Search

This study compared the pharmacokinetic and glucodynamic profiles of biosimilar SAR341402 insulin aspart to Japan-approved insulin aspart (NovoRapid) in healthy Japanese males. In this single-center, randomized, double-blind, single-dose, two-period, crossover study, subjects received 0.3 U/kg of SAR341402 or NovoRapid before undergoing a 10 h euglycemic clamp procedure. Plasma insulin aspart concentrations and blood glucose levels were measured, and glucose infusion rates (GIRs) were assessed. Primary endpoints were maximum plasma insulin aspart concentration (INS-Cmax), area under the plasma insulin concentration–time curve to the last quantifiable concentration (INS-AUClast), area under the GIR–time curve during the clamp (GIR-AUC0–10 h), and maximum GIR (GIRmax). Forty subjects were randomized with 39 completing both treatment periods. Pharmacokinetic exposure showed a mean ratio between products of 1.00 (90% confidence interval [CI] 0.94–1.05) for INS-Cmax and 1.02 (90% CI 1.00–1.04) for INS-AUClast. Glucodynamic activity showed a mean ratio between products of 1.00 (95% CI 0.93–1.06) for GIR-AUC0–10 h and 1.01 (95% CI 0.95–1.08) for GIRmax. The 90% CIs for pairwise treatment ratios were within the predefined equivalence range of 0.80–1.25. Both treatments were well tolerated. We concluded that similar pharmacokinetic exposure and glucodynamic potency were shown for SAR341402 and NovoRapid in healthy Japanese males.

Background: The aim was to assess the safety and tolerability of the insulin aspart biosimilar/follow-on product SAR341402 (100 U/mL solution; SAR-Asp) and originator insulin aspart (100 U/mL; NN-Asp; NovoLog®) self-administered through an insulin pump. Materials and Methods: This randomized, open-label, 2 × 4-week crossover study enrolled 45 adults with type 1 diabetes (T1D). Participants were randomized 1:1 to the treatment sequence SAR-Asp/NN-Asp or NN-Asp/SAR-Asp. The basal and prandial insulin doses were individually titrated. The primary outcome was the number of participants with at least one infusion set occlusion (infusion set change due to failure-to-correct hyperglycemia [plasma glucose ≥250 mg/dL] by insulin pump bolus) during the 4-week treatment. The main secondary outcome was the number of participants with at least one episode of unexplained hyperglycemia (regardless of correction by an insulin pump bolus without apparent material defect, medical, dietary, insulin dosing reason, or pump problem). Results: The number of participants reporting ≥1 infusion set occlusion were similar between treatments: 14/43 on SAR-Asp (33 events) and 12/43 on NN-Asp (24 events). The estimated difference in infusion set occlusion risk for SAR-Asp versus NN-Asp was 4.1% (95% confidence interval: −9.3% to 17.4%). The number of participants with ≥1 episode of unexplained hyperglycemia was similar between treatments (31/43 on SAR-Asp [154 events]; 32/43 on NN-Asp [175 events]). Hypoglycemia, treatment-emergent adverse events, hypersensitivity, and injection site reactions were similar between treatments. Conclusions: SAR-Asp and NN-Asp were well tolerated and had similar infusion set occlusions over a 4-week period in insulin pump users with T1D.

Background: The objective of this study was to demonstrate the pharmacokinetic and pharmacodynamic similarity among SAR341402 insulin aspart biosimilar/follow-on product, United States-sourced insulin aspart (NovoLog®), and European Union-sourced insulin aspart (NovoRapid®). Materials and Methods: This was a single-center, randomized, double-blind, 3-treatment, 3-period, single-dose, crossover euglycemic study (NCT03202875) in 30 adult male subjects with type 1 diabetes (T1D). Subjects received 0.3 U/kg of each treatment under fasted conditions and underwent a 12-h euglycemic clamp technique to assess pharmacokinetic and pharmacodynamic activity for up to 12 h. Primary endpoints were area under the plasma insulin concentration–time curve from time zero to the last quantifiable concentration (INS-AUClast), and extrapolated to infinity (INS-AUCinf), maximum plasma insulin concentration (INS-Cmax), and the area under the body weight-standardized glucose infusion rate (GIR)–time curve from 0 to 12 hours (GIR-AUC0–12h) among the three treatments. GIRmax was the main secondary endpoint. Results: Of the 30 subjects randomized, 29 completed all 3 treatment periods. Pharmacokinetic and pharmacodynamic profiles were similar in all groups. The extent of exposure (INS-Cmax, INS-AUClast, and INS-AUCinf) and glucodynamic activity (GIR-AUC0–12h, GIRmax) was similar among the three treatments. The corresponding 90% confidence intervals for pairwise treatment ratios were completely contained within the limits of 80%–125%. SAR341402 was well tolerated. Conclusions: The present study demonstrated similar pharmacokinetic exposure profiles and glucodynamic potency among SAR341402, NovoLog, and NovoRapid in subjects with T1D, supporting further clinical evaluation of SAR341402 as a biosimilar/follow-on product.

