 0.001, exenatide vs placebo). Baseline to end-point bodyweight changes (kg) were -0.47 ± 0.39 (placebo), -0.39 ± 0.28 (exenatide 5 µg) and -1.54 ± 0.27 (exenatide 10 µg; P = 0.026, exenatide 10 µg vs placebo). Nausea, generally mild to moderate, was reported in 8.6% (placebo), 25.0% (exenatide 5 µg) and 36.1% (exenatide 10 µg) of patients. Mild to moderate hypoglycemia was reported in 22.9% (placebo), 51.4% (exenatide 5 µg) and 58.3% (exenatide 10 µg) of patients. CONCLUSIONS: Over 24 weeks, exenatide vs the placebo improved glycemic control, reduced bodyweight (10 µg) and was well tolerated in Japanese patients with type 2 diabetes mellitus suboptimally controlled, despite oral therapy including a sulfonylurea. This trial was registered with ClinicalTrials.gov (no. NCT00577824). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00084.x, 2011).

Long-term safety and efficacy of exenatide twice daily in Japanese patients with suboptimally controlled type 2 diabetes.

UNLABELLED: Aims/Introduction: We assessed the long-term (52 weeks) safety and efficacy of exenatide b.i.d. in Japanese patients with type 2 diabetes and suboptimal glycemic control. MATERIALS AND METHODS: Participants completing a 24-week randomized controlled trial of exenatide (5 µg, 10 µg or placebo b.i.d.) were invited to continue in a 28-week open-label extension study (5 µg, n = 64; 10 µg, n = 53). Safety measures included treatment-emergent adverse events (TEAE). Efficacy measures included change from baseline in glycosylated hemoglobin A1c (HbA1c) levels, proportion of participants achieving HbA1c target levels, fasting and seven-point, self-monitored blood glucose concentrations (SMBG), 1,5-anhydroglucitol concentrations, and bodyweight. RESULTS: A total of 60 and 49 participants in the exenatide 5 and 10 µg groups completed the study. The 52-week incidence of TEAE considered by investigators as related to the study drug was 80.6% (58/72) and 88.9% (64/72) in the exenatide 5 and 10 µg groups, respectively. Mild hypoglycemia and nausea were the most common TEAE. Most TEAE occurred during the first 24 weeks. Eight participants experienced serious adverse events. Exenatide treatment was associated with sustained decreases in HbA1c values, with 33.3-47.9% of participants achieving <6.9% HbA1c, sustained decreases in fasting plasma glucose concentrations and SMBG, and sustained increases in 1,5-anhydroglucitol concentrations. Exenatide 10 µg was associated with sustained weight loss. CONCLUSIONS: Long-term exenatide treatment had a similar safety profile to that observed previously and was efficacious in improving glycemic control in Japanese patients with suboptimally controlled type 2 diabetes. This trial was registered with ClinicalTrials.gov (no. NCT00577824). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00137.x, 2011).

Safety, tolerability, pharmacokinetics, and pharmacodynamics of exenatide once weekly in Japanese patients with type 2 diabetes.

This randomized, placebo-controlled, double-blind, parallel study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of exenatide once weekly (QW) in 30 Japanese patients with type 2 diabetes (T2D) suboptimally controlled by diet and exercise alone or combined with biguanide, sulfonylurea, thiazolidinedione, or combinations of these agents (58.6% male; 58+/-9 years; body mass index 26.3+/-2.9 kg/m(2); hemoglobin A(1c) [HbA(1c)] 7.4+/-0.8%; fasting plasma glucose [FPG] 156.1+/-29.1 mg/dL; duration of T2D 6+/-5 years; means +/- SD). Patients were randomized in a 1:1:1 ratio to subcutaneous placebo QW, exenatide QW 0.8 mg, or exenatide QW 2.0 mg for 10 weeks. All evaluable patients were analyzed (placebo QW, n=10; exenatide QW 0.8 mg, n=10; exenatide QW 2.0 mg, n=9), unless otherwise stated. Steady-state plasma exenatide concentrations were observed by Week 8 of the study. For the evaluable pharmacokinetic population, geometric mean (90% confidence interval) steady-state plasma concentrations (pg/mL) were 81.2 (68.3-96.4) and 344.5 (256.5-462.7) with exenatide QW 0.8 mg (n=8) and exenatide QW 2.0 mg (n=5), respectively. Baseline-to-Week 10 glycemic improvements with placebo QW, exenatide QW 0.8 mg, and exenatide QW 2.0 mg, respectively, were: HbA(1c) (%): -0.4+/-0.3, -1.0+/-0.7, and -1.5+/-0.7; FPG (mg/dL): -20.5+/-20.4, -25.2+/-10.9, and -50.8+/-27.8; and 2-hour postprandial plasma glucose excursions (mg/dL): -8.8+/-26.9, -50.0+/-41.1, and -59.7+/-26.8 (means +/- SD). No serious adverse events (AEs) were reported and no AEs led to study discontinuation in any group. The most frequent AE observed was mild-to-moderate injection site induration. No serious hypoglycemia was reported. Exenatide QW for 10 weeks was well tolerated and improved short-term glycemic control in Japanese patients with suboptimally controlled T2D.

