Recommendations for Systematic Statistical Computation of Immunogenicity Cut Points.

Today, the assessment of immunogenicity is integral in nonclinical and clinical testing of new biotherapeutics and biosimilars. A key component in the risk-based evaluation of immunogenicity involves the detection and characterization of anti-drug antibodies (ADA). Over the past couple of decades, much progress has been made in standardizing the generalized approach for ADA testing with a three-tiered testing paradigm involving screening, confirmation, and quasi-quantitative titer assessment representing the typical harmonized scheme. Depending on a biotherapeutic's structural attributes, more characterization and testing may be appropriate. Unlike bioanalytical assays used to support the evaluation of pharmacokinetics or toxicokinetics, an important component in immunogenicity testing is the calculation of cut points for the identification (screening), confirmation (specificity), and titer assessment responses in animals and humans. Several key publications have laid an excellent foundation for statistical design and data analysis to determine immunogenicity cut points. Yet, the process for statistical determination of cut points remains a topic of active discussion by investigators who conduct immunogenicity assessments to support biotherapeutic drug development. In recent years, we have refined our statistical approach to address the challenges that have arisen due to the evolution in biotherapeutics and the analytical technologies used for quasi-quantitative detection. Based on this collective experience, we offer a simplified statistical analysis process and flow-scheme for cut point evaluations that should work in a large majority of projects to provide reliable estimates for the screening, confirmatory, and titering cut points.

Comparison of a novel insulin bolus-patch with pen/syringe injection to deliver mealtime insulin for efficacy, preference, and quality of life in adults with diabetes: a randomized, crossover, multicenter study.

OBJECTIVE: This study compared the efficacy, safety, device satisfaction, and quality of life (QOL) in people with diabetes using an insulin bolus-patch versus current devices (pen/syringe) to deliver mealtime insulin. RESEARCH DESIGN AND METHODS: Thirty-eight subjects with diabetes (26 with type 1 and 12 with type 2) were randomized to bolus-patch or current injection device (55% pen and 45% syringe) to deliver mealtime insulin in a multicenter, 6-week crossover study. Efficacy was assessed by equivalence in mean daily seven-point blood glucose (MDBG). Safety assessments included severe hypoglycemia episodes, adverse device effects (ADEs), and adverse events (AEs). Device satisfaction was determined by the validated Insulin Delivery System Rating Questionnaire (IDSRQ) and QOL by the validated Diabetes Specific QOL Scale (DSQOLS). RESULTS: Using bolus-patch, MDBG (mean±SE) was equivalent to that using pen/syringe (8.61±0.28 vs. 9.02±0.26 mmol/L; P=0.098). SD of the seven-point blood glucose measurements was lower using bolus-patch (3.18±0.18 vs. 3.63±0.17 mmol/L; P=0.004), as was the coefficient of variation (CV) (37.2±1.7 vs. 40.3±1.7%; P=0.046). Hemoglobin A1c, 1,5-anhydroglucitol, fructosamine, and insulin use were similar between groups. There were no severe hypoglycemia episodes or serious ADEs. Between-device AEs were comparable. Subjects scored better on six of seven subscales on the DSQOLS and five of six subscales on the IDSRQ while using bolus-patch versus pen/syringe. At study completion, 76% of subjects would choose to switch to bolus-patch (P=0.001). CONCLUSIONS: Delivery of mealtime insulin with bolus-patch compared with pen/syringe resulted in equivalent MDBG, lower SD and CV of seven-point blood glucose measurements, good safety, significant device satisfaction, and improved QOL.

Exenatide added to insulin therapy: a retrospective review of clinical practice over two years in an academic endocrinology outpatient setting.