This phase 1 study compared the pharmacokinetic (PK) and glucose pharmacodynamic (PD) characteristics of biosimilar SAR342434 insulin lispro and Japan-reference Humalog insulin lispro. This was a randomized, double-blind, 2-period, crossover study. Thirty-six healthy Japanese male subjects underwent a 10-hour euglycemic clamp following a single subcutaneous 0.3-U/kg dose of SAR342434 or Humalog. Insulin lispro concentration and blood glucose were measured, and the glucose infusion rate (GIR) was adjusted to maintain the target blood glucose level. Primary PK end points were maximum plasma insulin lispro concentration and area under the plasma insulin concentration-time curve (AUC) from time 0 to the last quantifiable concentration. Primary PD end points were area under the GIR-time curve from time 0 to 10 hours and maximum GIR. PK exposure (maximum plasma concentration and AUC from time 0 to the last quantifiable concentration) and PD activity (GIR-AUC from time 0 to 10 hours and maximum GIR) were similar between treatments. Geometric mean ratios were close to 1, and the corresponding 90% and 95%CIs (PK and PD activity, respectively) were within the 0.80 to 1.25 equivalence range. SAR342434 and Humalog were well tolerated. In healthy Japanese males, SAR342434 and Humalog showed similar PK exposure profiles and PD potency, in support of SAR342434 use as a biosimilar product.

Unimolecular triple incretins, combining the activity of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon (GCG), have demonstrated reduction in body weight and improved glucose control in rodent models. We developed SAR441255, a synthetic peptide agonist of the GLP-1, GCG, and GIP receptors, structurally based on the exendin-4 sequence. SAR441255 displays high potency with balanced activation of all three target receptors. In animal models, metabolic outcomes were superior to results with a dual GLP-1/GCG receptor agonist. Preclinical in vivo positron emission tomography imaging demonstrated SAR441255 binding to GLP-1 and GCG receptors. In healthy subjects, SAR441255 improved glycemic control during a mixed-meal tolerance test and impacted biomarkers for GCG and GIP receptor activation. Single doses of SAR441255 were well tolerated. The results demonstrate that integrating GIP activity into dual GLP-1 and GCG receptor agonism provides improved effects on weight loss and glycemic control while buffering the diabetogenic risk of chronic GCG receptor agonism.

Aim To compare the pharmacokinetic exposure of SAR341402 Mix 70/30 (SARAsp‐Mix) with US‐ and European (EU)‐approved versions of insulin aspart Mix 70/30 (NovoLog Mix 70/30 [NN‐Mix‐US]/NovoMix 30 [NN‐Mix‐EU]) and SAR341402 insulin aspart solution (SAR‐Asp) in subjects with type 1 diabetes. Materials and Methods This was a randomized, double‐blind, crossover trial in two cohorts. Fifty‐two subjects received a single subcutaneous 0.3 U/kg dose of each treatment and underwent a euglycaemic clamp procedure lasting for a maximum of 24 hours after dosing. In cohort 1, subjects (N = 36) were exposed once each to SARAsp‐Mix, NN‐Mix‐US and NN‐Mix‐EU. In cohort 2, subjects (N = 16) were exposed once each to SARAsp‐Mix and SAR‐Asp. Results Of the 52 subjects randomized, 48 completed all treatment periods. In cohort 1, the extent of exposure (total and maximum concentration) was similar among the three treatments, with the 90% confidence intervals for pairwise treatment ratios meeting the predefined acceptance range (0.80 to 1.25). In cohort 2, statistically significant differences (P

Background: SAR342434 (U100; SAR-Lis; insulin lispro) is a biosimilar/follow-on to insulin lispro (U100; Ly-Lis). Similar pharmacokinetics/pharmacodynamics between the two products has been demonstrated in a hyperinsulinemic euglycemic clamp study. The current study evaluated the safety of SAR-Lis and Ly-Lis when administered by continuous subcutaneous insulin infusion (CSII; insulin pumps). Methods: This was a randomized, open-label, 2 × 4-week, two-arm crossover study in 27 patients with type 1 diabetes mellitus (NCT02603510). The main outcome was the incidence of infusion set occlusions (ISOs), defined as failure to correct hyperglycemia (plasma glucose ≥≥ 300 mg/dl) by 50 mg/dl within 60 minutes by insulin bolus via the pump. Secondary outcomes included intervals between infusion set changes, treatment-emergent adverse events (TEAEs) including infusion site, hypersensitivity reactions and hypoglycemic events, and safety. Results: The number of patients reporting at least one ISO was small: 6/25 patients on SAR-Lis reported 14 ISOs and 4/27 on Ly-Lis reported nine ISOs. The estimated difference in ISO risk for SAR-Lis versus Ly-Lis was 7.9% (95% CI, –1.90 to 17.73). Mean interval between infusion set changes for any reason was similar with SAR-Lis (3.09 days) and Ly-Lis (2.95 days). The event rate (events/patient-month) of any hypoglycemia was similar with SAR-Lis (7.15) and Ly-Lis (7.98), as was the percentage of patients who experienced any TEAE (12.0% and 14.8%). Conclusion: Both SAR-Lis and Ly-Lis were well tolerated by patients using insulin pumps. The results do not suggest a clinically significant difference in the risk of ISO between SAR-Lis and Ly-Lis when used in CSII.

Aims To characterize the variability in exposure and metabolic effect of insulin glargine 300 U/ml (Gla-300) at steady state in people with type 1 diabetes (T1DM). Methods A total of 50 participants with T1DM underwent two 24-h euglycaemic clamps in steady-state conditions after six once-daily administrations of 0.4 U/kg Gla-300 in a double-blind, randomized, two-treatment, two-period, crossover clamp study. Participants were randomized to receive Gla-300 as a standard cartridge formulation in the first treatment period, and as a formulation with enhanced stability through polysorbate-20 addition in the second treatment period, or vice versa. This design allowed the assessment of bioequivalence between formulations and, subsequently, within- and between-day variability. Results The cumulative exposure and effect of Gla-300 developed linearly over 24 h, and were evenly distributed across 6- and 12-h intervals. Diurnal fluctuation in exposure (within-day variability) was low; the peak-to-trough ratio of insulin concentration profiles was