Exenatide exhibits dose-dependent effects on glycemic control over 12 weeks in Japanese patients with suboptimally controlled type 2 diabetes.

This study assessed the dose-dependent efficacy and safety of exenatide over 12 weeks in Japanese patients with type 2 diabetes suboptimally controlled despite therapeutic doses of sulfonylurea (SU), SU plus biguanide, or SU plus thiazolidinedione. Patients were randomly assigned to placebo (N = 40), 2.5 microg (N = 38), 5 microg (N = 37), or 10 microg (N = 38) exenatide administered subcutaneously twice daily (BID). Patients randomly assigned to 10 microg exenatide received 5 microg BID for the first 4 weeks, with the dose escalated to 10 microg BID for the final 8 weeks. Patients were 60.3 +/- 9.7 years old, with body mass index 25.3 +/- 4.3 kg/m(2) and hemoglobin A1c (HbA1c) 8.0 +/- 0.8%. Baseline-to-endpoint HbA1c changes (%) were +0.02 +/- 0.1 (placebo), -0.9 +/- 0.1 (2.5 microg), -1.2 +/- 0.1 (5 microg), and -1.4 +/- 0.1 (10 microg) (all p < 0.001 vs. placebo). Of patients with baseline HbA1c -7%, 5.1% (placebo), 50.0% (2.5 microg), 71.4% (5 microg), and 79.4% (10 microg) achieved HbA1c <7% at endpoint (p < 0.001, trend test). Baseline-to-endpoint fasting plasma glucose changes (mg/dL) were +6.0 +/- 4.8 (placebo), -18.6 +/- 5.7 (2.5 microg), -25.0 +/- 7.0 (5 microg), and -28.9 +/- 5.9 (10 microg) (all p < or = 0.001 vs. placebo). Treatment-emergent adverse events were mostly mild; dose-dependent increases in incidence were observed for hypoglycemia, nausea, anorexia, decreased appetite, and diarrhea (all p < or = 0.044, trend test). Over 12 weeks, exenatide dose-dependently improved glycemic control in Japanese patients with type 2 diabetes.

Pharmacokinetics, pharmacodynamics, tolerability, and safety of exenatide in Japanese patients with type 2 diabetes mellitus.

In this single-blind, parallel, placebo-controlled study, the pharmacokinetics, pharmacodynamics, tolerability, and safety of subcutaneous exenatide were evaluated in 40 Japanese patients with type 2 diabetes. Patients were allocated to 4 groups and randomized to receive exenatide (n = 8/group) or placebo (n = 2/group), with all receiving placebo on day 1. On day 2, patients received single-dose exenatide (2.5 microg [group A] or 5 microg [groups B, C, and D]) or placebo and then bid on days 3 to 5. On days 6 to 10, groups A and B continued on 2.5 and 5 microg bid; groups C and D received 10 and 15 microg bid, respectively. The last dose was given on the morning of day 10. All adverse events were mild or moderate in severity. Exenatide was generally well tolerated up to 10 microg. Exenatide was well absorbed with a median t(max) of 1.5 hours and mean t((1/2)) of 1.6 hours; exposure increased with dose. Up to 10 microg, exenatide reduced postprandial glucose concentrations in a dose-dependent fashion compared with placebo; decreases were similar for 10 and 15 microg. An E(max) model demonstrated that doses higher than 2.5 microg were necessary for adequate glycemic response. Based on tolerability and pharmacokinetic/pharmacodynamic relationships, 5 and 10 microg exenatide may be considered for further clinical development in Japanese patients with type 2 diabetes.

Improvement of glycemic control and quality-of-life by insulin lispro therapy: Assessing benefits by ITR-QOL questionnaires.

OBJECTIVE: To investigate the impact of insulin lispro on patients' quality of life (QOL) in diabetic patients who need insulin treatment. METHODS: In this open-label, 12-week study 770 diabetic patients whose medications were switched to insulin lispro from human insulin were evaluated. Main outcome measures were compliance with insulin injection timing, HbA(1c), postprandial blood glucose, frequency and time of onset of hypoglycemia, and QOL measurements. RESULTS: After switching to insulin lispro, approximately 95% of patients "Always" or "Usually" complied with the timing of insulin injections as instructed by their physician. HbA(1c) was improved from 8.2 to 7.8% without increasing the number of hypoglycemic episodes. In terms of QOL, statistically significant improvements were observed in the insulin-therapy-related QOL measure questionnaire (ITR-QOL) total score. Statistically significant correlations were found between compliance with insulin injection timing and glycemic control, as well as glycemic control and QOL. CONCLUSION: The improvement in patient convenience obtained by switching to insulin lispro provided better compliance with insulin injection timing, and this in turn led to better glycemic control and improved QOL. Especially, a better QOL was seen to be clearly related with better glycemic control.