BACKGROUND: Exenatide is an antidiabctic agent currently indicated as adjunctive therapy with oral agents for the treatment of type 2 diabetes mellitus (T2DM). Limited published data exist on the off-label use of exenatide in conjunction with insulin in the treatment of T2DM. OBJECTIVE: The aim of this retrospective study was to examine the effects of exenatide on glycemic control, weight, and insulin dose in patients with T2DM treated with insulin. METHODS: Patients with T2DM receivirg insulin and adjuvant therapy with exenatide at an endocrinology clinic at a university hospital for up to 27 months were eligible for inclusion. Glycosylated hemoglobin (HbA(1c)), weight, insulin doses (total, prandial, and basal), concurrent oral antidiabetic medications, and adverse events were ascertained by retrospective review of medical records and were considered the clinical parameters of interest. The last observation in 4 specified time intervals (0-6, 6-12, 12-18, and 18-27 months) for each clinical parameter was used in the analysis. RESULTS: Of the 3397 patients with a confirmed diagnosis of T2DM who were seen at the clinic during the study period, 268 patients met inclusion criteria and were enrolled in the study. Of the 268 patients enrolled, 38 discontinued therapy within the first 2 months, 30 were lost to follow-up, and 12 did not have evaluable data. These latter patients without sufficient data (n = 42) were not included in the primary analysis but were included in the adverse events analysis. Overall, data from 188 patients (mean [SD] age, 56 (9) years; 85 [45%] men; body mass index, 40.4 [8.4] kg/m(2); 160 [85%] white) were evaluated (mean duration of treatment, 350 [208] days) and included in all analyses. The mean baseline values for HbA(1c), weight, and total daily insulin dose before exenatide therapy were 8.05% (1.47%), 117.8 (24.7) kg, and 99.9 (90.0) U, respectively. For the 4 time intervals, the mean changes in HbA(1c) were: -0.66% (1.54%) at 0 to 6 months (P < 0.001); -0.55% (1.4%) at 6 to 12 months (P < 0.001); -0.54% (1.83%) at 12 to 18 months (P = 0.019); and -0.54% (1.37%) at 18 to 27 months (P = 0.020). Mean weight significantly declined with increasing treatment duration. Mean changes in weight were: -2.4 (5.1) kg at 0 to 6 months (P < 0.001); -4.3 (7.2) kg at 6 to 12 months (P < 0.001); -6.2 (9.7) kg at 12 to 18 months (P < 0.001); and -5.5 (10.8) kg at 18 to 27 months (P < 0.01). After 18 months, an increase in weight was observed; but the increase remained lower than baseline. The mean insulin total daily dose (TDD) was decreased in all patients at the 0- to 6-month (-18.0 [49.9] U; P < 0.001) and the 6- to 12-month (-14.8 [35.3] U; P < 0.001) intervals. Mean changes in insulin TDD during the 12- to 18-month and 18- to 27-month intervals were not statistically significant. The mean percent change from baseline in the basal insulin dose at 0 to 6 months, 6 to 12 months, 12 to 18 months, and 18 to 27 months was not statistically significant. For the 4 intervals, the mean percent change from baseline in the prandial insulin dose was -33.5% (56.2%) at 0 to 6 months (P < 0.001); -25.9% (59.7%) at 6 to 12 months (P = 0.002); -29.7% (74.8%) at 12 to 18 months (P = 0.02); and -55.7% (56.8%) at 18 to 27 months (P = 0.005). Of the 226 patients who were treated with exenatide + insulin for any length of time (including within the first 2 months), 59 (26.1%) discontinued exenatide because of adverse events. The adverse events were largely considered mild and included nausea (n = 51 [22.6% of patients]), vomiting (22 [9.7%]), hypoglycemia (9 [4.0%]), heartburn (2 [0.9%]), diarrhea (1 [0.4%]), constipation (1 [0.4%]), malaise (1 [0.4%]), and generalized edema (1 [0.4%]). Two serious adverse events occurred during the study period: acute renal failure not attributed to exenatide (1 [0.4%]); and pancreatitis (1 [0.4%]), both of which required hospitalization 1 month after the start of exenatide therapy. CONCLUSION: In this retrospective review of patients with T2DM treated in an outpatient setting, the addition of exenatide to insulin-based therapy was associated with reductions in mean HbA(1c), weight, and prandial insulin requirements for treatment periods of up to 27 months, and in total insulin requirements for treatment periods of up to 12 months.

Relating glucose clamp profiles to reduction of blood glucose after insulin administration.

A model was established allowing prediction of blood glucose response from glucose clamp results performed in healthy volunteers. Data from published studies performed in healthy volunteers were used to establish, test, and validate a model for the evaluation of glucose reductions from glucose clamp results. Studies included those that measured blood glucose and glucodynamic response over time after administration of 0.05 U/kg of regular human insulin (HR) and insulin lispro (LP) with and without the benefit of a glucose clamp procedure. An inhibitory effect E(max) model was used to describe the relationship; the model differed between the HR and LP responses by the intensity of the counterregulatory response as assessed by glucagon measurements. The relationships were used to predict blood glucose responses from a clamp study assessing NPH insulin and HR administrations. Glucose concentrations measured after administration of NPH insulin and HR without a clamp were compared to the model-predicted results to assess the accuracy of the model predictions. The E(max) model successfully correlated the glucose clamp results with the blood glucose depressions in the presence and absence of a counterregulatory response. However, predictions of glucose depression were only accurately modeled in the absence of a counterregulatory glucagon response. The correlations established with a minimal counterregulatory response underscore the value of glucose clamp procedures in defining the time-activity profiles of insulins when the clamp is established at fasting glucose concentrations.